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Biocentrum Helsinki in 2012
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Page 1: Biocentrum Helsinki in 2012 Helsinki in 2012.pdfPekka Lappalainen ... Markku Varjosalo ..... 50 Systems Biology Unit (SBU) ... breaks for . Biocentrum Helsinki in 2012 | ...

Biocentrum Helsinki in 2012

Page 2: Biocentrum Helsinki in 2012 Helsinki in 2012.pdfPekka Lappalainen ... Markku Varjosalo ..... 50 Systems Biology Unit (SBU) ... breaks for . Biocentrum Helsinki in 2012 | ...

Biocentrum Helsinki in 2012

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2 | Biocentrum Helsinki in 2012

ContentsDirector’s Foreword .................................. 3

Aalto University in Biocentrum Helsinki .............................. 4

”Connecting Scientists” – Interdisciplinary Collaboration between Aalto University and University of Helsinki ........................................ 5

Biocentrum Helsinki Research Groups 2011–2013 .................... 7

Biotechnology and Bioinformatics

Computational Systems Biology Sampsa Hautaniemi ................................8

Computational Genomics Liisa Holm ....................................................9

Individualized Systems Medicine Olli Kallioniemi ....................................... 10

Cell and Molecular Biology

Autophagosome Biogenesis Eeva-Liisa Eskelinen ...............................11

RNA Splicing Mikko Frilander ........................................ 12

Intracellular Cholesterol Transport Elina Ikonen ..............................................13

Androgen Receptor Pathway Olli A. Jänne ............................................. 14

Actin and Plasma Membrane Dynamics Pekka Lappalainen ..................................15

Cell Growth Regulation, Signaling and Metabolism Tomi Mäkelä .............................................. 16

Human Pluripotent Stem Cells Timo Otonkoski .........................................17

Growth Control and Cancer Jussi Taipale .............................................. 18

Biocentrum Helsinki Core Facilities .............................................. 37

Biomedicum Flow Cytometry Core Facility (FACS Core Facility) Nina Peitsaro ............................................38

Biomedicum Functional Genomics Unit (FuGU) Outi Monni & Juha Klefström...............39

Biomedicum Helsinki High Throughput Center (HTC) Anna Lehto ................................................40

Biomediucum Imaging Unit (BIU) Elina Ikonen .............................................. 41

Biomedicum Stem Cell Center (BSCC) Timo Otonkoski ........................................42

DNA Sequencing and Genomics Laboratory (BIDGEN) Petri Auvinen ............................................43

Electron Cryo-Microscopy Facility (CryoEM Facility) Sarah Butcher ..........................................44

Finnish Biological NMR Center Perttu Permi ..............................................45

Genome Biology Unit (GBU) Tea Vallenius .............................................46

GM Mouse unit of the Laboratory of Animal Center Petra Sipilä ................................................47

Light Microscopy Unit (LMU) Kimmo Tanhuanpää................................48

Meilahti Clinical Proteomics Core Facility Marc Baumann .........................................49

Proteomics Unit Markku Varjosalo ....................................50

Systems Biology Unit (SBU) Sampsa Hautaniemi ................................51

Viikki Metabolomics Unit (ViMU) Tapio Palva & Risto Kostiainen ........... 52

Graduate Programs ................................... 53

Start-up Grants ........................................... 55

Administration and FundingDirector, Board, Budget ............................56

Developmental Biology

Evolutionary Developmental Biology Jukka Jernvall ............................................ 19

Development and Renewal of Ectodermal Organs Irma Thesleff .............................................20

Macromolecular Structure and Biophysics

Virus Evolution Dennis Bamford ....................................... 21

Macromolecular Structure and Function Sarah Butcher ..........................................22

Helsinki Bioenergetics Mårten Wikström .....................................23

Molecular Cancer Biology

Angiogenesis in Cancer and Cardiovascular Disease Kari Alitalo .................................................24

Cancer Gene Therapy Akseli Hemminki ..................................... 25

Molecular Genetics

Tumor Genomics Lauri A. Aaltonen .....................................26

Metapopulation Research Ilkka Hanski .............................................. 27

Gene-Culture Co-Evolution in Music Irma Järvelä ...............................................28

Complex Diseases Juha Kere ....................................................29

Canine Genomics Hannes Lohi ..............................................30

Hereditary Cancer; Genetic and Epigenetic Mechanisms of Cancer Predisposition Päivi Peltomäki ........................................ 31

Molecular Neuroscience

Neurobiology Kai Kaila .....................................................32

Molecular Neuroscience Mart Saarma ............................................. 33

FinMIT – Molecular pathology of mitochondrial disease Anu Wartiovaara ......................................34

Plant Biotechnology and Molecular Biology

Genetic Basis of Wood Development Yrjö Helariutta .......................................... 35

Plant Stress Jaakko Kangasjärvi .................................36

Biocentrum Helsinki in 2012

Editors: Lauri Aaltonen, Heli Lehtonen, Riitta Smahl-El HamrauiLayout: Olli LuotonenCover photo: Tecan robot by the courtesy of PhD, Laboratory director Petri Auvinen.

Printing: Unigrafia Oy 2012

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B iocentrum Helsinki has experienced exceptional success during its lifetime from 1994, and the recent years have

been no exception. This is no wonder. The organization has been ahead of its time by forming a dynamic umbrella struc-ture which develops and responds to the many changes in our working environment with much greater ease than many tradi-tional structures. The flexibility and continuous ability to evolve guided by international peer review form a firm operating basis also in the post university reform era.

One key action point for BCH is to gather together the very best research groups in life sciences. The member groups are selected after rigorous international peer review, and only the very best groups are successful in this continuous evaluation process. The position of the BCH groups nationally can be exemplified in multiple ways. A very simple measure is the num-ber of Science and Nature papers with a Finland-based senior (last) author. Dur-ing the previous and current BCH terms (2007–2010, and 2011–2013, respec-tively) 25 such papers were published. Of these, ten were from BCH. Thus the current 29 BCH PIs have accounted for more than one third of this most prestig-ious publication category, all disciplines and the whole nation included. Similar message arises through other relevant measures, such as Academy of Finland’s Centers of Excellence and Academy Pro-fessorships. As an international measure of stature six out of 18 ERC advanced grants for Finland based researchers – again all disciplines included – have been won by BCH members.

The continuous success is important for many reasons, but for one it justifies the support from the host organizations. Indeed through BCH, funding is directed

based on scientific excellence. One key BCH activity is to sup-port the relevant core services tightly linked to the most pro-ductive scientific sector. BCH cores form a key infrastructure for the scientific performance of the Helsinki region internation-ally. Supporting repatriation of promising young independent investigators is another BCH investment for the future. The University of Helsinki has set an ambitious strategic goal to be among 50 best universities in the world. While many measures can be used for this ranking it is clear that the past, present and future BCH is an integral part of successful implementation of the strategy.

The particular value of the Biocentrum Helsinki has been its ability to connect the two main biocampuses, Viikki and

Meilahti, under one umbrella. This has greatly facilitated both scientific collabo-ration, as well as efficient building of vital infrastructure. Along these lines, an im-portant recent development has been the expansion of BCH to the Aalto University. BCH now forms a bridge between the two Universities in life sciences, and vigorous efforts to enhance collaboration in par-ticular on junior level, but more recently also on the principal investigator level, have been launched. The efforts conduct-ed 2011 and this year in the young investi-gator level have been a joy to watch.

Thus the future of BCH, despite the many challenges ahead, looks bright. The tremendous technological advances are turning life sciences into a format where truly interdisciplinary partners are a pre-requisite of success, and dynamic struc-tures are essential to keep up with the pace required for truly competitive perfor-mance.

Director’s Foreword

Lauri A. AaltonenAcademy Professor

Director of Biocentrum Helsinki

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4 | Biocentrum Helsinki in 2012

A alto University’s recently launched strategy contains three observations particularly interesting for BCH. First, based

on the Aalto Research Assessment Exercise, the current re-search strength of Aalto is in five areas which include Compu-tational and modelling, Materials and ICT. In these fields, Aalto hosts several Centres of Excellence of the Academy of Finland. The second interesting observation is that Aalto intends to build strong partnerships in research and education; in Finland there is long-term cooperation with University of Helsinki. In ICT, Helsinki Institute for Information Technology HIIT is already a joint depart-ment between the two universities, and in neuroscience, for instance, new initia-tives have recently been launched. The third interesting observation is the vision statement which starts by “The best con-

Aalto University in Biocentrum Helsinkinect and succeed at Aalto University”. So who to connect to in life sciences? It may not be a coincidence that Aalto has now cooperated with University of Helsinki in BCH since 2010.

Strategic top-down planning and organizational reforms may be necessary but are definitely not sufficient. In the mid-dle of the current constant university reform process it has been uplifting to follow the bottom-up formation of unex-

pected interdisciplinary ideas in the yearly networking event BCH launched for postdocs and young group leaders of Aalto and University of Helsinki. New wild ideas and ability to take the neces-sary scientific risks in pursuing them are among the most important sufficient reasons for why our institutions exist, after all!

Samuel KaskiProfessor, Director of Helsinki Institute

for Information Technology HIITRepresentative of Aalto in the board of BCH

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C ollaboration – discovering the truth? The terms interdisci-plinary and multidisciplinary are often heard in discussions.

When checking the definition of the word from the web, I run into a story of six blind men trying to recognize an elephant by each of them touching one part of the animal. This old, often cited Indian story describes the difficulty to perceive the big picture if you only know a small piece of the whole – in this case the blind men could assemble the truth only by communi-cating and combining the information they each had.

The prevailing board of Biocentrum Helsinki (BCH) gathered together in the fall of 2010 to collect ideas on how BCH could increase collaboration between University of Helsinki biomedi-cine researchers and Aalto University. In this meeting it was decided to encourage especially young researchers to interact by allocating so called seed-funding for inter-university proj-ects. The initiative aimed at strengthening the connections between the two parties of BCH, to seek solutions for the current challenges in biomedical research – also keeping in mind the possibilities of true in-novations that can originate from combin-ing ideas from experts in their own fields.

In March 2011, following the original idea, a planning group formed of people from both University of Helsinki and Aalto University come up with a 3-step scheme to promote interaction: 1) Creation of a web database of research/expertise pro-files to provide easily accessible informa-tion about activities in the two universities and to enable search for collaborators, 2) organizing a networking event to further facilitate connections, and 3) providing seed funding for projects in the context of life-sciences, proposed jointly by research-ers from the two universities.

In the year 2011, 86 profiles, visualized as postcards, were submitted to the database. In the networking event in Dipoli, Otaniemi held on the 1st of June, around 50 researchers from Aalto University and University of Helsinki met and discussed. Of the many good grant applications received later in the fall, the BCH board decided to fund eight joint projects (by PhD students/post-docs/young PIs). In 2012 similar activities were organized, the profile submission count reaching 74. The possi-bility of novel connections on the 2nd interdisciplinary network-ing day on 31st of May was again evident. Based on this activ-ity, young researchers have been open-minded even though planning an interdisciplinary study and finding a common lan-guage can be demanding. So far the contacts have been main-So far the contacts have been main-ly formed between University of Helsinki and Aalto School of Science but hopefully in the future more connections will also

be made with the other five schools of Aalto.

Improving the competiveness of a small country like Finland should be in our interests in all fields of science, and therefore uniting the expertise al-ready on the level of young research-ers is an important but yet underrated goal. Therefore, BCH has taken an im-portant step by aiming at supporting specifically inter-university studies. In addition to the pure scientific value of collaboration, I personally find the creation of a wide network as an in-vestment for the future. I expect that Biocentrum Helsinki succeeds in facili-tating these significant connections.

”Connecting Scientists” – Interdisciplinary collaboration between Aalto University

and University of Helsinki

Heli LehtonenCoordinator of Biocentrum Helsinki

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The ”Connecting Scientists” is an output of several people from University of Helsinki and Aalto University, including the people participating in the organization of the event and other practicalities,

as well as the senior support and communications personnel. In the picture is the organizing team of the ”Connecting Scientists”

in the year 2012. Left to right: Margarita Walliander, Tiia Pelkonen, Heli Lehtonen, Pekka Marttinen, Elodie Renvoisé, and Outi Kilpivaara. BCH administrative

secretary Riitta Smahl-El Hamraui is missing from the group picture.

More information about the collaboration initiative: http://www.helsinki.fi/biocentrum/collaboration/index.htm

The networking event in 2012 was held in Hanasaari, Espoo on 31st of May.

Each of the 48 participants introduced themselves and their main research

interests in a 2min presentation. After each presentation session, breaks for

free discussion enabled further contacts with possible collaboration partners. The lively discussions continued later on over

a dinner. The call for grant applications, to be opened later in 2012, will show the concrete collaborative connections made

on that day.

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Biocentrum Helsinki in 2012 | 7

Biocentrum Helsinki reseach groups 2011–2013

Sampsa Hautaniemi Liisa Holm Olli Kallioniemi

Sarah ButcherDennis Bamford

Tomi Mäkelä Jussi TaipaleTimo OtonkoskiPekka Lappalainen

Mårten Wikström

Eeva-Liisa Eskelinen

Kari Alitalo

Mikko Frilander Elina Ikonen Olli A. Jänne

Lauri A. AaltonenAkseli Hemminki

Irma ThesleffJukka Jernvall

Ilkka Hanski

Irma Järvelä Juha Kere Hannes Lohi

Jaakko KangasjärviYrjö Helariutta

Päivi Peltomäki Kai Kaila Mart Saarma Anu Wartiovaara

Biotechnology and Bioinformatics . . . Cell and Molecular Biology . . .

Developmental Biology . . .

Macromolecular Structure and Biophysics . . . Molecular Cancer Biology . . . Molecular Genetics . . .

Molecular Neuroscience . . .

Plant Biotechnology and Molecular Biology

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Computational Systems Biology

Development and application of computational tools that allow comprehensive and whole-genome analysis of complex diseases

Systems biology approaches to integrate deep sequencing data from DNA, RNA and epigenetics experiments

Development and maintaining scalable computational infrastructure for data-intensive biomedical research

Background With the advent of high-throughput measure-ment technologies, such as deep sequencing methodologies, microarrays, and automated imaging techniques, computa-tional methods have become an integral part of biomedical research. Furthermore, comprehensive and reliable characteri-zation of complex diseases, such as cancers, requires genome-scale measurements from several levels including DNA, tran-scriptome, proteomics and epigenetics as well as clinical data. Translation of these data into knowledge and medical benefits requires systems biology, which is an interdisciplinary effort to gain understanding of the function and control of biological processes using mathematical methods and statistical experi-mental design principles.

Recent progress and aims The overall goal of the Compu-tational Systems Biology group is to develop novel computa-tional methods and apply them to multidimensional molecular data to achieve systems level understanding on key cell deci-sion processes driving cancer. In order to analyze and integrate massive amounts of high-throughput molecular data we have

developed Anduril framework (Ovaska et al., Genome Medicine 2010). Anduril is a modular and open source workflow frame-work for data analysis. It is based on joining algorithms (com-ponents) as executable flows (pipelines) that allow easy reuse of the algorithms. A component can be implemented with any programming language, such as R, MATLAB, Java and C++, which allows us to take advantage of the efforts in the bioin-formatics community as well as parallelize computationally de-manding tasks. With this computational infrastructure we are able to process large numbers of deep sequencing data as well as analyze existing computational methods in order to identify situations where an algorithm works the best (Louhimo et al., Nature Methods 2012). We have been, and will remain, active in collaboration between biomedical groups and three recent highlights of collaborative studies are: (1) the role of androgen receptor and FoXA1 in prostate cancer (Sahu et al., EMBO Jour-nal 2011), (2) the role of cathepsin and ErbB2 in breast cancer (Rafn et al., Molecular Cell 2012), and (3) the role of rituximab therapy in diffuse large B-cell lymphoma (Koivula et al., Oncol-ogy Reports 2011).

Group leader

Sampsa HautaniemiDTech, DocentAcademy of Science ResearcherGenome-Scale Biology Research Program, Institute of Biomedicine

email: [email protected]: http://www.ltdk.helsinki.fi/sysbio/csb/

Biotechnology and Bioinformatics

Schematic of analysis of large-scale cancer data. Data from genetics, transcriptomics and epigenetics levels are analyzed and integrated to clinical information. The results are linked to existing knowledge in biodatabases, which facilitate interpreta-tion of the analysis results. This approach allows analysis and interpretation of heterogeneous data from complex diseases.

Selected publicationsComparative analysis of algorithms for integration of copy num-ber and expression data. Louhimo R, Lepikhova T, Monni O, Hauta-Monni O, Hauta-

niemi S. Nat Methods 2012;9:351–355.

Rule-based induction method for haplotype com-parison and identification of candidate disease loci. Karinen S, Saarinen S, Lehtonen R, Rastas P, Vahteristo P, Aaltonen L A, Hautaniemi S. Genome Med-icine 2012;4:2.

Comprehensive exon array data processing method for quantitative analysis of alternative spliced vari-ants. Chen P, Lepikhova T, Hu YZ, Monni O, Hautaniemi S. Nucl Acids Res 2011;39:e123.

Early recovery from cow's milk allergy is associated with decreasing IgEand increasing IgG4 binding to cow's milk epitopes. Savilahti EM, Rantanen V, Lin J, Karinen S, Saarinen KM, Goldis M, Mäkelä M, Hautan-iemi S, Savilahti E, Sampson H. J Allergy Clin Immunol 2010;125:1315–1321.

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Biocentrum Helsinki in 2012 | 9

Computational Genomics Elucidating functional correlates from sequence and

structure

Genome annotation

Background The dramatically decreasing cost of sequencing the whole genome of novel species has brought this possibil-ity to a larger part of the scientific community. Unfortunately, the data are meaningless unless one can actually estimate the biological functions of the genes in the genome. Our main ob-jective is to model evolutionary relationships in sequence and structure data and to elucidate their functional correlates. The development of novel and efficient algorithms is an important part of the work.

Recent progress and aims The research of the group fo-cuses on genome function prediction. In particular, we have developed tools that predict (a) the best free text description of molecular function and (b) the best Gene Ontology catego-ries for an uncharacterized sequence. Our tool called PANNZER works on these two tasks by calculating summary statistics for all the information from a sequence similarity search. PANNZER was one of the top performers in an international competition for gene annotation methods (CAFA 2011 challenge) with over 50 competing methods. In addition to our own lab, the PANNZ-ER system has already been installed at foreign and domestic research centers to analyze new genomes.

The rapid advances in genomics technologies are now ena-bling whole genome analysis of non-model species and envi-ronmental samples. Our future research will address a number of bottlenecks in genome analysis. Specific goals include: 1) using phylogenetic comparative information to improve scaf-folding of de novo sequenced genomes, 2) speeding up se-quence similarity searches, 3) identifying sequence features, such as short protein motifs and protein domains, to use as input to various machine learning algorithms applied to func-tional classification.

Selected publications Dali server: conservation mapping in 3D. Holm L, Rosenström P. Nucl Acids Res 2010;38:W545–549.

A novel method for assigning functional linkages to proteins us-ing enhanced phylogenetic trees. Ta XH, Koskinen P, Holm L Bioin-formatics 2010;27:700–706.

Bayesian search of functionally divergent protein subgroups and their function specific residues. Marttinen P, Corander J, Törönen P, Holm L. Bioinformatics 2006;22: 2466–2474.

Unraveling protein interaction networks with near-optimal effi-ciency. Lappe M, Holm L. Nat Biotechnol 2004;22:98–103.

Group leader

Liisa HolmPhDGenome Biology Research Program, Institute of Biotechnology

e-mail: [email protected]

Biotechnology and Bioinformatics

View of comparative genomics analysis of soft rot bacteria generated using in-house software.

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10 | Biocentrum Helsinki in 2012

Biotechnology and Bioinformatics

Individualized Systems Medicine

Identifying driver mutations and signals in cancer using next-generation sequencing and HTS drug testing

Building individualized systems medicine models of cancer therapy response and drug resistance

Translating the models to the clinic for guiding individualized cancer therapy

Background Making cancer care more effective and individu-alized is a central aim for cancer researchers worldwide. This is usually being pursued via DNA sequencing-based efforts and the identification of oncogenic driver mutations in drug-gable targets, such as kinases. We believe and have emerging evidence that this will miss many therapeutic opportunities. In contrast, direct testing of patient-derived cells ex vivo and in primary culture may help to uncover targeted drugs and drug combinations with unexpected cancer-specific therapeutic po-tential. Recent progress and aims During the past year, we have applied drug sensitivity and resistance testing (DSRT) for the identification of novel efficacies of existing and emerging drugs in vitro, such as Disulfiram and Monensin in prostate cancer. We also published one of the first next-generation RNA sequencing papers in breast cancer highlighting 24 novel fu-

sion genes (Edgren et al., 2011) and developed an ultra-high-throughput cell microarray method for RNAi screening to iden-tify cancer driver signals (Rantala et al., 2011).

Our individualized systems medicine study is as part of a large “grand challenge” program at FIMM to improve cancer therapy. Using adult Acute Myeloid Leukemia (AML) as a model disease, we aim to: i) identify effective targeted drugs for AML patients by applying high-throughput ex-vivo DSRT as well as genomic and molecular profiling, ii) understand how the mo-lecular and functional features change during drug response and resistance based on paired samples, iii) create individual systems medicine models of AML driver signals and drug re-sponse/resistance, iv) translate these data towards individual-ized treatment of cancer patients. The personalized medicine collaboration also involves the groups of Wennerberg, Heck-man/Knowles, Aittokallio and Lundin at FIMM as well as clini-cal collaborators at HUS.

Group leader

Olli KallioniemiMD, PhDDirector, ProfessorInstitute for Molecular Medicine Finland (FIMM)

email: [email protected]

Sensitivity of cancer cells to 130 drugs.

Selected publicationsSomatic STAT3 Mutations in Large Granular Lymphocyte Leuke-mia. Koskela HLM, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki

H, Andersson EI, Lagström S, Clemente MJ, Olson T, Jalkanen SE, Majumder MM, Almusa H, Edgren H, Lepistö M, Mattila P, Guinta K, Koistinen P, Kuittinen T, Penttinen K, Parsons A, Knowles J, Saarela J, Wenner-berg K, Kallioniemi O, Porkka K, Loughran TP, Heckman C, Maciejewski JP, Mustjoki S. New Engl J Med 2012;in press.

Emerging molecular biomarkers-blood-based strategies to detect and monitor cancer. Hanash SM, Baik CS, Kallioniemi O Nat Rev Clin Oncol 2011;8:142–150.

Identification of fusion genes in breast cancer by paired-end RNA-sequencing. Edgren H, Murumagi A, Kangaspeska S, Nicorici D, Hongisto V, Kleivi K, Rye IH, Ny-berg S, Wolf M, Borresen-Dale AL, Kallion-iemi O. Genome Biol 2011;12:R6.

International Cancer Genome Consortium. International network of cancer genome projects. Nature 2010;464:993–998.

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Cell and Molecular Biology

Autophagosome Biogenesis Elucidation of autophagosome biogenesis and

maturation

Characterization of the physiological functions of lysosomal membrane proteins

Light and electron microscopy, three-dimensional electron microscopy, freeze-fixation

Background Autophagosomes engulf cytosol and/or orga-nelles and deliver them to lysosomes for degradation, thereby supplying nutrients to the cell. Autophagosomes are formed by phagophores that elongate and wrap parts of cytoplasm. De-spite advances in understanding the molecular basis of this process, the origin of phagophore membranes and the mecha-nisms of autophagosome maturation are still unclear. Beclin 1 is a central molecule in the regulation of autophagosome bio-genesis, but its exact function is still unknown. Autophagy ena-bles the cell to recycle its cytoplasmic constituents to replenish intracellular amino acid and ATP levels and to degrade non-functional organelles and harmful aggregates. Non-functional autophagy contributes to many diseases like cancer, myopa-thies and neurodegeneration, but at present there are no ther-apies that specifically target autophagy. Better understanding of the process is a prerequisite for such clinical applications.

Recent progress and aims We have used electron tomog-raphy to provide novel information on the 3D structure of pha-gophores. Our results showed that phagophores have direct

connections with endoplasmic reticulum via short extensions of the membrane. We have also identified key molecules need-ed for autophagosome-lysosome fusion, i.e., the small GTPases Rab7 and Rab24 and the lysosomal membrane protein LAMP-2. Further, we have shown that LAMP-2 has an unexpected role in intracellular cholesterol transport. Our future goal is to elucidate the origin of phagophore membranes by systematic 3D visualization of phagophores and adjacent organelles. We will use both high-resolution 3D imaging, i.e., electron tomog-raphy, to visualize membrane connections, and 3D imaging of whole cells to visualize the location of organelles, using high-resolution scanning electron microscopy with serial imaging of the block face. Further, we aim to investigate the role of Beclin 1 localization during autophagosome formation. Our second goal is to elucidate the molecular mechanisms that mediate the functions of Rab24 and LAMP-2 in autophagy and choles-terol transport.

Selected publicationsRole for LAMP-2 in endosomal cholesterol transport. Schneede A, Schmidt CK, Hölttä-Vuori M, Heeren J, Willenborg M, Blanz J, Doman-skyy M, Breiden B, Brodesser S, Landgrebe J, Sandhoff K, Ikonen E, Saftig P, Eskelinen E-L. J Cell Mol Med 2011;15:280–295.

3D tomography reveals connections between the phagophore and endoplasmic reticulum. Ylä-Anttila P, Vihinen H, Jokitalo E, Es-kelinen E-L. Autophagy 2009;5:1180–1185.

LAMP proteins are required for fusion of lysosomes with phago-somes. Huynh KK, Eskelinen E-L, Scott CC, Malevanets A, Saftig P and Grinstein S. EMBO J 2007;26:131–324.

Role for Rab7 in maturation of late autophagic vacuoles. Jäger S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, and Eskelinen E-L J Cell Sci 2004;117:4837–4848.

Group leader

Eeva-Liisa EskelinenPhD, University LecturerDepartment of Biosciences, Viikki Biocenter

email: [email protected]

Electron micrograph showing one nascent autophagosome that is enwrapping a peroxisome (p) and one autophagosome that contains a mitochondrion (m).

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Cell and Molecular Biology

RNA Splicing Rate-limiting regulation of gene expression by the U12-

dependent spliceosome

RNA processing and RNA -protein interaction quantification by RNAseq

RNA biochemistry and in vitro reconstitution of RNA processing events

Background Most multicellular organisms carry two different types of introns in their genomes. The majority consists of U2-type introns that constitute more than 99% of of all introns. Ad-ditionally, in human genome there is around 800 introns that are removed by a separate splicing machinery (spliceosome). These U12-type introns are spliced more slowly than normal introns are and regulate the gene expression levels of their “host” genes. We are investigating the cellular and organismal level significance of this regulation.

Recent progress and aims Our recent work has focused on intron recognition process of the U12-type introns. Our bio-chemical investigations of the RNA-protein interactions in the U12-type intron recognition led to identification of a regula-tory pathway that affects cellular levels of the U12-type spliceo-

some. This regulatory program is evolutionarily ancient and is conserved from humans to plants. We are currently manipulat-ing the regulatory circuit to uncover its cellular and organismal-level significance. Recently a mutation in the U4atac snRNA component of the U12-type spliceosome have been shown to cause MOPD I/Taybi-Lindren disease, which is characterized by severe growth retardation, wide-spread developmental defects in many organs, and eventual death of the affected children. The mutation leads to defective splicing of U12-type introns, and consequently we are currently working with the patient cell lines using RNA biochemistry methods and RNAseq analysis to identify gene expression changes associated with the splicing defect. These investigations will allow us to understand how the U12-type introns affect gene expression in healthy and sick cells and tissues.

Group leader 

Mikko Frilander PhDInstitute of Biotechnology, Genome Biology Program

email: [email protected]

Sequence conservation plotting identifies highly conserved elements from U11/U12-65K that functions in the intron recognition complex.

Selected publicationsAn ancient mechanism for splicing control: U11 snRNP as an ac-tivator of alternative splicing. Verbeeren J, Niemelä EH, Turunen JJ,

Will CL, Ravantti JJ, Lührmann R, Frilander MJ. Mol Cell 2010;37:821–833.

Gene expression profiling of U12-type spliceosome mutant Drosophila re-veals widespread changes in metabol-ic pathways. Pessa HKJ, Greco D, Kvist J, Wahlström G, Heino TI, Auvinen P, Frilan-der MJ. PLoS ONE 2010;5:e13215.

Minor spliceosome components are predominantly localized in the nucle-us. Pessa HKJ, Will CL, Meng X, Schneider C, Watkins NJ, Perälä N, Nymark M, Tu-runen JJ, Lührmann R, Frilander MJ. P Natl Acad Sci USA 2008;105:8655–8660.

The U11-48K protein contacts the 5’ splice site of U12-type introns and the U11-59K protein. Turunen JJ, Will CL, Grote M, Lührmann R, Frilander MJ. Mol Cell Biol 2008;28:3548–3560.

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Cell and Molecular Biology

Intracellular Cholesterol Transport

Development of new lipid imaging techniques

Mechanisms of sterol and sphingolipid transport in mammalian cells

Intracellular lipid imbalance in human diseases

Background Lipids are major constituents of biomembranes and about half of cellular proteins are associated with mem-branes. Cholesterol is the most abundant lipid species in mammalian cells. It dictates important biophysical properties of membranes and orchestrates protein and lipid interactions but when in excess, it severely compromises them. The contri-bution of lipids in cellular functions has remained poorly un-derstood. This is largely due to methodological challenges in analyzing lipids. The research of the group focuses on cellular cholesterol trafficking, cholesterol storage and sterol-depend-ent membrane domains.

Recent progress and aims We develop and apply novel li-pid detection methods, to gain insight into key aspects of cel-lular sterol metabolism and its alterations in human disease. Besides sterols, we develop tools for analyzing sphingolipids and triglycerides because they interact with sterols in bilayers and lipid droplets, respectively. For example, we have reported that a novel therapeutically used sphingolipid alters cholester-ol trafficking in macrophages, thereby exerting antiatherogenic effects (Blom et al., 2010) and that the cholesterol transporter

NPC1 modulates hepatic triglyceride metabolism (Uronen et al., 2010). Particular focus of interest is how cholesterol-rich membrane domains regulate protein functions, such as actin dynamics at membrane contacts. We recently discovered that the actin-binding protein Coronin-1A functions as a negative regulator of endo-lysosomal maturation and lipoprotein hy-drolysis (Hölttä-Vuori et al., 2012).

In the future, we will employ both fluorescent reporters as well as novel, label-free imaging techniques based on coher-ent anti-Stokes Raman spectroscopy, to visualize lipids in living cells and tissues. The future goals are: 1) to characterize how lipid-binding proteins regulate sterol-dependent membrane domains and functions of associated proteins, 2) to elucidate novel structural and functional aspects of cellular lipid storage in droplets, and 3) to uncover mechanisms of sterol trafficking and homeostasis in the central nervous system, both during development and in neurodegenerative conditions.

Group leader

Elina IkonenMD, PhD, Academy ProfessorInstitute of Biomedicine, Anatomy

e-mail: [email protected]

Snapshot of a lipid loaded macrophage (lipid droplets green, nucleus blue)

Selected publicationsEndosomal actin remodeling by Coronin-1A controls lipoprotein uptake and degradation in macrophages. Hölttä-Vuori M, Vainio S, Kauppi M, Van Eck M, Jokitalo E, Ikonen E. Circ Res 2012;110:450–455.

Niemann-Pick C1 modulates hepatic tri-glyceride metabolism and its genetic variation contributes to serum triglycer-ide levels. Uronen R-L, Lundmark P, Orho-Melander M, Jauhiainen M, Larsson K, Sieg-bahn A, Wallentin L, Zethelius B, Melander O, Syvänen A-C, Ikonen E. Arterioscler Thromb Vasc Biol 2010;30:1614–1620.

FTY720 stimulates 27-hydroxycholesterol production and confers atheroprotective effects in human primary macrophages. Blom T, Bäck N, Mutka AL, Bittman R, Li Z, de Lera A, Kovanen PT, Diczfalusy U, Ikonen E. Circ Res, 2010;106:720–729.

Cellular cholesterol trafficking and com-partmentalization. Ikonen E. Nat Rev Mol Cell Biol 2008;9:125–138.

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Cell and Molecular Biology

Androgen Receptor Pathway

Tissue- and cell-specific androgen signaling and transcription programs

Cross-talk among nuclear receptors in prostate cancer

Biology of protein SUMOylation in metabolism and inflammation

Background High androgen receptor (AR) level in primary prostate tumor predicts poor prognosis, but mechanisms that regulate AR function in prostate cancer are poorly known. We address AR signaling and transcription programs in prostate cancer cells and mouse tissues by using genome-wide ap-proaches. In particular, we characterize the importance of other DNA-binding transcription factors (e.g. members of the FoxA family) for localization of AR-binding events on chroma-tin, androgen-dependent transcription programs, and deter-mination of the specificity of receptor binding. In addition, we address genome-wide cross-talk between AR and other nuclear receptors, such as the glucocorticoid and vitamin D receptors. The results are anticipated to offer new opportunities for thera-peutic intervention in prostate cancer. Another line of research deals with the importance of protein SUMOylation in metabo-lism and inflammation. SUMOylation is a dynamic process in-volving the covalent attachment of SUMO to target proteins, such as nuclear receptors.

Recent progress and aims We described recently a new paradigm for the forkhead protein FoxA1 action in AR pathway.

Besides being a pioneer factor in AR signaling, FoxA1 has other important functions as well; its depletion elicits extensive re-distribution of AR-binding sites (ARBs) on prostate cancer cell chromatin that is commensurate with changes in androgen-de-pendent gene expression signature. We identified three classes of ARBs and androgen-responsive genes; (i) independent of FoxA1, (ii) require FoxA1, and (iii) unmasked by FoxA1 deple-tion. FoxA1 depletion also reprograms glucocorticoid receptor binding and glucocorticoid-dependent signaling. High FoxA1 level in primary prostate cancers is associated with poor dis-ease prognosis, whereas low FoxA1 level, even in the presence of high AR expression, predicts good disease outcome.

Ongoing work addresses the following topics: (i) tissue- and cell-specific AR pathways; (ii) cross-talk of AR with other nucle-ar receptors in prostate cancer; and (iii) protein SUMOylation in fat cell biology.

Selected publicationsDual role of FoxA1 in androgen receptor binding to chromatin, an-drogen signalling and prostate cancer. Sahu B, Laakso M, Ovaska K, Mirtti T, Lundin J, Rannikko A, Sankila A, Turunen J-P, Lundin M, Kon-sti J, Vesterinen T, Nordling S, Kallioniemi O, Hautaniemi S, Jänne OA. EMBO J 2011;30:3962–3976.

Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Wang O, Li W, Zhang Y, Yuan X, Xu K, Yu J, Chen Z, Beroukhim R, Wang H, Lupien M, Wu T, Regan MM, Meyer CA, Carroll JS, Manrai K, Jänne OA, Balk SP, Mehra R, Han B, Chinnaiyan AM, Rubin MA, True L, Fiorentino M, Fiore C, Loda M, Kantoff PW, Liu XS, Brown M. Cell 2009;138:245–256.

Sumo-1 function is dispensable in normal mouse development. Zhang F-P, Mikkonen L, J. Toppari J, Palvimo JJ, Thesleff I, Jänne OA. Mol Cell Biol 2008;28:5381–5390.

A hierarchical network of transcription factors governs androgen receptor dependent prostate cancer growth. Wang Q, Li W, Liu XS, Carroll JS, Jänne OA, Krasnickas Keeton E, Chinnaiyan AM, Pienta KJ, Brown M. Mol Cell 2007;27:380–392.

Group leader

Olli A. JänneMD, PhDProfessor of Medical SciencesDirector, Biomedicum HelsinkiInstitute of Biomedicine, PhysiologyBiomedicum Helsinki

email: [email protected]

Redistribution of androgen receptor (AR) and gluco-corticoid receptor (GR) binding events upon FoxA1 depletion (siFoxA1) in pros-tate cancer cells.

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Cell and Molecular Biology

Actin and Plasma Membrane Dynamics

Mechanisms of actin filament disassembly and actin monomer recycling

Regulation of the interplay between the actin cytoskel-eton and plasma membrane

Assembly and turnover of contractile actin filament structures

Background Coordinated polymerization of actin filaments against membranes provides force for the formation of plasma membrane protrusions and invaginations during cell morpho-genesis, motility and endocytosis. In addition, actin filaments together with myosin filaments form contractile structures in muscle and non-muscle cells. Recent studies have shown that abnormalities in actin-dependent processes, including cell motility and cytokinesis, often occur in cancer cells, and that many pathogens exploit the actin polymerization machinery of the host cell during the infection process. Thus, elucidating the mechanisms of actin dynamics will also be valuable for under-standing these actin-dependent pathological states.

Recent progress and aims Our laboratory uses a wide range of biochemical, cell biological, and genetic methods to reveal how the structure and dynamics of the actin cytoskel-eton are regulated during various cellular and developmental processes. We are especially interested in elucidating how evolutionarily conserved proteins ADF/cofilin, twinfilin, cyclase-associated protein, and GMF interact with actin in vitro and regulate the cytoplasmic actin monomer pool in animal cells. Furthermore, we study how contractile actomyosin arrays, such as stress fibers in non-muscle cells and myofibrils in striated muscle cells, are generated and maintained. Finally, we aim to elucidate how membrane phospholipids regulate actin dynam-ics, and how the I-BAR domain family proteins deform PI(4,5)P2-rich membranes to coordinate actin and plasma membrane dynamics during various cellular and physiological processes.

Group leader

Pekka LappalainenPhD, Professor Institute of Biotechnology

email: [email protected]

Actin stress fiber network of a motile human osteosarcoma cell.

Selected publicationsPinkbar is an epithelial-specific BAR domain protein that gen-erates planar membrane structures. Pykäläinen A, Boczkowska

M, Zhao H, Saarikangas J, Re-bowski G, Jansen M, Hakanen J, Koskela EV, Peränen J, Vihinen H, Jokitalo E, Salminen M, Ikonen E, Dominguez R, Lappalainen P. Nat Struct Mol Biol 2011;18:902–907.

A molecular pathway for myo-sin II recruitment to stress fibers. Tojkander S, Gateva G, Schevzov G, Hotulainen P, Nau-manen P, Martin C, Gunning PW, Lappalainen P. Curr Biol 2011;21:539–550.

Molecular mechanisms of membrane deformation by I-BAR domain proteins. Saarikan-gas J, Zhao H, Pykäläinen A, Lau-rinmäki P, Mattila PK, Kinnunen P, Butcher SJ, Lappalainen P. Curr Biol 2009;19:95–107.

Structure of the actin-depo-lymerizing factor homology domain in complex with actin. Paavilainen VO, Oksanen E, Gold-man A, Lappalainen P. J Cell Biol 2008;182:51–59.

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Cell and Molecular Biology

Cell Growth Regulation, Signaling and Metabolism

Tumor suppression mechanism and signaling network of the LKB1 kinase

Transcriptional regulation by cyclin-dependent kinases Cdk7 and Cdk8 in growth and differentiation

Background Major human diseases such as diabetes and cancer are due to deregulated intracellular and cell-to-cell signaling. Signaling in pathways and in larger networks typi-cally involves sequential activation of kinases phosphorylating substrates and thus relaying and amplifying signals modulat-ing transcriptional responses in target gene sets and ultimately cell fate and tissue homeostasis. Our longstanding interest is to characterize signaling pathways regulating mammalian cell growth and how these impinge on transcriptional responses in human disease.

Recent progress and aims Transcriptional regulation by cyclin-dependent kinases Cdk7 and Cdk8 in growth and differentiation. Cdk7 and Cdk8 are two mediators of transcriptional responses involved in cancer and metabolism and mediating signals to RNA poly-merase II through TFIIH and Mediator, respectively. We are in-vestigating the molecular mechanisms and in vivo functions of Cdk7 and Cdk8 in mice and flies as well using cell-based screening approaches. Recent discoveries include identifying Cdk7 acts as a roadblock to adipogenesis and to development of fatty liver. Our goal is to understand the basis for the speci-

ficity of transcriptional regulation by metazoan Cdk7 and Cdk8 and their contribution to metabolism, growth control and dif-ferentiation.

Signaling by the metabolic regulator and tumor supressor kinase LKB1. LKB1 is one of the rare kinases acting normally to suppress aberrant tumor growth and acts through phos-phorylating and activating 14 AMPK related kinases involved in metabolism and polarity regulation. We are interested in how LKB1 mediates its tumor suppressing function, and recently identified that LKB1 acts as a “landscaper” tumor suppressor by suppressing epithelial proliferation in polyps from stromal cells. We are currently investigating both stromal-epithelial interactions as well as which of the 14 kinases are involved in tumor suppression. For this a combination of tissue- and cell type specific targeting approaches in vivo (conditional mouse models) and in vitro (2D and 3D RNAi & conditional deletions) of LKB1 and LKB1 substrate mutations will be used with a spe-cific interest in the Nuak2 and AMPK kinases and cytoskeletal regulation.

Selected publicationsTumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity. Partanen JI, Tervonen TA, Myllynen M, Lind E, Imai M, Katajisto P, Dijkgraaf GJP, Kovanen PE, Makela TP, Werb Z, Klefstrom J. Proc Natl Acad Sci USA 2012;109:E388–E397.

An association between NUAK2 and MRIP reveals a novel mecha-nism for regulation of actin stress fibers. Vallenius T, Vaahtomeri K, Kovac B, Osiceanu AM, Viljanen M, Mäkelä TP. J Cell Sci 2011;124:384–393.

Requirement of TFIIH kinase subunit Mat1 for RNA Pol II C-termi-nal domain Ser5 phosphorylation, transcription and mRNA turn-over. Helenius K, Yang Y, Tselykh TV, Pessa HK, Frilander MJ, Makela TP. Nucleic Acids Res 2011;39:5025–5035.

LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis. Katajisto P, Vaahtomeri K, Ekman N, Ventela E, Ristimaki A, Bardeesy N, Feil R, DePinho RA, Mäkelä TP. Nat Genet 2008;40:455–459.

Group Leader

Tomi P. Mäkelä MD, PhDProfessor, DirectorInstitute of Biotechnology

Time-lapse imaging of epithelial cells expressing GFP-tagged protein of interest during wound healing.

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Cell and Molecular Biology

Human Pluripotent Stem Cells Optimization of iPS cell generation from human

somatic (patient-derived) cells

Targeted differentiation of pluripotent stem cells into definitive endoderm and its derivatives (pancreas, liver, intestine)

Development of disease-specific hepatocyte- and beta cell- models for monogenic diabetes and liver diseases

Background The iPS cell technology enables to generate cells or tissues that recapitulate human genetic diversity, physi-ology and pathology, thus providing the possibility to create unique cellular disease models for pathogenetic studies and therapeutic exploration. Currently, the major challenges in this field are related with the maintenance of the genomic integrity in the reprogrammed cells and the development of methods for the differentiation of physiologically functioning cell types from the stem cells.

Recent progress and aims The Otonkoski group was among the pioneers to establish human iPS cell derivation in 2008 and was the first to show that pluripotent reprogramming is associated with frequent copy number variation.

Currently, the group is using non-integrating “second gen-eration” technologies to generate genetically intact stem cells. The major aim of the group is to establish methods for the der-

ivation of functional pancreatic beta-cells from the pluripotent stem cells. This model can then be used: 1) to study mecha-nisms of beta-cell dysfunction and 2) to develop new thera-peutic strategies for various forms of diabetes.

Selected publications iPSC clones reprogrammed via rAAV-mediated transduction con-tain integrated vector sequences. J. Weltner, A. Anisimov, K. Alitalo, T. Otonkoski, R. Trokovic. J Virol 2012;86:4463–4467.

Copy number variation and selection during reprogramming to pluripotency Hussein SM, Batada N, Vuoristo S, Ching RW, Autio R, Närvä E, Ng S, Sourour M, Hämäläinen R, Olsson C, Lundin K, Mikkola M, Trokovic R, Peitz M, Brüstle O, Bazett-Jones DP, Alitalo K, Lahesmaa R, Nagy A and Otonkoski T. Nature 2011;471:58–62.

EGF-receptor signaling is needed for murine beta cell mass ex-pansion in response to high fat diet and pregnancy but not after pancreatic duct ligation. Hakonen E, Ustinov J, Mathijs I, Palgi J, Bou-wens L, Miettinen P, Otonkoski T. Diabetologia 2011;54:1735–1743.

Physical exercise-induced hypoglycemia caused by failed silenc-ing of monocarboxylate transporter 1 in pancreatic beta cells. Otonkoski T, Jiao H, Kaminen-Ahola N, Tapia-Paez I, Ullah MS, Parton

LE, Schuit F, Quintens R, Sipilä I, Mayatepek E, Meissner T, Halestrap AP, Rutter GA and Kere J. Am J Hum Genet 2007;81:467–474.

Group leader

Timo OtonkoskiMD, PhDProfessor of Human Stem Cell ResearchMolecular Neurology Research Program

email: [email protected]

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Cell and Molecular Biology

Growth Control and Cancer Identification of the genes and the mechanisms

essential for cell cycle progression on a genome-wide level

Understanding the molecular basis of organ-specific growth control

Background Organ specific growth control remains one of the major, unresolved questions in developmental biology. It is not understood what determines organ size and shape, and it is not clear why tumors arising in different tissues har-bor different oncogenic mutations. Much of what we do know about physiological mechanisms controlling cellular growth in mammals has been revealed by human cancer genetics. These studies have revealed that a large number of genes can con-tribute to aberrant cell growth. More than 350 genes have been linked to cancer and mutations found in cancer are often cell type specific, suggesting that different pathways in different cell lineages are coupled to the cell cycle machinery. Our hy-pothesis is that the problems of organ-specific growth control and specificity of oncogenes to particular tumors represent two sides of the same coin; that is, mutations in tumors are tissue specific, because tumors arise by the most economical muta-genic route, aberrantly activating the organ-specific growth mechanisms.

Recent progress and aims We are taking a systems-biology approach to understand how tissue-specific factors collabo-rate with oncogenic signals to drive cell proliferation. For this purpose, we have developed computational and experimental methods to identify direct target genes of oncogenic transcrip-tion factors that are commonly activated in major forms of hu-man cancer. In addition, we have used high-throughput RNAi screening to identify genes required for cell cycle progression. Combining these two sets of data allows identification of spe-cific transcription factors and gene regulatory elements which drive growth in particular tissues and tumor types.

Selected publicationsGenome-wide analysis of ETS-family DNA-binding in vitro and in vivo. Wei GH, Badis G, Berger MF, Kivioja T, Palin K, Enge M, Bonke M, Jolma A, Varjosalo M, Gehrke AR, Yan J, Talukder S, Turunen M, Taipale M, Stunnenberg HG, Ukkonen E, Hughes TR, Bulyk ML, Taipale J. EMBO J 2010;29:2147–2160.

Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Varjosalo M, Björklund M, Cheng F, Syvänen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg HG, He WW, Ojala P, Taipale J. Cell 2008;133:537–548.

Identification of pathways regulating cell size and cell-cycle pro-gression by RNAi. Björklund M, Taipale M, Varjosalo M, Saharinen J, Lahdenperä J, Taipale J. Nature 2006;439:1009–1013.

Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E, Taipale J. Cell 2006;124:47–59.

Group leader

Jussi TaipalePhD, Academy Professor, Professor of Medical Systems BiologyKarolinska Institutet, Stockholm, SwedenAcademy ProfessorGenome-Scale Biology Research ProgramResearch Programs Unit, Biomedicum Helsinki

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Developmental Biology

Evolutionary Developmental Biology

Computational and quantitative analyses of patterning

Discovering developmental basis of phenotypic com-plexity

Background Evolutionary developmental biology is a field of biology aiming to uncover how developmental mechanisms and genes have changed in the evolution of phenotypes. Our aim is to construct developmental-based models that are used to explain and predict phenotypic evolution. Most of our work uses mammalian dentition as a model system in the context of both micro- and macroevolution, and methods ranging from developmental biology experiments to computer models simu-lating development.

Recent progress and aims Tooth phenotypes are invariably complex and difficult to fully characterize, and we are devel-oping approaches to allow fast-throughput analysis of three-dimensional shapes. To study natural and mutant phenotypes, we have developed a computerized MorphoBrowser database for three-dimensional phenotypes. MorphoBrowser allows the linking of macroevolution level collections on fossils, micro-evolution level data collected from natural populations, and experimentally changed morphologies of mouse mutants (mor-phobrowser.biocenter.helsinki.fi/). Our future aims include 1) finding out what regulates dental complexity during develop-ment and evolution, 2) the role of cell behavior (e.g. cell adhe-sion, cell shape) in fine-tuning tooth shape, and 3) linking mi-croarray data to computational models of tooth development.

Selected publicationsAdaptive radiation of multituberculate mammals before the ex-tinction of dinosaurs. Wilson GP, Evans AR, Corfe IJ, Smits P, Fortelius M, Jernvall J. Nature 2012;483:457–460.

On the difficulty of increasing dental complexity. Harjunmaa E, Kallonen A, Voutilainen M, Hämäläinen K, Mikkola ML, Jernvall J. Na-ture 2012;483:324–327.

A computational model of teeth and the developmental origins of morphological variation. Salazar-Ciudad I, Jernvall J. Nature 2010; 464:583–586.

Predicting evolutionary patterns of mammalian teeth from devel-opment. Kavanagh KD, Evans AR, Jernvall J. Nature 2007;449:427–432.

Group leader

Jukka JernvallPhD, Academy ProfessorDevelopmental Biology Program, Institute of Biotechnology

e-mail: [email protected]

In cultured ShhGFP reporter mouse teeth, adjusting multiple signaling pathways simultaneously produces an increase in cusp number (control on the left, treatment on the right).

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Developmental Biology

Group leader

Irma Thesleff DDS, PhD Research Director Research Program in Developmental Biology, Institute of Biotechnology

email: [email protected] website: www.biocenter.helsinki.fi/bi/thesleff/

Development and Renewal of Ectodermal Organs

Intercellular communication regulating formation and renewal of ectodermal organs – teeth, hairs, and glands

Mouse models and organ cultures to analyse the functions of FGF, TGFβ, Hedgehog, Wnt and Ectodysplasin pathways

Background Interactions between cells constitute a key mechanism in the regulation of embryonic development. We explore the cell interactions involved in the development and renewal of organs forming as appendages of the surface ecto-derm. Our focus is in the formation of teeth, hairs and some glands, and the roles of signaling networks mediating inter-cellular communication. We examine how these networks regulate the patterns, numbers, sizes, shapes and renewal of ectodermal organs. We use mouse models and organ culture techniques to study the functions of conserved signal path-ways including FGF, TGFβ, Hedgehog, Wnt and Ectodysplasin (Eda). Some of the mice are models for human syndromes such as ectodermal dysplasias and tooth agenesis.

Current progress and aims 1) Our particular interest is the formation of placodes initiating the development of all ectoder-mal appendages. We have shown that stimulation of Wnt and Eda signaling induces extra placodes resulting in the formation of extra teeth, whiskers and hairs. We have identified a number of Eda targets which include both positive and negative effec-tors of other conserved signal pathways, and several mouse lines are currently used to examine the signaling networks. 2) We are focusing increasingly on the mechanisms of tooth re-newal. We discovered in 1999 a stem cell niche in continuously

growing mouse teeth and this has allowed research on dental stem cell regulation. Our work on these epithelial stem cells has revealed that their maintenance, proliferation and differen-tiation is regulated by a complex signaling network involving several TGFβ and FGF signals, and that microRNAs are impor-tant modulators of this network. The aim of our current work is to characterize the dental stem cells and their progeny, and to explore the possibilities to generate teeth using these cells. The results of our research may have clinical implications in the diagnosis, prevention and treatment of congenital defects as well as in the design of regenerative therapies.

Selected publicationsAn integrated gene regulatory network controls epithelial stem cell proliferation in teeth. Wang, X-P, Suomalainen M, Felszeghy S, Zelarayan LC, Alonso MT, Plikus MV, Maas R, Chuong C-M, Schimmang T, Thesleff I. PLoS Biol 2007;5:1324–1333.

Continuous tooth generation in mouse is induced by activated epithelial Wnt/ β catenin signalling. Järvinen E, Salazaar-Ciudad I, Birchmeier W, Taketo MM, Jernvall J, Thesleff I. Proc Natl Acad Sci USA 2006;103:18627–18632.

Follistatin regulates enamel patterning in mouse incisors by asymmetrically inhibiting BMP signaling and ameloblast differ-entiation. Wang X-P, Suomalainen M, Jorgez CJ, Matzuk MM, Werner S, Thesleff I. Dev Cell 2004;7:719–730.

Identification of BMP-4 as a signal mediating secondary induc-tion between epithelial and mesenchymal tissues during early tooth development. Vainio S, Karavanova I, Jowett A, Thesleff I. Cell 1993;75:45–58.

Epithelial stem cells in the tooth express Sox2

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Macromolecular Structure and Biophysics

Virus Evolution Hypothesis on virus evolution and origins:

there are only a limited number of ways that a virion can be constructed

Characterization of prokaryotic viruses from ecological niches e.g. human bacterial infections, high saline environments and Baltic Sea to test the hypothesis

Background It has been estimated that there are 1031–1032 viruses in the biosphere. This number exceeds the number of their host cells by at least one order of magnitude. Conse-quently practically every organism is constantly under viral at-tack and viruses may cause the highest selection pressure that cellular organisms encounter. Viruses play an important role as obligate cellular parasites ensuring their own reproduction and modulating their host cells. Due to their adverse effects on the well being of their host organism, the emphasis in virology has focused on detection and prevention of pathogenic viruses infecting humans and domesticated animals and plants. How-ever, how the entire domain of viruses is organized, what is the origin of viruses and how they evolve are deep questions in bi-ology in general and in virology in particular.

Recent progress and aims Our research has advanced by discovering how viral molecular machines work, what deter-mines the size in certain icosahedral viruses, how a complex infectious viral particle self-assembles from its purified struc-tural constituents, and how RNA dependent RNA polymerases operate. The accumulating information on virus structures has led to a surprising new hypothesis on virus evolution and ori-

gins. It is postulated that there are only a limited number of ways that a virion can be constructed.

The underpinning hypothesis is that we can probe deep evolutionary relationships in general and for viruses in particu-lar by combining structural and functional information. We wish to test the hypothesis that prokaryotic viruses are homologues to viruses infecting multicellular eukaryotic organisms. Rec-ognizing such connections will also lead to major revisions in how we classify viruses.

Currently we have combined virology, genetics, biochemis-try, biophysics, and structural analysis to describe in detail the viral model systems under study (predominantly viruses infect-ing prokaryotic hosts). We are now also extending to virus ecol-ogy by isolating and characterizing prokaryotic viruses from different ecological niches such as human bacterial infections, highly saline and high temperature environments to test our hypothesis and to allow us to search for novel virus types with unknown structural principles.

Group leader

Dennis H. BamfordPhD, Academy ProfessorProgramme on Molecular Virology, Institute of Biotechnology and Department of Biosciences, Viikki Biocenter

e-mail: [email protected]

3D images of virus particles generated by X-ray crystallography or cryo electron microscopy.

Selected publicationsThe DNA/RNA-dependent RNA polymerase QDE-1 generates aber-rant RNA and dsRNA for RNAi in a process requiring replication protein A and a DNA helicase. Lee HC, Aalto AP, Yang Q, Chang SS, Huang G, Fisher D, Cha J, Poranen MM, Bamford DH, Liu Y. PLoS Biol 2010;8:e1000496.

qiRNA is a new type of small inter-fering RNA induced by DNA dam-age. Lee HC, Chang SS, Choudhary S, Aalto AP, Maiti M, Bamford DH, Liu Y. Nature 2009;459:274–277.

Insights into virus evolution and membrane biogenesis from the structure of the marine lipid-containing bacteriophage PM2. Abrescia NG, Grimes JM, Kivela HM, Assenberg R, Sutton GC, Butcher SJ, Bamford JK, Bamford DH, Stuart DI. Mol Cell 2008;31:749−761.

Virus evolution: How far does the double beta-barrel viral lineage extends? Krupovic M, Bamford DH. Nat Rev Microbiol 2008;6: 941−948.

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Macromolecular Structure and Biophysics

Macromolecular Structure and Function

The understanding of how structure, function and interactions of proteins and lipids influence disease

The understanding of the assembly of macromolecu-lar machines exemplified by viruses from all three domains of life

Main methodologies are virology and biochemical characterization to isolate complexes followed by electron cryo-microscopy, mass spectrometry and X-ray crystallography to characterize the interactions in three dimensions

Background The virus universe is vast and yet also mainly uncharted, and thus there is very little knowledge of distant evolutionary relationships between viruses, or structure-based drug-design for emergent pathogenic viruses. We combine electron cryo-microscopy, three-dimensional image reconstruc-tion and X-ray crystallography to image these viruses and their interaction with cell-surface proteins used for recognition.

Recent progress and aims Recently we have made signifi-cant advances in determining the structures of several viruses, including a newly discovered group of pleomorphic, envel-oped, archaeal viruses with Dennis Bamford, African horsesick-ness virus, and several picornaviruses (Seitsonen et al., 2010;

Seitsonen et al., 2012). Electron cryo-tomography now allows us to investigate irregularly-shaped pathogenic viruses that have previously been intractable to high resolution studies. Most importantly we have recently elucidated the structure of measles virus (Liljeroos et al., 2011) showing that the matrix protein orchestrates compaction and incorporation of the ribo-nucleocapsid into the budding virus. These studies have shed light on membrane-protein interactions, virus assembly, viral evolution and receptor-host interactions. To complement these studies, we have collaborated with Pekka Lappalainen to look at proteins that modulate membrane function in cells such as the I-BAR domain proteins (Saarikangas et al., 2009). In the near future we will extend our studies to other pleomorphic RNA viruses, and investigate in more detail the infection and assembly of measles virus, developing methods for correlative light and electron microscopy studies of viruses and infected cells.

Selected publications Electron cryotomography of measles virus reveals that ma-trix protein coats the ribonucleocapsid within intact virions. Liljeroos L, Huiskonen J, Ora A, Susi P, Butcher SJ. P Natl Acad Sci USA 2011;108:18085–18090.

Structural analysis of coxsackievirus A7 reveals conformational changes associated with uncoating. Seitsonen, J, Shakeel S, Susi P, Pandurangan A, Sinkovits RS, Hyvönen H, Laurinmäki P, Ylä-Pelto J, Topf M, Hyypiä T, Butcher SJ. J Virol 2012;epub doi:10.1128/JVI.06425–11.

Interaction of αVβ3 and αVβ6 integrins with Human parechovirus 1. Seitsonen J, Susi P, Heikkilä O, Sinkovits RS, Laurinmäki P, Hyypiä T, Butcher SJ. J Virol 2010;84:8509–8519.

Molecular mechanisms of membrane deformation by I-BAR do-main proteins. Saarikangas J, Zhao H, Pykäläinen A, Laurinmäki P, Mattila P, Kinnunen P, Butcher SJ, Lappalainen P. Curr Biol 2009;19:95–107.

Group leader

Sarah ButcherProfessor Structural Biology and Biophysics Programme, Institute of Biotechnology

email: [email protected]

Organization of the matrix and nucleocapsid in measles virions. (A) Three-dimensional structures for the matrix (blue) and nucleocapsid (orange) filaments are super-imposed on a section of a virion tomogram (shown in gray scale, positive density is black). (B–D) End-on views of the bundles in A are shown from the directions indicated with arrows in A. (Reproduced from Liljeroos et al. (2011) PNAS 108:1808 with permission.)

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Macromolecular Structure and Biophysics

Helsinki Bioenergetics Elucidation of the molecular mechanism of proton

translocation by respiratory chain complexes I and IV, using methods of

Time-resolved (µs) optical spectroscopy and electrom-etry, site-directed mutagenesis, and molecular dynam-ics, electrostatic and quantum-chemical calculations

Background Primary biological energy transduction occurs in photosynthesis and cell respiration, where electron trans-fer (redox) reactions within membrane-bound enzyme com-plexes drive translocation of protons across the membrane. The created electrochemical proton gradient is then used for the synthesis of ATP by an ATP synthase complex in the same membrane. ATP is the common energy currency in all cells; its hydrolysis drives virtually all energy-requiring reactions either directly or indirectly. Cell respiration is catalysed by the so-called respiratory chain complexes I, III and IV, which are well conserved throughout the three domains of life, bacteria, ar-chaea, and eukaryota, even though some interesting variations occur. These complexes function as molecular machines that transduce free energy from the electron transfer reactions into the free energy of an electrochemical proton gradient across the bacterial or mitochondrial membrane. The molecular mech-

anisms of this energy transduction is fairly well understood for complex III, less so for complex IV, and still quite poorly under-stood for complex I.

Recent progress and aims Our work focuses on the pro-tonmotive function of complexes I and IV, the aim being to elucidate the molecular mechanisms using a combination of different techniques, such as site-directed mutagenesis, time-resolved biophysical methods, and computational methodol-ogy. Most recently, we have found reasons to revise the proton-pumping stoichiometry of complex I from 4 to 3 H+/2e–, which has far-reaching consequences with respect to possible mech-anisms. We have also for the first time demonstrated fully effi-cient proton pumping by the cytochrome cbb3-type complex IV after isolation and reconstitution into liposomes. Cytochrome cbb3, which is found only in certain bacteria, is distantly relat-ed to mitochondrial complex IV (cytochrome c oxidase). Some structures necessary for proton-pumping in the mitochondrial complex are lacking from cbb3, and other groups had in the past reported only very inefficient proton-pumping activity. Our finding requires revision of the view that proton-pumping by all members of the heme-copper oxidase family (complex IV) oc-curs by a common mechanism.

Selected publicationsThe mechanistic stoichiometry of proton translocation by cyto-chrome cbb3 Rauhamäki V, Bloch DA, Wikström M. Proc Natl Acad Sci USA, in press.

Stoichiometry of proton translocation by respiratory Complex I and its mechanistic implications. Wikström M, Hummer G. Proc Natl Acad Sci USA 2012;109:4431–4436.

Proton-coupled electron transfer in cytochrome oxidase. Kaila VRI, Verkhovsky MI, Wikström M. Chem Re. 2010;110:7062–7081.

A Complete Neandertal Mitochondrial Genome Sequence Deter-mined by High-Throughput Sequencing. Green RE, Malaspinas A-S, Krause J, Briggs A, Johnson PLF, Uhler C, Meyer M, Good JM, Maricic T, Stenzel U, Prüfer K, Siebauer M, Ronan M, Egholm M, Rudan P, Brajko-vic D, Kucan Z, Gusic I, Wikström M, Laakkonen L, Kelso J, Slatkin M, Pääbo, S. Cell 2008;134:416–426.

Group leader

Mårten WikströmMD, PhDProfessor of Physical BiochemistryResearch Director for the Structural Biology & Biophysics Programme of the Institute of BiotechnologyInstitute of Biotechnology

[email protected]

Structure and function of the mitochondrial respiratory chain

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Molecular Cancer Biology

Angiogenesis in Cancer and Cardiovascular Disease

Development of growth factor therapy for tissue ischemia

Development of improved combinatorial anti-angio-genic therapies against cancer

Understanding stem cell dynamics in colon cancer

Background Because of the importance of the growth of new blood vessels, or angiogenesis, in tumor progression, the first anti-angiogenic agents have been approved for clinical use. However, most patients are either refractory or eventually ac-quire resistance to anti-angiogenic therapeutics. A combina-tion of angiogenesis and lymphangiogenesis inhibitors based on solid knowledge of the major interacting angiogenesis sign-aling pathways could be used to significantly improve the effi-cacy of tumor therapy. – The opposite idea of a proangiogenic therapy is to grow new functional blood vessels and thus re-store blood flow to ischemic tissue.

The growth of lymphatic vessels, lymphangiogenesis, is ac-tively involved in a number of pathological processes including tissue inflammation and tumor dissemination but is insufficient in patients suffering from lymphedema, a debilitating condition characterized by chronic tissue edema and impaired immunity. Lymphangiogenic growth factors, such as VEGF-C provide pos-sibilities to treat these diseases. – Thus, there is considerable potential for the development of therapeutics based the bio-logical functions of vascular endothelial growth factors.

Recent progress and aims We have identified by molecular cloning several receptors and growth factors that govern the

development and maintenance of blood vessels and lymphatic vessels. We have found that tumor lymphangiogenesis greatly enhances tumor metastasis, which can be blocked by signal transduction inhibitors that also improve anti-angiogenic tu-mor therapy. Some of these inhibitors are now in clinical trials.

Our studies indicate that VEGF-C and VEGFR-3 provide also new targets to complement current anti-angiogenic therapies. Because of their ability to attenuate angiogenic sprouting and to inhibit lymphatic metastasis, VEGFR-3 blocking antibod-ies are now being tested in phase I clinical (safety) trials and permission has been obtained for clinical phase I study using VEGF-C blocking antibodies. – Furthermore, our studies indi-cate that antibody combinations may be used for increased ef-ficacy of inhibition of angiogenic signal transduction pathways.

Several attempts have been made to stimulate angiogene-sis and arteriogenesis in tissue ischemia, with limited success. VEGF-B, a coronary vascular growth factor has recently stimu-lated our interest in such therapy for cardiac ischemia.

Group leader

Kari AlitaloMD, PhDAcademy ProfessorTranslational Cancer Biology Program

email: [email protected]

Selected publications Lymphatic vascular biology and disease. Alitalo, K. Nat Med 2011; 17:1371–1380.

Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascu-lar leak, or inflammation. Bry M, Kivelä R, Holopainen T, Anisimov A, Tammela T, Soronen J, Silvola J, Saraste A, Jeltsch M, Korpisalo P, Car-meliet P, Lemström KB, Shibuya M, Ylä-Herttuala S, Alhonen L, Mervaa-

la E, Andersson LC, Knuuti J, Alitalo K. Circulation 2010;122:1725–1733.

VEGF and angiopoietin signaling in tumor angiogenesis and metas-tasis. Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K. Trends Mol Med 2011;7:347–362.

Effective suppression of vascular network formation by combina-tion of antibodies blocking VEGFR ligand binding and receptor di-merization. Tvorogov D, Anisimov A, Zheng W, Leppänen VM, Tammela T, Laurinavicius S, Holnthoner W, Heloterä H, Holopainen T, Jeltsch M, Kalkkinen N, Lankinen H, Ojala PM, Alitalo K. Cancer Cell 2010;18:630–640.

Saharinen et al.,Trends in Molecular Medicine, 17: 347–62, 2011

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Molecular Cancer Biology

Cancer Gene Therapy Arming oncolytic viruses with immunostimulatory

molecules

Immunology of oncolytic viruses in model systems and humans

Cancer immunology in the context of oncolytic virus treatment

Translating preclinical results into clinical trials

Background Oncolytic virotherapy is currently under investi-gation in phase I-III clinical trials for treatment of cancer. Onco-lytic viruses are specifically engineered to preferentially infect, replicate in, and kill tumor cells (Figure below). For the past few decades, the therapeutic efficacy of these agents has been thought to depend mostly on the direct tumor cell destructive effect of replication. This thinking has changed with the discov-ery that oncolytic viruses not only elicit bystander anti-tumor effects through ‘generic’ inflammation but may also induce an-tigen-specific adaptive immunity against the tumor. As adeno-virus interacts with a variety of receptors of the innate immune system mainly expressed in antigen presenting cells (APC), we hypothesized that by arming our oncolytic viruses with immu-nostimulatory transgenes we could increase the magnitude of the ensuing immune response.

Recent progress and aims We constructed adenoviruses coding for granulocyte-macrophage colony-stimulating factor and tested them preclinically. An Advanced Therapy Access Program was set up to facilitate personalized therapy under the “Hospital exemption” EY1394/2007. A University spin-off company, Oncos Therapeutics Ltd., was founded for converting

patient-by-patient treatments into clinical trials, and the first ever Finnish oncolytic virus trial opened recently.

Next we generated an oncolytic adenovirus that expresses the soluble form of CD40 ligand, which was also used in in-divdualized patient treatments and a clinical trial is now in development. Our patient data is in accord with the recent realization that the problem in cancer immunotherapy is not achieving an anti-tumor response, but dealing with tumor in-duced immunosuppression. To this end, we have utilized met-ronomic cyclophosphamide to selectively downregulate regu-latory T cells.

Another approach not yet tested in patients but promising in the laboratory is to counter tumor immunosuppression by blocking the cytotoxic T lymphocyte-associated antigen-4 by a full length human monoclonal antibody produced by tumor cells from an oncolytic adenovirus.

Selected publicationsUpregulation of interferon signaling and MXA as an in vivo es-cape mechanism from oncolytic adenovirus. Liikanen I, Monsurrò V, Laakso M, Diaconu I, Ahtiainen L, Raki M, Hakkarainen T, Hautaniemi S, Monni O, Cerullo V, Kanerva A, Pesonen S, Marzioni D, Colombatti M, Hemminki A. Mol Ther 2011;19:1858–1866.

Desmoglein 2 is a receptor crucial for attachment and spreading of human adenoviruses in epithelial cells. Wang H, Li Z, Liu Y, Pers-son J, Beyer I, Yumul R, Koyuncu D, Drescher M, Zhang X-B, Strauss R, Wahl JK, Hemminki A, Fender P, Lieber A. Nat Med 2011;17:96–104.

Immune response is an important aspect of the anti-tumor effect of an oncolytic adenovirus coding for CD40L. Diaconu I, Cerullo V, Hirvinen MLM, Escutenaire S, Ugolini M, Pesonen SK, Bramante S, Parviainen S, Kanerva A, Löskog ASI, Eliopoulos AG, Pesonen S, Hem-minki A. Cancer Res 2012;72:2327–2338.

Oncolytic immunotherapy of advanced solid tumors with Ad5/3-hTERT-CD40L (CGTG-401): assessment of safety and immuno-logical responses in patients. Pesonen S, Diaconu I, Kangasniemi L, Ranki T, Kanerva A,, Pesonen SK, Gerdemann U, Leen AM, Oksanen M, Haavisto E, Holm S-L, Karioja-Kallio A, Kauppinen S, Partanen K, Laasonen L, Kairemo K, Joensuu T, Alanko T, Cerullo V, Hemminki A. Cancer Res 2012;72:1621–1631.

Group leader

Akseli HemminkiMD, PhDK. Albin Johansson Research Professor for the Foundation for the Finnish Cancer Institute Molecular Cancer Biology Research Program and Transplantation Laboratory, Haartman Institute

email: [email protected]

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Molecular Genetics

Tumor Genomics Identification of high- and low-risk genetic variants

in tumor susceptibility

Characterization of somatic mutations in common tumors

Exome & whole-genome sequencing, registry-based search for cancer families

Background Many genes for common high-penetrance Men-delian cancer syndromes have already been identified. How-ever, these conditions explain ~5% of the common cancers. It is likely that many such conditions – especially those lacking easily recognizable syndromic features and those caused by polygenic inheritance – remain unknown. Importantly, cancer is a disease involving two unique genomes - germline, and that of the respective tumor. In order to fully understand the tumori-genesis mechanisms and to be able to translate the molecular findings into clinical benefits, both the inherited risk variants and alterations in the tumor genome are of interest.

Recent progress and aims The research of the Tumor Genomics group focuses on human tumor susceptibility. Par-ticular focus of interest has been hereditary colorectal cancer (CRC), where the group has contributed to several key discov-eries. Molecular background events in microsatellite unstable CRC is one of our long term interests. We have also identified a novel cancer predisposition syndrome, hereditary leiomyoma-tosis and renal cell cancer (HLRCC), and the gene (FH) underly-ing the disease. In addition, we have identified germline muta-

tions in the AIP gene in pituitary adenoma predisposition, and subsequently developed molecular tools for diagnosis of the condition.

The rapid advances in genomic technologies are now enabling whole genome analysis of individuals and cancers. Whole-exome and -genome sequencing will finally allow thor-ough dissection of germline and somatic genetic variation con-tributing to neoplasia. An excellent example of the power of these methods is our discovery of MED12 as a key mutational target in uterine leiomyomas. Future general goals of the field will be: 1) Identification of high/moderate-penetrance cancer predisposition conditions, and the respective susceptibility genes 2) Characterization of common variants in cancer sus-ceptibility. 3) Characterization of mutatomes of all clinically rel-evant tumor types. Registry-based approaches are central for us in obtaining the study materials, in particular in search for high/moderate penetrance predisposition genes.

Group leader

Lauri A. AaltonenMD, PhD Academy Professor Genome Scale Biology Research Program, Department of Medical Genetics, Biomedicum Helsinki

e-mail: [email protected]

Development of sequence data processing pipeline and analysis tools is part of the activities in tumor Genomics lab. The figure illustrates a view of lab’s own data analysis software (Rikurator).

Selected publications MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Mäkinen N, Mehine M, Tolvanen J, Kaasinen E, Li Y, Lehtonen HJ, Gentile M, Yan J, Enge M, Taipale M, Aavikko M, Katainen R, Virolainen E, Böhling T, Koski TA, Launonen V, Sjöberg J, Taipale J, Vahteristo P, Aaltonen LA. Science 2011;334:252–255.

The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signal-ing. Tuupanen S, Turunen M, Lehtonen R, Hallikas O, Vanharanta S, Kivioja T, Björklund M, Wei G, Yan J, Niittymäki I, Mecklin JP, Järvinen H, Ristimäki A, Di-Bernardo M, East P, Carvajal-Carmona L, Houlston RS, Tomlinson I, Palin K, Ukkonen E, Karhu A, Taipale J, Aaltonen LA. Nat Genet 2009;41:885–890.

Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TM, Salmela PI, Paschke R, Gündogdu S, De Menis E, Mäkinen MJ, Launonen V, Karhu A, Aaltonen LA. Science 2006;312:1228–1230.

Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell can-cer. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomäki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA; Multiple Leiomyoma Consortium. Nat Genet 2002;30:406–410.

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Molecular Genetics

Metapopulation Research Development and implementation of genetic tools for

the study of genetic variation in natural populations of non-model species

Sequencing of the genome and the transcriptome of the Glanville fritillary butterfly

Development of Glanville fritillary system as a popu-lation biological model by adding genomics and molecular genetics to existing ecological research

Background Our flagship project is the long-term study (since 1991) of ecological, genetic and evolutionary spatial dy-namics in the Glanville fritillary butterfly, inhabiting a network of 4,000 meadows in the Åland Islands in Finland. This large metapopulation has become an internationally recognized model system for the study of population biological and micro-evolutionary consequences of habitat loss and fragmentation. Recently, rapid development of genomics methods has ena-bled their use in the study of non-model organisms.

Recent progress and aims The aim of the current research in the Metapopulation Research Group (MRG) is to investigate the genetic basis of phenotypic variation, life history traits and population dynamic parameters in populations inhabiting het-erogeneous environments. We have previously found signifi-cant associations of molecular variation in the phosphoglucose isomerase gene (Pgi) with these traits. We have sequenced the transcriptome of the Glanville fritillary and have recently com-pleted the sequencing of the 400 Mb genome with next-gener-

ation methods. The genomics and genetic methods developed in the butterfly project have been applied in other projects in MRG, such as in the study of coevolution of plant- fungal path-ogen system and evolutionary radiation of Malagasy dung bee-tles.

The future goals the Glanville fritillary project include: 1) Complete the analysis of the genome, including the genetic map, and make it publicly available through the Ensembl ge-nome browser. 2) Design genotyping assays for large-scale variation analyses, including thousands of samples and thou-sands of markers. 3) Complete sequencing of up to 300 RNA samples from 7 populations living in different kinds of environ-ments to study variation in gene expression and allelic varia-tion within and between populations. 4) Indentify genetic loci and variants which contribute to phenotypic and life history traits and construct a pedigree using genetic and spatial infor-mation for the large natural metapopulation.

Group leader

Ilkka HanskiDPhil, Academy ProfessorDepartment of Biosciences

e-mail: [email protected]

Volcano plots highlighting expression differences in unfolded protein response and proteasome genes in relation to the age of local populations of the Glanville fritillary and the peak flight metabolic rate of individual butterflies. Note that the same sets of highlighted genes are highly expressed in both data sets, supporting the ecological results which show that butterflies with high flight metabolic capacity are overrepresented in newly-established local populations (from Wheat et al., 2011).

Selected publicationsTemperature treatments during larval development reveal exten-sive heritable and plastic variation in gene expression and life

history traits. Kvist J, Wheat CW, Kallion-iemi E, Saastamoinen M, Hanski I, Frilan-der MJ. Mol Ecol 2012; Epub Mar 19.

Functional genomics of life history variation in a butterfly metapopula-tion. Wheat CW, Fescemyer HW, Kvist J, Tas E, Vera JC, Frilander MJ, Hanski I, Marden JH. Mol Ecol 2011;20:1813–1828.

Eco-evolutionary spatial dynamics in the Glanville fritillary butterfly. Hans-ki IA. Proc Natl Acad Sci USA 2011;108: 14397–14404.

Rapid transcriptome characterization for a nonmodel organism using 454 pyrosequencing. Vera JC, Wheat CW, Fescemyer HW, Frilander MJ, Crawford DL, Hanski I, Marden JH. Mol Ecol 2008; 17:1636–1647.

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Molecular Genetics

Gene-culture Co-evolution in Music

Identification of genetic variants that contribute to sound perception in music

The effect of music on gene expression

The effect of music exposure in the environment (lis-tening, education) on genetic profiles

Background Music perception and performance are com-prehensive human cognitive functions and thus provide an ex-cellent model system for studying human behavior and brain function. However, the molecules involved in mediating music perception and performance are so far largely unknown. Musi-cal aptitude is sensory perception, an ability to understand and perceive rhythm, pitch, timbre, tone duration and formal struc-ture in music. In terms of evolution listening to music can be considered as producing and interpreting sounds that are uni-versal to humans and other mammals. Musical aptitude needs music as a trigger from the environment to develop thus offer-ing an ideal model to study the gene-environment interaction in man. Listening to music doesn’t require practice. Infants are naturally interested in music and their musical receptive skills appear very early when the environmental exposure is negligi-ble suggesting that interest in music is an inborn property of human beings. Musical ability varies between individuals, and seems to be expressed at the population level in such a way that both extremes (extremely capable/incapable individu-als) are rare and the majority of individuals express moderate ability. This is a typical feature of a complex trait influenced by several underlying genes with varying effects, environmental factors.

The progress and aims To elucidate molecular background of sensory perception in man by characterization of genetic and expression profiles associated with music perception. Up till now, 98 Finnish pedigrees composed of 792 participants have participated in the study. We have shown that musical aptitude defined by three tests, the auditory structuring ability test (the Karma Music test) and Carl Seashore’s pitch and time discrimination subtests, has high heritability in Finnish multi-generational families. Data about environmental exposure to music has been collected using web-based questionnaire. High music test scores in the Finnish families are significantly as-sociated with creative functions in music. Significant evidence for linkage with musical aptitude at 4q22 (LOD 3.33.) together with additional loci with suggestive evidence was identified, suggesting that musical aptitude is associated with several predisposing genetic variants. Genetic architecture of musical aptitude is further dissected using genome wide scan of 730K SNPs and gene expression profiling. The data will be combined with the data obtained from environmental exposure to music in large Finnish pedigrees to study gene-gene and gene-envi-ronment interactions.

The group is interested also in other genetic variants asso-ciated with neuronal function including genetic variants in au-tism spectrum disorders and intellectual disability.

Group leader

Irma JärveläMD, PhD Associate professor Department of Medical Genetics

email: irma.jarvela@)helsinki.fiwebsite: http://www.hi.helsinki.fi/music/english/index.htm

Genome wide scan of musical aptitude in Finnish families.

Selected PublicationsGenetic and functional analyses of SHANK2 mutations provide evidence for a multiple hit model of autism spectrum disorders. Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, Konyukh M, Chaste P, Ey E, Rastam M, Anckarsäter H, Nygren G, Ståhlberg O, Gillberg IC, Melke J, Toro R, Regnault B, Fauchereau F, Mer-cati O, Lemière N, Skuse D, Poot M, Holt R, Järvelä I, Kantojärvi K, Van-hala R, Curran S, Collier D, Bolton P, Chiocchetti A, Klauck SM, Poustka

F, Freitag CM, Bacchelli E, Minopoli F, Maestrini E, Mazzone L, Ruta L, Sousa I, Vicente A, Oliveira G, Pinto D,Scherer S, Zeleni-ka D, Delepine M, Lathrop M, Guinchat V, Devillard F, Assouline B, Mouren MC, Leboyer M, Gillberg C, Boeckers TM ,Bourgeron T. PLoS Genet 2012;8:e1002521.

Association of the arginine vasopressin receptor 1A (AVPR1A) haplotypes with listening to music. Ukkola-Vuoti L, Oikkonen J, Onkamo P, Karma K, Raijas P, Järvelä I. J Hum Genet 2011;56:324–329.

Linkage and Candidate Gene Studies of Autism Spec-trum Disorders in European Populations. Holt R, Barnby G, Maestrini E, Bacchelli E, Brocklebank D, Sousa I, Mulder E, Kantojarvi K, Järvelä I, Klauck S, Poustka F, Bailey AJ, Monaco AP and the EU Autism MOLGEN Consortium. Eur J Hum Genet 2010;18:1013–1019.

Musical aptitude is associated with AVPR1a haplotypes. Ukkola L, Onkamo P, Karma K, Raijas P, Järvelä I. PLoS ONE 2009;4:e5534.

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Molecular Genetics

Complex Diseases The general, long-term aim of our group is

to understand the functions, molecular pathways and pathogenetic mechanisms of susceptibility genes in a number of complex disorders, such as asthma, dyslexia and psoriasis

We work also to understand gene expression at the beginning of life, in oocytes, zygotes and early embryos up to the 8-cell stage

Background Biochemical and functional characterization of the newly implicated genes provide exciting new challenges, as it becomes possible to consider pathways and gene net-works in normal physiology and in complex disorders. We combine genomic and biochemical approaches, such as high-throughput sequencing of genomes, exomes and RNA as well as cell models, protein analyses and bioinformatics, aiming at systems-level understanding of the regulatory networks and pathogenetic processes. We collaborate widely with research-ers of complementary backgrounds in clinical sciences, neuro-biology, neuroimaging, reproduction, and computer science.

Recent progress and aims After a decade of gene mapping efforts, since 2003 we have successively identified susceptibil-ity genes for the complex diseases of asthma (NPSR1), dyslexia (DYX1C1, ROBO1, DCDC2, C2Orf3, MRPL19, CYP19A1) and other disorders as well as studied a psoriasis candidate gene (CCH-

CR1). We have moved to study the functional aspects of the newly implicated pathways and engineered relevant cell and mouse models. We have adopted advanced methods, such as single-cell transcriptome sequencing to work on scarce sam-ples and advanced cell models.

Selected publicationsSwedish population substructure revealed by genome-wide sin-gle nucleotide polymorphism data. Salmela E, Lappalainen T, Liu J, Sistonen P, Andersen PM, Schreiber S, Savontaus ML, Czene K, La-hermo P, Hall P, Kere J. PLoS ONE 2011;6:e16747.

Increased expression of the dyslexia candidate gene DCDC2 af-fects length and signaling of primary cilia in neurons. Massinen S, Hokkanen M-E, Matsson H, Tammimies K, Tapia-Paez I, Dahlström-Heuser V, Kuja-Panula J, Burghoorn J, Jeppsson KE, Swoboda P, Pey-rard-Janvid M, Toftgård R, Castrén E, Kere J. PLoS ONE 2011;6:e20580.

Multiple polymorphisms affect expression and function of the Neuropeptide S Receptor (NPSR1). Anedda F, Zucchelli M, Schepis D, Hellquist A, Corrado L, D’Alfonso S, Achour A, McInerney G, Bertorel-lo A, Lördal M, Befrits R, Björk J, Bresso F, Törkvist L, Halfvarson J, Kere J, D’Amato M. PLoS ONE 2011;6:e29523.

The zebrafish transcriptome during early development. Vester-lund L, Jiao H, Unneberg P, Hovatta O, Kere J. BMC Dev Biol 2011;11:30.

Group leader

Juha Kere ProfessorKarolinska Institutet, Stockholm, SwedenFolkhälsan Institute of Genetics, HelsinkiResearch Programs Unit, Biomedicum Helsinki

email: [email protected], [email protected]

Rat hippocampal neurons transfected with the human dyslexia susceptibility gene DCDC2 construct (green) show DCDC2 pro-tein in the primary cilium (arrow). (From Massinen et al., 2011)

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Molecular Genetics

Canine Genomics Genetic characterization of various morphological,

behavioral and disease traits in dogs and replication of the risk variants in human patient cohorts

GWA, exome and whole genome sequencing, canine DNA bank (40 000 samples, 250 breeds)

Background Our approach takes advantage of an experi-ment initiated by man ~15,000 years ago, taming of the wolf and, more recently, generating 400 inbred dog breeds. Canine purebreeding has resulted in highly uniform genomes within each breed, in which the “noise” of background genetic varia-tion is reduced making it easier to detect genetic “signals” that contribute to disease. As a result 10 to 100-fold fewer individu-als are needed to map genes for a polygenic trait. Aggressive breeding has resulted in extreme phenotypic and behavioral diversity as well as an enrichment of hundreds of natural ge-netic disorders, which are biologically analogous to human disorders. Dogs provide a unique opportunity for genetic dis-coveries that have significant impact on general biology and human medicine.

Recent progress and aims We have established a large Dog DNA bank (>40 000 samples from 250 breeds) and utilized this resource to successfully identify novel loci or genes for epi-lepsy, ataxia, skeletal, vision and autoimmune disorders. These discoveries have revealed disease pathways, provided new candidate genes for human disorders, and enabled the devel-opment of DNA tests for breeding purposes. Our new ERCStG-funded project (DOGPSYCH) aims to identify novel genetic and environmental risk factors predisposing to canine anxiety. This project may contribute to the molecular understanding of hu-man obsessive-compulsive, panic and general anxiety disor-ders.

Selected publicationsLGI2 Truncation Causes A Remitting Focal Epilepsy in Dogs. Sep-pälä EH, Jokinen TS, Fukata M, Webster MT, Karlsson EK, Kilpinen S, Steffen F, Dietschi E, Leeb T, Eklund R, Xiaochu Z, Rilstone J, Lindblad-Toh K, Minassian BA, Lohi H. PLoS Genet 2011;7:e1002194. (Highlight-ed in “Disease models and mechanisms” Journal, 2011, p. 558.)

Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex. Wilbe M, Jokinen P, Truvé K, Seppälä E, Karlsson E, Biagi T, Hughes A, Bannasch D, Andersson G, Hansson-Hamlin H, Lohi H, Lindblad-Toh K. Nat Genet 2010;42:250-254.

Identification of the canine hairless mutation reveals an essen-tial role for FOXI3 in ectodermal development. Drögemuller C, Karlsson EK, Hytönen MK, Perloski M, Dolf G, Sainio K, Lohi H, Linblad K, Leeb T. Science 2008;321:1462.

Expanded repeat in canine epilepsy. Lohi H, Young EJ, Fitzmaurice S, Rusbridge C, Chan EM, Vervoort M, Turnbull J, Ianzano L, Paterson AD, Sutter N, Ostrander EA, Andre C, Shelton DG, Ackerley CA, Scherer SW, Minassian BA. Science 2005;307:81. (Highlighted in the Kids Sum-mary in the same issue.)

Group leader

Hannes LohiPhD, ProfessorDepartment of Veterinary Biosciences, Faculty of Veterinary MedicineResearch Programs Unit, Molecular Medicine, Faculty of Medicine

email: [email protected]

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Molecular Genetics

Hereditary Cancer; Genetic and Epigenetic Mechanisms of Cancer Predisposition

Search for novel predisposing genes and mechanisms for hereditary/familial cancer

Use Lynch syndrome as a model to dissect genetic and epigenetic mechanisms of common cancers

Targeted and global analyses of constitutional & can-cer genomes and epigenomes from clinical cases

Background We use familial/hereditary forms of common cancers as tools to study the mechanisms of cancer predispo-sition, initiation and progression in hereditary and sporadic settings. The rationale is that hereditary cancers provide short-cuts to the identification of genes and mechanisms that turn out to be important in sporadic cancers as well. Clinical enti-ties we focus on include Hereditary Non-Polyposis Colorectal Cancer (comprising Lynch syndrome and Familial colorectal carcinoma, type X), familial polyposis syndromes, and familial endometrial carcinoma. The basis of cancer susceptibility is

unknown in one-third of clinically typical families and in a ma-jority of less typical families representing the syndromes men-tioned above. Apart from gene mutations, we focus on mecha-nisms that may change gene function without altering the DNA sequence itself (epigenetic changes). Such changes may occur at all stages of cancer development, including hereditary tumor predisposition.

Recent progress and aims Funded by the European Re-search Council (AdG 232635, “Epigenome and Cancer Sus-ceptibility”) we aim to provide a synthesis of interactions be-tween the major players in common human cancers, covering endogenous (inherited susceptibility) and exogenous (dietary) causes of cancer, the genome and epigenome as targets, and most major anatomic sites of adult cancer. This is achieved by using the human hereditary multi-organ cancer syndromes Lynch syndrome and Familial adenomatous polyposis and their murine counterparts, the Mlh1+/– mouse and the ApcMin/+ mouse, as models for multistep tumorigenesis. Predisposed individuals are enrolled in life-long surveillance programs and specimens taken in the course of screening allow for the re-constitution of the natural histories of the cancers afterwards. Our ultimate aim is to use information of clinical and family characteristics, germline alterations (epigenetic, genetic), and changes observed in somatic cells (epigenetic, genetic, cell phenotypic) to predict cancer risk and thereby enable appro-priate counseling and efficient cancer prevention in high-risk individuals.

Group leader

Päivi PeltomäkiMD, PhDProfessor in Biomedical Cancer ResearchDepartment of Medical Genetics, Haartman Institute

e-mail: [email protected]

Design (A) and outcome (B) of methylation-specific multiplex ligation-dependent probe amplification assay to study methyla-tion at microRNA-associated CpG islands. (From Pavicic et al., 2011)

Selected publicationsEpigenetic signatures of familial cancer are characteristic of tumor type and family category. Joensuu EI, Abdel-Rahman WM, Ollikainen M, Ruosaari S, Knuutila S, Peltomäki P. Cancer Res 2008; 68:4597–4605.

Large genomic rearrangements and germline epimutations in Lynch syndrome. Gylling A, Ridanpää M, Vierimaa O, Aittomäki K, Avela K, Kääriäinen H, Laivuori H, Pöyhönen M, Sallinen S-L, Wall-gren-Pettersson C, Järvinen HJ, Mecklin J-P, Peltomäki P. Int J Cancer 2009;124:2333–2340.

BMPR1A mutations in hereditary nonpolyposis colorectal cancer without mismatch repair deficiency. Nieminen TT, Abdel-Rahman WM, Ristimäki A, Lappalainen M, Lahermo P, Mecklin J-P, Järvinen HJ, Peltomäki P. Gastroenterology 2011;141:e23–e26.

Altered methylation at microRNA-associated CpG islands in he-reditary and sporadic carcinomas: MS-MLPA-based approach. Pavicic W, Perkiö E, Kaur S, Peltomäki P. Mol Med 2011;17:726–735.

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Molecular Neuroscience

Neurobiology Molecular, cellular and network mechanisms of

neuronal signalling: focus on interactions among GABAergic transmission, plasmalemmal ion-regulatory proteins and trophic factors

Translational work on epileptiform syndromes, with an emphasis of early-life progression of disease states based on novel animal models

Design of therapies of epileptiform syndromes based on manipulation of brain pH

Background Mechanisms of GABAergic transmission and on the role of ion-regulatory proteins (IRPs) in the control of neu-ronal excitability and of network functions both in vitro and in vivo have revealed an amazing versatility of IRP functions (cf. Figure). Our team uses a wide spectrum of electrophysiological techniques (patch clamp, field recordings, invasive EEG, ion-sensitive microelectrodes) and live-cell imaging, molecular bio-logical techniques, and methods for human studies (e.g. full-band EEG technique originally developed by this team). Kaila’s HI is 48, and the number of citations in 2011 is >750.

Recent progress and aims IRPs are not only responsible for neuronal chloride and pH homeostasis, but some IRPs act as structural proteins that sculpt neuronal morphology, including

KCC2 which is involved in the formation of dendritic spines in cortical neurons. This multifunctionality of IRPs has major im-plications in brain functions and plasticity, including neonatal and adult epilepsies where KCC2 interacts with BDNF/TrKB signalling and with the Ca2+-dependent protease, calpain, in an age-dependent manner. Another major branch of research is on the neuronal carbonic anhydrase isoform VII which has unique properties in the control of neuronal pH and, again, morphology. Knowledge gained from basic research on brain pH regulation has led to promising novel therapies of epilepti-form syndromes of the developing and adult human brain with clinical work already in progress and expanding.

Selected publicationsCation-chloride cotransporters and neuronal function. Blaesse P, Airaksinen MS, Rivera C, Kaila K. Neuron 2009;61:820–838.

Experimental febrile seizures are precipitated by a hyperther-mia-induced respiratory alkalosis. Schuchmann S, Schmitz S, Rivera C, Vanhatalo S, Mackie K, Sipila ST, Voipio J, Kaila K. Nat Med 2006;12:817–823.

The K-Cl cotransporter KCC2 renders GABA hyperpolarizing dur-ing neuronal maturation. Rivera C., Voipio J., Payne J.A., Ruusuvuori E., Lahtinen H., Lamsa K., Saarma M., Kaila K. Nature 1999;397:251–255.

Postsynaptic fall in intracellular pH induced by GABA-activated bicarbonate conductance. Kaila K., Voipio J. Nature 1987;330:163–165.

Group leader

Kai KailaPhD, ProfessorDepartment of Biosciences and Neuroscience Center

e-mail: [email protected]

Cation-chloride cotransporter (CCC) functions are regulated by transcriptional control, alterna-tive splicing, subcellular targeting and post-translational modifications which lead to neuron age and type-specific as well as distinct subcel-lular protein expression patterns. Upper panels, transcriptional control of the K-Cl cotransporter isoform KCC2, and alternative splicing of KCC2 and the Na-K-2Cl cotransporter NKCC1, where the various splice variants have binding sites for distinct kinases. Lower panel left shows an example of subcellular targeting of NKCC1 into the axon and of KCC2 into dendritic shafts and spines. Lower panel right shows that expres-sion levels of plasmalemmal functional CCCs are influenced by the rate of insertion from exocytotic vesicles and removal by endocytotic vesicles. Kinases (e.g. PKC) can modify CCC function by influencing the relative rates. There is little evidence (indicated by a question mark) for direct modulation of the intrinsic (catalytic) rate of ion transport by neuronal CCCs. The ex-pression patterns of CCCs are strongly modified during neuronal development, plasticity and trauma, and they are likely to contribute to both disease-promoting and protective mechanisms. (Modified from Blaesse et al., 2009.)

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Molecular Neuroscience

Molecular Neuroscience Characterization of signalling, biology and therapeutic

potential of novel neurotrophic factors CDNF and MANF

Investigations on the structure and biology of GDNF family ligands and their receptors

Development of new therapeutic strategies for the Parkinson’s disease

Background Neurotrophic factors (NTFs) are smalls secretory proteins that control the number of neurons in development and in adult organisms regulate neuronal plasticity and protect neurons against injury. Classical NTFs have shown therapeutic potential in animal experiments, but only modest clinical ben-efits have been obtained so far. Therefore we search for new neurotrophic factors that can more specifically and efficiently protect and repair degenerating neurons in neurodegenerative diseases.

Recent progress and aims We have recently discovered a new mammalian NTF – cerebral dopamine neurotrophic factor (CDNF) and found that it can protect and repair midbrain do-pamine (DA) neurons in animal models of Parkinson’s disease (PD) more efficiently and specifically than any other known NTF. CDNF and its homologous protein MANF have unique 3-di-menstional structure and they act on neurons differently from other NTFs. In the coming years we will test the therapeutic po-tential of CDNF and its fragments in different models of PD. We have recently developed CDNF and MANF knockout mice and found that CDNF-deficient mice have sensory deficits and prob-lems in the gastrointestinal and in the midbrain DA systems. We will mainly focus on the analysis of the DA system of the CDNF and MANF mutant mice. Another NTF, glial cell line-de-rived neurotrophic factor (GDNF) supports the survival of mid-brain DA neurons and has strong therapeutic potential for the treatment of PD. We have recently discovered syndecan-3 as a new GDNF receptor and to study the biological role of GDNF and its receptor GFRα1 we have developed mice with condi-tionally deleted GDNF and GFRα1 alleles, as well as hypermor-phic conditional GDNF knock-in mice. In the coming years we will analyse in detail the role of GDNF and GFRα1 in the devel-opment and maintenance of DA neurons.

Selected publicationsNovel neurotrophic factor CDNF protects and rescues midbrain dopaminergic neurons in vivo. Lindholm, P, Voutilainen MH, Lau-rén J, Peränen J, Leppänen V-M, Andressoo J-O, Lindahl M, Janhunen S, Kalkkinen N, Timmusk T, Tuominen RK, Saarma M. Nature 2007;448: 73–77.

KCC2 interacts with the dendritic cytoskeleton to promote spine development. Li H, Khirug S, Cai C, Ludwig A, Blaesse P, Ko-likova J, Afzalov R, Coleman SK, Lauri S, Airaksinen MS, Keinänen K,

Khiroug L, Saarma M, Kaila K, Rivera C. Neuron 2007;56,1019-1033.

Characterization of the intracellular lo-calization, processing and secretion of two GDNF splice isoforms. Lonka-Nevalaita L, Lume M, Leppänen S, Jokitalo E, Peränen J, Saarma M. J Neurosci 2010; 30:11403–11413.

Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin and artemin. Bespalov MM, Sidorova Y A, Tumova S, Ahonen-Bishopp A, Magalhães AC, Kuless-kiy E, Paveliev M, Rivera C, Rauvala H, Saarma M. J Cell Biol 2011;192:153–169.

Group leader

Mart SaarmaPhD, Academy ProfessorResearch Program in Developmental Biology, Institute of Biotechnology

email: [email protected]

Structure of CDNF-MANF family of neurotrophic factors.Left: CDNF and MANF are secre-tory proteins. They contain the signal sequence (Pre) that is cleaved off cotranslationally and the mature proteins with eight conserved cysteines (yellow verti-cal bars) are about 160 amino acids long. Right: Crystal and NMR structure of CDNF and MANF show that the proteins contain saposin-like N-terminal domain (blue) and SAP-protein like C-terminal domain (green).

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Molecular Neuroscience

FinMIT – Molecular Pathology of Mitochondrial Disease

Our aim is to understand causes and consequences of mitochondrial dysfunction in disease, and to develop diagnostics and treatment for mitochondrial disorders

We apply the mechanisms identified in single-gene disordes to general mechanisms of e.g. neurodegen-eration and obesity

We utilize wide methodology from next generation sequencing to molecular and cellular biology, protein biochemistry and modelling

Background Mitochondrial disorders are the most common cause of inherited neurodegeneration and metabolic disease in children and adults. The disorders are typically progres-sive, and can manifest at any age, in any tissue, with any in-heritance model. The childhood-onset disorders often lead to early death, and adult-onset disorders vary in severity from catastrophic epilepsy to cardiomyopathy, myopathy, ataxia, or parkinsonism. The basis of tissue-specificity of these disorders, involving basic energy metabolism, is not known.

Recent progress and aims By novel next-generation se-quencing methodology we have identified novel genes and disorders: AARS2 mutations in early-infantile or prenatal car-diomyopathy and TK2 in late-onset mitochondrial myopathy (Götz et al., 2011; Tyynismaa et al., Hum Mol Genet 2012).

We have identified pathophysiological consequences of mitochondrial disease: oxidative ATP production defect in skel-etal muscle initiates a starvation response, signalled to the whole organism by secreted myokine FGF21. This mechanism is conserved in human patients, making FGF21 a novel diag-nostic biomarker for muscle respiratory chain deficiency (Hum Mol Genet 2010a; Lancet Neurology 2011). We proposed that mixed nutrient sensing signalling may participate in progres-sion of mitochondrial disease (Cell 2012) and indicated that type of nutrition may modify the disease progression (Hum Mol Genet 2010b).

We showed that in mitochondrial premature aging model, mtDNA mutation accumulation affects the somatic stem cell pool, underlying the progeroid symptoms. This dysfunction was shown to be caused by subtle production of oxygen radi-cals or modified redox environment, due to mitochondrial dys-function (Ahlqvist et al., 2012 / Cell Metab 2012).

Group leader

Anu Wartiovaara (née and in publications Suomalainen)

MD, PhDSigrid Jusélius Professor of Clinical Molecular Medicine

email: [email protected]

Neural stem cell sphere, with dif-ferentiated neurons on the surface (green neurons, blue nuclei). The somatic stem cell functions are disturbed in prema-turely aging mice with mitochondrial DNA accumulation (Ahlqvist et al., 2012)

Selected publicationsMitochondria: in sickness and in health. Nunnari J, Suomalainen A. Cell 2012;148:1145-1159.

Somatic  progenitor cell vulnerability to mitochondri-al DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Ahlqvist KA, Hämäläinen RH, Yat-suga S, Uutela M, Terzioglu M, Götz A, Forsström S, Salven

P, Angers-Loustau A, Kopra O, Tyynismaa H, Larsson NG, Wartiovaara K, Prolla T, Trifunovic A, Suomalainen A. Cell Metab 2012;15:100–109.

FGF-21 as a biomarker for muscle-manifesting mito-chondrial respiratory chain deficiencies: a diagnostic study. Suomalainen A, Elo JM, Pietiläinen KH, Hakonen AH, Sevastianova K, Korpela M, Isohanni P, Marjavaara SK, Tyni T, Kiuru-Enari S, Pihko H, Darin N, Ounap K, Kluijt-mans LA, Paetau A, Buzkova J, Bindoff LA, Annunen-Rasila J, Uusimaa J, Rissanen A, Yki-Järvinen H, Hirano M, Tulinius M, Smeitink J, Tyynismaa H. Lancet Neurol 2011;10:806–818.

Exome Sequencing Identifies Mitochondrial Alanyl-tRNA Synthetase Mutations in Infantile Mitochondrial Cardiomyopathy. Götz A, Tyynismaa H, Euro L, Ellonen P, Hyötyläinen T, Ojala T, Hämäläinen RH, Tommiska J, Raivio T, Oresic M, Karikoski R, Tammela O, Simola KO, Paetau A, Tyni T, Suomalainen A. Am J Hum Genet 2011;88:635–842.

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Plant Biotechnology and Molecular Biology

Genetic Basis of Wood Development

Characterization of genetic mechanisms regulating specification and differentiation of vascular tissues in plants

Characterization of genetic mechanism regulating cell proliferation during vascular morphogenesis

Engineering of vascular morphogenesis and biomass

Background Vascular plants have a long-distance transport system consisting of two tissue types, phloem and xylem. Dur-ing root primary development, xylem is specified as an axis of two vessel element cell files, centrally located metaxylem and peripherally located protoxylem. During secondary develop-ment, secondary xylem (wood) is formed.

Recent progress and aims Using the genetic model Arabi-dopsis thaliana, we have recently identified AHP6, an inhibitory pseudophosphotransfer protein for cytokinin signaling as a spatially specific regulator facilitating protoxylem specification. Subsequently, we have identified two regulatory interactions

that regulate AHP6 and the xylem pattern. First, we have shown that cytokinin and auxin interact in a spatially specific manner during procambial development to specify the AHP6 pattern. Furthermore, in collaboration with Philip Benfey’s laboratory, we have shown that the miR165/6 species act non-cell autono-mously to regulate the differential gene dosage of the class III HD-ZIP genes, and thus the AHP6 pattern during protoxylem and metaxylem development. Finally, through identification of dominant mutations affecting callose biosynthesis, we have engineered a temporally and spatially controlled system to control plasmodesmatal trafficking during root procambial de-velopment. More recently we have also shown the relevance of the Arabidopsis derived information for cambial development in tree species (Populus and Betula).

Selected publications Callose Biosynthesis Regulates Symplastic Trafficking During Root Development. Vatén A, Dettmer J, Wu S, Stierhof Y, Roberts CJ, Yadav SR, Miyashima S, Campilho A, Bulone V, Lichtenberger R, Lehes-ranta S, Mähönen AP, Kim JY, Sauer N, Scheres B, Carlsbecker A, Gal-lagher KL, Helariutta Y. Dev Cell 2011;13:1144–1155.

Cell signaling by microRNA165/6 mediates gene dosage depen-dent root cell fate. Carlsbecker A, Lee J-Y, Roberts C, Dettmer J, Lehes-ranta S, Zhou J, Lindgren O, Moreno M, Honkanen A, Thitamadee S, Campilho A, Sebastian J, Bowman JL, Helariutta Y, Benfey PN. Nature 2010; 465:316–321

Cytokinin signaling and its inhibitor AHP6 regulate cell fate dur-ing vascular development. Mähönen AP, Bishopp A, Higuchi M, Nieminen KM, Kinoshita K, Törmäkangas K, Ikeda Y, Oka A, Kakimoto T, Helariutta Y. Science 2006;311:94–98.

APL regulates vascular identity in Arabidopsis. Bonke M, Thita-madee S, Mähönen AP, Hauser MT, Helariutta Y. Nature 2003;426:181–186.

Group leader

Yrjö HelariuttaPhDInstitute of Biotechnology, Department of Biosciences, Viikki Biocenter

email: [email protected]

The picture presents an Arabidopsis thaliana root five days post germination. The yellow signal represents cytokinin oxidase1 (CKX1) fused to YFP. The transgene was induced in the stele by oestrogen, under a promoter of a root specific cytokinin receptor CRE1. After a few days induction, the lowered cytokinin levels lead to formation of ectopix protoxylem cells inside the stele.

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Plant Biotechnology and Molecular Biology

Plant Stress Understanding how plants perceive and use reactive

oxygen species (ROS) to regulate defense signaling, programmed cell death and stomatal aperture

Identification of hormone(s) and transcription factors regulating wood development

Sequencing the birch genome to generate genetic resources for improved forestry management

Background Plants utilize sophisticated defence systems to overcome stresses imposed by biotic (e.g. pathogens and in-sects) and abiotic (e.g. extreme temperatures and air pollut-ants) factors. Many stresses trigger the production of reactive oxygen species, which function as important signaling mol-ecules in defence pathways. In order to understand the role of ROS in plants we use the model plant Arabidopsis thaliana and apply genetics combined with genomics, transcriptomics and protein biochemistry. In a parallel approach we study trees, an important source of renewable materials (wood, pulp, bioen-ergy). In particular we elucidate biological processes which are unique for trees, including overwintering and wood develop-ment. This has revealed a role for the stress hormone ethylene in wood development.

Recent progress and aims Elucidation of a series of ROS-sensitive mutants has identified several proteins intimately in-volved in plant ROS signaling and responses. The absence of extracellular ROS-responses in the slac1 mutant revealed im-paired stomatal anion channel activity and led to the identifi-cation of a long-sought-after plasma membrane anion channel.

The RCD1 protein is a novel type of transcription factor interact-ing protein that integrates multiple ROS signaling pathways in stress adaptation and development. Future work will elucidate the molecular mechanism underlying their function and role of RCD1 in driving specific changes in gene expression. Other mutants have identified several novel components in ROS signaling and perception which suggest previously unidenti-fied mechanisms. These include cytoplasmic and membrane-localized protein kinases and an extracellular protein, GRIM REAPER.

Our research on trees aims at identifying direct regulators of dormancy and wood development. In addition we are involved in sequencing the birch genome which will facilitate mapping genetic determinants of desired traits in this species. Together, these results will lead to improved resources for forest biotech-nology and management.

Group leader

Jaakko KangasjärviProfessorDepartment of Biosciences, Plant Biology

email: [email protected]

A.Ozone sensitive mutant after 24h ozone exposure (350ppb). B.CRK7 expression profile in planta after 24h ozone exposure (CRK7::GUS line). C.Expression of CRK7 in leaf tissues after 24h ozone exposure.

Selcted publicationsSLAC1 is required for plant guard cell S-type anion channel func-tion in stomatal signalling. Vahisalu T, Kollist H, Wang Y-F, Chan W-Y, Valerio G, Lamminmäki A, Brosché M, Moldau H, Desikan R, Schroeder JI, Kangasjärvi J. Nature. 2008;452:487–491.

Arabidopsis GRI is involved in the regu-lation of cell death induced by extracel-lular ROS. Wrzaczek M, Brosché M, Kol-list H, Kangasjärvi J. P Natl Acad Sci USA 2009;106:5412–5417.

Ethylene is an endogenous stimulator of cell division in the cambial meristem of Populus. Love J, Björklund S, Vahala J, Hertz-berg M, Kangasjärvi J, Sundberg B. P Natl Acad Sci USA 2009;106:5984–5989.

Chilling of dormant Populus buds hyper-induces FLOWERING LOCUS T and recruits GA -inducible 1,3-ß-glucanases to release dormancy and restore signal conduits. Rinne PLH, Welling A, Vahala J, Ripel L, Ru-onala R, Kangasjärvi J, van der Schoot C. Plant Cell 2011;23: 130–146.

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Biocentrum Helsinki Core Facilities

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Core Facilities

Biomedicum Flow Cytometry Core Facility (FACS Core Facility)

T he Biomedicum Flow Cytometry Core Facility has been run-ning at Biomedicum Helsinki 1 since January 2005. The facil-

ity has a total of around 80 users mainly from research groups at the University of Helsinki and Helsinki University Central Hospital at the Meilahti campus but also from other research institutes and the Viikki campus. The core facility is providing state-of-the art instrumentation for flow cytometric cell sorting and analyzing experiments. The experiments can be performed by the researcher or ordered as a service from the core facility personal. This service is unique at the campus. The core facility is supported by Biocentrum Helsinki.

EquipmentsThe FACS core facility in Biomedicum Helsinki harbours two FACS machines located in room B416b. A BD FACSAria IIu Cell Sorting System and a BD FACSArray Bioanalyser. The FACSAria IIu was updated May 2012, the instrument has three lasers (vi-olet 407 nm, blue 488 nm and red 633 nm) and the possibil-ity for multiple color analysis and sorting into desired format; tubes, plates, microscope slides.

The FACSArray has two lasers (yellow 532 nm and red 635 nm) providing a fast and sensitive system for analysis of pro-teins and cells in 96-well plate format.

The facility provides a computer with flow cytometric soft-wares for advanced data analyzes.

Services– Instrument training for new users– Experimental setup and analysis assistance– Sorting and analysis as ordered service

Selected publications using the core facility

Immune response is an important aspect of the anti-tumor effect produced by a CD40L-encoding oncolytic adenovirus. Diaconu I, Cerullo V, Hirvinen ML, Escutenaire S, Ugolini M, Pesonen SK, Bra-mante S, Parviainen S, Kanerva A, Loskog AS, Eliopoulos A, Pesonen S, Hemminki A. Cancer Res 2012; Mar 6, epub.

Mono/oligoclonal T- and NK-cells are common in chronic my-eloid leukemia patients at diagnosis and expand during dasat-inib therapy. Kreutzman A, Juvonen V, Kairisto V, Ekblom M, Stenke L, Seggewiss R, Porkka K, Mustjoki S. Blood 2010;116:772–782.

Expansion of highly differentiated CD8(+) T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalo-virus reactivation. Kreutzman A, Ladell K, Koechel C, Gostick E, Ek-blom M, Stenke L, Melo T, Einsele H, Porkka K, Price DA, Mustjoki S, Seggewiss R. Leukemia 2011;25:1587–1597.

Interferon alpha treated patients with chronic myeloid leukemia (CML) in prolonged complete remission have increased numbers of NK cells and clonal gamma-delta T cells, and a distinct plasma cytokine profile. Kreutzman A, Rohon P, Faber E, Indrák K, Juvonen V, Kairisto V, Vo-glóva J, Sinisalo M, Flochová E, Arstila P, Porkka K, Mustjoki S. PLoS One 2011;6:e23022.

DirectorNina Peitsaro, PhDInstitute of Biomedicine, Biomedicum Flow Cytometry Facility, Biomedicum Helsinki

Email: [email protected]: http://research.med.helsinki.fi/corefacilities/facs/

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Core Facilities

Biomedicum Functional Genomics Unit (FuGU)Genome Profiling– Transcript and miRNA expression profiling by four micro-

array systems (Affymetrix, Agilent, Illumina, Nimblegen)– Copy number profiling by arrayCGH – Next-generation sequencing (incl. library preparation,

template amplification, sequencing)– Data pre-processing and analyses for microarray

and NGS data– Nucleic acid extraction and QC

(Qubit, NanoDrop, Bioanalyzer)

Recombinant Virus Technologies– Lenti- and retroviral particles for gene silencing and expres-

sion (regular titer, concentrated)– Whole human and mouse genome TRC1 libraries,

tot. 159.000 shRNA constructs (3–5 per gene), provided as glycerol stock, DNA, or lentiviral particles

– Biosafety tests (p24, RCV)– Biosafety level 2 space for working with lentiviral particles

Biomedicum Functional Genomics Unit (FuGU) is a compre-hensive and state of the art functional genomics technology service provider in Meilahti campus of the University of Hel-sinki. The unit was established in 2006 as a center supporting functional genomics research in Helsinki area and nationwide. FuGU joins the operations of Biomedicum Biochip Center and Biomedicum VirusCore and is co-directed by Outi Monni (ge-nome profiling) and Juha Klefström (recombinant virus technol-ogies). FuGU is located in Biomedicum Helsinki 1 building at the Institute of Biomedicine and Research Programs Unit. The unit operates under the national Biocenter Finland infrastruc-ture network and is supported by both Biocentrum Helsinki and Biocenter Finland. In 2011, FuGU had customers from 73 different research groups from University of Helsinki, other Bio-center Finland Universities, Helsinki University Central Hospital, research institutes as well as non-academic groups/units. The annual turnover in 2011 was 0.5 M EUR.

ServicesFuGU provides a wide range of services related to functional genomics. These services cover areas such as genome profiling (microarrays and next-generation sequencing), computational analyses and virus mediated gene silencing and overexpres-sion. FuGU is also housing a genome-wide shRNA library that contains hairpins for 16,000 human and mouse genes each.

Selected publications from University of Helsinki affiliated groups using the core services

Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity. Partanen JI, Tervonen TA, Myllynen M, Lind E, Imai M, Katajisto P, Dijkgraaf GJP, Kovanen PE, Makela TP, Werb Z, Klefstrom J. P Natl Acad Sci USA 2012;109:E388-397.

Dual role of FoxA1 in androgen receptor binding to chromatin, an-drogen signalling and prostate cancer. Sahu B, Laakso M, Ovaska K, Mirtti T, Lundin J, Rannikko A, Sankila A, Turunen JP, Lundin M, Kon-sti J, Vesterinen T, Nordling S, Kallioniemi O, Hautaniemi S, Jänne OA. EMBO J 2011;30:3962-3976.

Comprehensive exon array data processing method for quantita-tive analysis of alternative spliced variants. Chen P, Lepikhova T, Hu Y, Monni O, Hautaniemi S. Nucleic Acids Res 2011;39:e123.

MicroRNA expression profiling reveals miRNA families regulating specific biological pathways in mouse frontal cortex and hippo-campus. Juhila J, Sipila T, Icay K, Nicorici D, Ellonen P, Kallio A, Korpe- Ellonen P, Kallio A, Korpe-Ellonen P, Kallio A, Korpe-lainen E, Greco D, Hovatta I . PLoS One 2011;6:e2149.

Directors

Outi Monni, PhDAcademy Research Fellow

Juha Klefström, PhDAcademy Research Fellow

Genome Scale Biology ResearchProgram, Institute of Biomedicine,Biomedicum Helsinki

email: [email protected],[email protected]

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Core Facilities

Biomedicum High Throughput Center (HTC)

Biomedicum Helsinki High Throughput Center (HTC), located in Biomedicum Helsinki 1 building, is a self-service facility

serving mainly the local research community in Meilahti cam-pus at the University of Helsinki. The HTC has been in operation since 2004 and is now operated jointly between Biocentrum Helsinki and the Institute for Molecular Medicine Finland FIMM. The equipment in the facility is suitable for performing chemi-cal, siRNA and related biochemical and cell-based screens in a semi-automated manner in 96- and 384-well format.

HTC users have access to a chemical collection of about 140 000 drugs and drug-like compounds and a library of 64 755 siRNAs mapping with 21 585 genes. The chemical col- 755 siRNAs mapping with 21 585 genes. The chemical col-755 siRNAs mapping with 21 585 genes. The chemical col-lections can be divided into two major classes, drugs and known bioactives, and chemical diversity libraries. The drugs and known bioactives are ideal for bio-logical profiling, drug repositioning and personalized medicine-type screens while the larger chemical diversity collections are best suited for molecular probe discovery screening. Through the co-operation with FIMM, researchers can get consultation and assistance on various aspects sur-rounding chemical biology and drug dis-

covery, such as assay development and optimization, as well as advice on screening and drug discovery strategies.

The HTC facility has more 60 registered users from almost 30 research groups. In year 2011 there were active users from 12 different research groups from the University of Helsinki and research companies. Training and project guidance are provid-ed to researchers free of cost through the Biocentrum Helsinki funding of the HTC, Biocenter Finland funding of staff in the High Throughput Biology unit at FIMM as well as FIMM internal funding.

FacilitiesAutomated liquid handling– Beckman Coulter Biomek FX with a 384 pipetting head– Beckman Coulter Biomek FXp with a 96 pipetting head– Hamilton STAR with 8 independently working channels– Thermo Scientific Multidrop Combi 8-channel 96/384

peristaltic dispenserPlate readers and cytometers– Perkin Elmer TopCount 12-detector 96/384 luminometer– 2 BMG Labtech Fluostar Optima fluorescence, luminescence

and absorbance plate reader– BD Biosciences FACSArray flow cytometer with blue 

(488 nm) and red (635 nm) lasers– TTP Labtech Acumen eX3 laser-scanning fluorescence

cytometerOther equipment– 2 ABI 9700 PCR machines, both with 384 Dual blocks– Essen BioScience Wound Maker tool, 96-well, for wound

healing experiments on automated, live-cell microscopy platforms such as the Essen BioScience IncuCyte at FIMM

LibrariesDrug and known bioactive collections– Microsource Spectrum collection (2 000 compounds)– ENZO FDA-approved library (640 compounds)– NIH Clinical Collection (450 compounds)– NIH NCI Library (2396 compounds)– Sigma Lopac collection (1280 compounds)– Tocriscreen Mini collection (1120 compounds)– FIMM Oncology set of approved and emerging investiga-

tional oncology drugs (ca. 300 compounds)Chemical diversity collections– ChemBridge DIVERset (20 000 compounds)– ChemBridge CNS-Set (10 000 compounds)– ChemDiv chemical diversity collections

(25 000 + 25 000 compounds)– ChemDiv Peptidomimetics collection (15 000 compounds)– Specs Consortium collection from (30 000 compounds)– Tripos diversity collection (6 000 compounds)siRNA collections– Ambion Silencer® Select Human siRNA Library V4

Selected publicationOncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses inpatients. Pesonen S, Diaconu I, Kan-ganiemi L, Ranki T, Kanerva A, Pesonen SK, Gerdemann U, Leen AM, Kairemo K, Oksanen M, Haavisto E, Holm SL, Karioja-Kallio A, Kaup-

pinen S, Partanen KP, Laasonen L, Joensuu T, Alanko T, Cerullo V, Hem-minki A. Cancer Res 2012;72:1621–1631.

Contact personAnna Lehto, Senior Laboratory Technician

Institute for Molecular Medicine Finland FIMM High Throughput Biology

Email: [email protected]

More informationWebsite: http://research.med.helsinki.fi/corefacilities/htc/default.htmFIMM: http://www.fimm.fi/en/technologycentre/

Anna Lehto

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Core Facilities

Biomedicum Imaging Unit (BIU)

Biomedicum Imaging Unit (BIU) is a core imaging facility providing imaging expertise and access to state-of-the-art

equipment for light microscopy and preclinical in vivo imaging applications. The BIU is located at the Biomedicum 1 build-ing on the Meilahti campus of the University of Helsinki, and is housed by the Institute of Biomedicine and the Research Programs. It currently operates within the Biocenter Finland’s Infrastructure Network and Technology Platforms, and receives additional infrastructure support from Biocentrum Helsinki, the Academy of Finland, and the University of Helsinki. During 2011, the unit provided services to 81 research groups and 195 individual researchers, corresponding to over 11 000 instru-ment hours, with an annual user fee turnover of over 100 K euro. The services offered are available for all researchers, ir-respective of their locations or affiliations.

Equipment HighlightsLight Microscopy Core

– Confocal and widefield live cell microscopy– Total internal reflection microscopy– Superresolution microscopy– Multiphoton and CARS microscopy– Cell based high content screening– Image deconvolution, modelling and analysis

In Vivo Core– Optical projection tomography– Intravital multiphoton microscopy– Preclinical in vivo fluorescence and bioluminescence

imaging– Magnetic resonance imaging

Services and equipmentThe BIU provides a comprehensive range of imaging services for both light microscopy and in vivo imaging activities. The equipment currently available at the BIU light microscopy core includes a number of confocal microscope scanners, fast widefield microscopes with live cell imaging capabilities, cells based high content screening platform, total internal reflection fluorescence (TIRF) microscope, stochastic optical reconstruc-tion microscopy (STORM) for sub-diffraction resolution, and a number of image post-processing workstations. The in vivo core offers optical projection tomography (OPT) for 3D recon-struction of embryos and model organisms, and two fluores-

cence and bioluminescence based preclinical molecular imag-ing systems. We also offer expertise in magnetic resonance imaging with a 155 mm-bore 4.7 Tesla MRI system capable of fast imaging of rodent models. We provide analysis and data services for user specific applications, and offer software plat-forms for image restoration and deconvolution, volume and surface reconstructions, and 3–4D animations of biological and biomedical image data.

Selected publications from University of Helsinki affiliated groups using BIU services

VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Tammela T, Zarkada G, Nurmi H, Jakob-sson L, Heinolainen K, Tvorogov D, Zheng W, Franco CA, Murtomäki A, Aranda E, Miura N, Ylä-Herttuala S, Fruttiger M, Mäkinen T, Eichmann A, Pollard JW, Gerhardt H, Alitalo K. Nat Cell Biol 2011;13:1202–1213.

KSHV-initiated Notch activation leads to membrane-type-1 matrix metalloproteinase-dependent lymphatic endothelial-to-mesen-chymal transition. Cheng F, Pekkonen P, Laurinavicius S, Sugiyama N, Henderson S, Günther T, Rantanen V, Kaivanto E, Aavikko M, Sarek G, Hautaniemi S, Biberfeld P, Aaltonen L, Grundhoff A, Boshoff C, Alitalo K, Lehti K, Ojala PM. Cell Host & Microbe 2011;10:577–590.

Donor simvastatin treatment abolishes rat cardiac allograft is-chemia/reperfusion injury and chronic rejection through micro-vascular protection. Tuuminen R, Syrjälä S, Krebs R, Keränen MA, Koli K, Abo-Ramadan U, Neuvonen PJ, Tikkanen JM, Nykänen AI, Lemström KB. Circulation 2011;124:1138–1150.

A photoconvertible reporter of the ubiquitin-proteasome sys-tem in vivo. Hamer G, Matilainen O, Holmberg CI. Nat Methods 2010; 7:473–478.

Core leadersBiomedicum Imaging Unit, Institute of Biomedicine, University of Helsinki

Elina Ikonen, MD, PhD, Academy Professoremail: [email protected]

Mika Hukkanen, PhD, Docentemail: [email protected]

Anthony Squire, PhD, Coordinatoremail: [email protected]

More information website: www.biu.helsinki.fi email: [email protected]

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Core Facilities

Biomedicum Stem Cell Centre (BSCC)

Provision of human pluripotent stem cells

Generation of patient-specific iPSC

Teratoma generation

Continuous visualization of live cells

Training

Services BSCC provides services related to human embryonic and in-duced pluripotent stem cells. These services include: provision of well-characterized human pluripotent stem cell lines upon request; high quality, reliable, and efficient reprogramming of patient specific cell lines using integrative (retroviruses) or non-integrative (Sendai viruses) methods; Teratoma genera-tion, a golden standard for demonstrating pluripotency of hu-man pluripotent stem cell lines; Live long-term visualization of cultured cells using Cell-IQ®, and tailored training packages for academic and industrial partners.

Description BSCC is a comprehensive provider of human pluri-potent stem cell services in Meilahti campus of the University of Helsinki. The unit was established in 2009 and is currently a part of the Biocenter Finland sponsored national infratructure platform for stem cells and biomaterials. BSCC is located at the 5th floor of the Biomedicum Helsinki 1 building within the Mo-lecular Neurology Research Program. The number of BSCC cus-tomers has steadily increased from 16 (2010) to 27 (2011). The annual turnover in 2011 was 30,000 EUR.

Core leader Timo Otonkoski, M.D., Ph.D.Professor of Human Stem Cell ResearchMolecular Neurology Research Program timo.otonkoski@helsinki

More informationhttp://research.med.helsinki.fi/neuro/[email protected]

Service provided

iPSC lines

Teaching (courses)

Hands-on training Teratoma

Customers: 10 5 11 5

– academic 9 5 6 5– non-academic 1 – 5 –Volume 98 5 11 52

lines courses individuals tumors

Flow-chart illustrating the use of iPSC

Mutation correction

Drug screening

Cell Replacement Therapy

Disease-specific functional analyses

Geno/phenotype correlations

Establishment of a differentiated cell/tissue model

Generation of iPSC

Genetically characterized patient cohorts

Selected publicationsA Defined and Xeno-free Culture Method Enabling the Establish-ment of Clinical-grade Human Embryonic, Induced Pluripotent and Adipose Derived Stem Cells. Rajala K, Lindroos B, Hussein S, Lappalainen RS, Pekkanen-Mattila M, Inzunza J, Miettinen S, Narkilahti S, Kerkelä E, Aalto-Setälä K, Otonkoski T, Suuronen R. Hovatta O, Skott-man H. PLOS One 2010;5:e10246.

The International Stem Cell Initiative (ISCI): Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat Biotechnol 2011;29:1132-1144.

Toward the defined and xeno-free differentiation of functional human pluripotent stem cell-derived retinal pigment epithelial cells. Vaajasaari H, Ilmarinen T, Juuti-Uusitalo K, Rajala K, Onnela N, Narkilahti S, Suuronen R, Hyttinen J, Uusitalo H, Skottman H. Mol Vis 2011;17:558–575.

iPSC can be generated from a variety of somatic cells lines.

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Core Facilities

DNA Sequencing and Genomics Laboratory (BIDGEN)

D NA sequencing and genomics laboratory (BIDGEN) is a multiplicinary core facility for genomics and functional

genomics lacated in the Viikki Campus of the University of Hel-sinki. Laboratory was founded 2008 by fusion of DNA sequenc-ing laboratory (founded 1990) and DNA microarray laboratory (founded 2000). Unit is belongs to the Genome Biology pro-gram in the Institute of Biotechnology. Laboratory is actively participating in two Biocenter Finland networks and is support-ed by both BF Finland and Biocentrum Helsinki. BIDGEN has a

wide customer base in University of Helsinki and other Biocent-er Finland universities and research institutes (MTT, VTT) and companies. The annual turnover is ca. 0.45 M €.

Service and technology highlights; Genomics and Metagenomics– Genome de novo sequencing and assembly

and resequencing (454, SOLiD, Illumina)– Metagenomics (16S, ITS and shot gun metagenomics

(454, SOLiD, Illumina) – Transcriptomics and other short read applications

(SOLiD and Illumina)– Sequencing and assembly of large clones

(fosmids, cosmids, bacs)– Amplicons sequencing (genes, exons, large PCR fragments)– Capillary sequencing (Sanger). MLST analysis and fragment

analysis (individual clones or 96–384 plate format)– Bioinformatics related to the above mentioned approaches

ServicesBIDGEN provides a wide range of services concentrating on DNA sequencing using first (capillary sequencers) second generation (454, SOLiD and Illumina) and third generation se-quencing technologies (Pac Bio). Our Sanger services vary from single PCR fragment analysis to large clone library sequencing projects. Using the second generation sequencing approaches we are providing genome sequecing both re-seqeucing and de novo sequencing for small bacterial genomes until large complex eukaryotic genomes. We also perform metagenome sequencing both targeted (16S, ITS) and shot gun metagen-ome sequencing. We perform RNA seq etc. functional genom-ics assays performed on our short read platforms (SOLiD and Illumina). We have the robotics machinery enabling growing and rearranging large clone libraries and isolation of DNA from plasmid libraries and tissue samples in 96 well format.

Selected publications from University of Helsinki affiliated groups using BIDGEN services.

Proteomic and transcriptomic characterization of bile stress re-sponse in Lactobacillus rhamnosus GG. Koskenniemi K, Laakso K, Koponen J, Kankainen M, Greco D, Auvinen P, Savijoki K, Nyman TA, Surakka A, Salusjärvi T, de Vos WM, Tynkkynen S, Kalkkinen N, Var-manen P. Mol Cell Proteomics 2011;10:2.

Comparison of dorsocervical with abdominal subcutaneous adi-pose tissue in patients with and without antiretroviral therapy-associated lipodystrophy. Sevastianova K, Sutinen J, Greco D, Siev-ers M, Salmenkivi K, Perttilä J, Olkkonen VM, Wågsäter D, Lidell M,

Enerbäck S, Eriksson P, Walker UA, Auvinen P, Ristola M, Yki-Järvinen H. Diabetes 2011;60:1894–1900.

Temperature treatments dur-ing larval development reveal extensive heritable and plastic variation in gene expression and life history traits. Kvist J, Wheat CW, Kallioniemi E, Saasta-moinen M, Hanski I, Frilander MJ. Mol Ecol 2012;doi: 10.1111/j.1365–294X. 2012.05521.x

Environmental biodiversity, human microbiota and allergy are interrelated. Hanski I, von Hertzen L, Fyhrquist N, Koskinen K, Torppa K, Laatikainen T, Karisola P, Auvinen P, Paulin L, Mäkelä MJ, Vartiainen E, Kosunen TU, Alenius H, Haahtela T. P Natl Acad Sci USA 2012;in press.

Petri Auvinen, PhD, Laboratory director, [email protected]

Lars Paulin, MSc, Laboratory engineer, [email protected]

Website: http://www.biocenter.helsinki.fi/bi/dnagen/index.htmStreet address: Viikinkaari 4, Helsinki.

Tecan robot

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Core Facilities

Electron Cryo-Microscopy Facility (CryoEM)

T he Biocenter Finland National Electron Cryo-Microscopy Unit is a comprehensive state of the art core facility in the

Viikki campus of the University of Helsinki, located in the In-stitute of Biotechnology, Biocenter 1. The unit was established in 2004 with support from Biocentrum Helsinki. Its mission is to support imaging and structural biology research in the Hel-sinki area. In 2010, it formed a consortium with the Electron Microscopy Units in Helsinki University and in Oulu University to provide a national technology platform in electron micros-copy under the umbrella of Biocenter Finland for academic and industrial users. The Electron Cryo-Microscopy facility brings three-dimensional visualization of macromolecular complexes to subnanometer resolution. It is directed by Sarah Butcher and is currently funded by Biocenter Finland. In 2011, the unit examined over 500 samples from Helsinki University, Turku University, Tampere University, VTT, Aalto University, as well as international customers. The unit runs regular training courses for beginners and advanced users, with 4 such courses in 2011, one of which was in conjunction with Aalto University.

Instruments and servicesThe service provides detailed project planning and assess-ment, based on over 20 years experience, optimizing the chances of success. Aqueous samples are vitrified to maintain their native hydrated state using a Leica vitrification robot ca-pable of temperature and humidity control. The samples are

then imaged in either an FEI tecnai 12 or an FEI tecnai F20 transmission electron microscope using Gatan 626, Gatan 914 (high tilt tomography) or Oxford CT3500 cryoholders. Both microscopes are equipped for data collection digitally and on film. Computational support and access to the necessary pro-grams are given on three-dimensional image reconstruction and electron tomography in order to generate high-resolution three-dimensional models.

Director: Prof. Sarah Butcher, Institute of Biotechnology and Biocentrum Helsinkiemail: [email protected]

Laboratory Engineer: Pasi Laurinmäki, pasi-laurinmä[email protected]

Research Assistant for external projects: Eevakaisa Vesanen, [email protected]

Systems Analyst: Veli-Pekka Kestilä, [email protected]

Website: http://blogit.helsinki.fi/butcher/cryoem.htmHELSINGIN YLIOPISTO

HELSINGFORS UNIVERSITETUNIVERSITY OF HELSINKI

Electron cryomicroscopy

INSTITUTE OF BIOTECHNOLOGY

CONTACT:http://blogit.helsinki.fi/butcher/cryoem.htm

Unit director: Prof. Sarah [email protected]

Technician: Eevakaisa [email protected]

IT specialist: Veli-Pekka Kestilä[email protected]

Electron cryomicroscopy (Cryo-EM) is a state-of-the-art imaging method best suited to thestudy of biological macromolecular complexes and other electron-beam sensitive materialsin aqueous solutions. It is used for characterizing particles that are ~10 to 300 nm indiameter.The data can be used with image processing software to make three-dimensional models.Depending on the approach used, subnanometer resolution can be achieved. Cryo-EM issuitable for projects in e.g. structural biology, nanotechnology, time-resolved assembly andphase transitions.

Interaction of alphaVbeta3 and alphaVbeta6 integrins with human parechovirus 1.Seitsonen J, Susi P, Heikkilä O, Sinkovits RS, Laurinmäki P, Hyypiä T, Butcher SJ.J Virol. 2010 Sep;84(17):8509-19.

Electron cryotomography of Tula hantavirus suggests a unique assembly paradigm for enveloped viruses.Huiskonen JT, Hepojoki J, Laurinmäki P, Vaheri A, Lankinen H, Butcher SJ, Grünewald K.J Virol. 2010 May;84(10):4889-97.

Molecular mechanisms of membrane deformation by I-BAR domain proteins.Saarikangas J, Zhao H, Pykäläinen A, Laurinmäki P, Mattila PK, Kinnunen PK,Butcher SJ, Lappalainen P.Curr Biol. 2009 Jan 27;19(2):95-107.

Measurements,statistical analyses

Single particle averaging,3D reconstruction

Electron cryotomography,3D reconstruction

FEI Tecnai F20200 kV TEM

Selected publications where the core services has been utilized

Bacteriophage Φ6 nucleocapsid surface protein 8 interacts with virus-specific membrane vesicles containing the major envelope protein 9. Sarin LP, Hirvonen J, Laurinmäki P, Butcher SJ, Bamford DH, Poranen MM. J Virol 2012;86:5376-5379.

Three-dimensional cryoEM reconstruction of native LDL particles to 16Å resolution at physiological body temperature. Kumar V, Butcher SJ, Öörni K, Engelhardt P, Heikkonen J, Kaski K, Ala-Korpela M, Kovanen PT. PLoS ONE 2011;6:e18841. doi:10.1371/journal.pone.0018841.

Production and characterization of virus-like par-ticles and the P domain protein of GII.4 norovi-rus. Koho T, Huhti L, Blazevic V, Nurminen K, Butcher SJ, Laurinmäki P, Kalkkinen N, Rönnholm G, Vesikari T, Hytönen VP, Kulomaa MS. Journal of Virological Methods 2011;doi:10.1016/j.jviromet.2011.05.009.

Cationic amphiphilic star and linear block copoly-mers: synthesis, self-assembly and in vitro gene transfection. Alhoranta A, Lehtinen J, Urtti A, Butcher SJ, Aseyev V, Tenhu H. Biomacromolecules 2011;12:3213-3222.

Flyer produced by the unit for Biocenter Finland outreach days.

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Core Facilities

Finnish Biological NMR Center

NMR spectroscopy is a method for characterization of struc-tures, interactions and dynamics of molecules from carbo-

hydrates to proteins. The Finnish Biological NMR Center (FB-NMR) is a state-of-the-art research infrastructure that provides full-range of services related to structural and functional stud-ies of biomolecules in solution state. FBNMR was established in 2001 by MinEdu and belongs to the national Biocenter Fin-land (BF) infrastructure network and is supported by Biocen-trum Helsinki and BF. The mission of FBNMR is to provide the state-of-the-art NMR instrumentation, methodology and exper-tise for the use of research groups in the fields of molecular biology, biotechnology and molecular medicine. In 2011, our services were used by 28 research groups from Helsinki area and other Biocenters/Universities in Finland, as well as indus-trial parties. The facility, located in Biocenter 3 building at the

Institute of Biotechnology in Viikki campus, houses four high-resolution, top-level NMR spectrometers. The 800 MHz system is the only one in Finland.

ServicesBiomolecular NMR studies are often regarded as structure de-termination of proteins. Fortunately, NMR can go far beyond by enabling studies of features that characterize function of a pro-tein e.g., protein dynamics and molecular interactions also in the case of weak binding. Remarkably, NMR based interaction studies do not require development of a system specific assay.

We provide several levels of service1. Collection of NMR data2. Data analysis (e.g., structure determination)3. Turn-key approach, including production and purification of

isotopically labeled samples in E. coliSpecific services may include e.g.:• ProductionofisotopicallylabeledsamplesinE. coli for NMR

studies• Structuredeterminationofproteins,protein-ligandcom-

plexes or other biomolecules• Characterizationofdisorderedproteins• StudiesofproteindynamicsandH/Dexchangeatresidue

level (timescales ps �� days)• Protein-ligandinteractions(Kd range pM–mM)• Bindingsite/epitopemapping• Kineticsandthermodynamicsofbinding• DeterminationofresiduespecificpKa’s,excitedstates,

tautomeric states, hydrodynamic radius

Selected publications using the core services

Diversity in prokaryotic glycosylation: An archaeal-derived N-linked glycan contains legionaminic acid. Kandiba L, Aitio O, Helin J, Guan Z, Permi P, Bamford D, Eichler J, Roine E. Mol Microbiol 2012;in press.

Neurotrophic factor MANF has a unique mechanism to rescue ap-optotic neurons. Hellman M, Arumäe U, Yu L-y, Lindholm P, Peränen J, Saarma M, Permi P. J Biol Chem 2011; 286:2675–2680.

Protein analysis by 31P-NMR spectroscopy in ionic liquid: Quan-titative determination of enzymatically created cross-links. Monogioudi E, Permi P, Filpponen I, Lienemann M, Li B, Argyropoulos D, Buchert J, Mattinen M-L. J Agr Food Chem 2011;59:1352–1362.

Characterization of intrinsically disordered prostate associated gene (PAGE5) at single residue resolution. Hellman M, Tossavainen H, Rappu P, Heino J, Permi P. PLoS One 2011;6:e26633.

DirectorPerttu Permi, PhDAcademy Research FellowProgram in structural biology & biophysics, Institute of BiotechnologyEmail: [email protected]

More informationWebsite: www.biocenter.helsinki.fi/bi/nmr/permi

A model of a six immuno-globulin-like domain fragment of filamin A built using residual dipolar couplings

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Core Facilities

Genome Biology Unit (GBU)

T he Genome Biology Unit (GBU) is a node of the Genome-Wide Methods (GWM) technology service platforms provid-

ing its services nationwide. The unit was established 2010 as a continuation of the yeast two-hybrid core-facility and currently locates at the Institute of Biotechnology, Viikki. GBU’s main activity is to maintain and distribute genome-scale reagents involving the ORFeome collection, which contains 14 000 ORF clones (open reading frame clones) in Gateway-based entry vectors, and the MGC (Mammalian Gene Collection) clone col-lection, which contains 21 000 full-length cDNAs in various vectors. In addition, we maintain and distribute knockdown li-braries, which are in-house generated shRNA libraries against ca. 2500 human and mouse genes. In 2011 GBU initiated Gateway-based cloning service from clones available in the

ORFeome collection. For cloning we have numerous Gateway destination vectors available enabling expression of a gene of interest in yeast, bacterial and mammalian cells. Since 2011, 30 research groups have used GBU’s services from the University of Helsinki and other Biocenter Finland Universities.

Service highlights– Maintenance and distribution of genome scale reagents:– ORFeome collection and Mammalian Gene Collection (MGC)– In-house generated knockdown libraries

Gateway-based cloning service:Enables expression of genes of interest in yeast, bacterial and mammalian cells

Value for scientists: Reduced costs, rapid delivery, easy access and screening pos-sibilities

DirectorTea Vallenius, MD, PhDInstitute of BiotechnologyEmail: [email protected]

More informationWebsite: http://www.biocenter.helsinki.fi/bi/gbu/Email: [email protected]

Contact person: Niina Roine, MSc

Selected publications where the GBU services has been utilized

An association between NUAK2 and MRIP reveals a novel mechanism for regulation of actin stress fibers. Valle-nius T, Vaahtomeri K, Kovac B, Osiceanu AM, Viljanen M, Mäkelä TP. J Cell Sci 2011;124:384–393.

Interactions with M-band titin and calpain 3 link myospryn (CMYA5) to tibial and limb-girdle muscular dystrophies. Sarparanta J, Blandin G, Charton K, Vihola A, Marchand S, Milic A, Hackman P, Ehler E, Richard I, Udd B. J Biol Chem 2010;285:30304–30315.

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Core Facilities

GM Mouse Unit of the Laboratory of Animal Center

Gene modified (GM) mouse models are one of the most im-portant research tools in biomedical and basic research.

GM mouse unit helps researchers in the different phases of gene modified mouse research. Services provided include transgenic mouse production, knock-out/knock-in mouse pro- knock-out/knock-in mouse pro-duction, embryo and sperm cryopreservation, mouse strain re-covery and conversion of mouse lines to specific pathogen free status.

GM mouse unit is located in the Viikki, Biocenter 2 building, but the unit operates also in Haartman-institute, Biomedicum and Ruskeasuo animal facilities. The unit is part of the national Biocenter Finland infrastructure network and is supported by both Biocentrum Helsinki and Biocenter Finland. In 2011, GM mouse unit had customers from 33 different research groups from University of Helsinki and other Finnish Universities.

Key services– Pronucleus injection– ES cell culture– Morula aggregation – Embryo and sperm cryopreservation– Mouse rederivation– In vitro fertilization

Selected publications using the core services

Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity. Partanen JI, Tervonen TA, Mylly-nen M, Lind E, Imai M, Katajisto P, Dijkgraaf GJ, Kovanen PE, Mäkelä TP, Werb Z, Klefström J. P Natl Acad Sci USA 2012;109:E388–397.

Somatic progenitor cell vulnerability to mitochondrial DNA mu-tagenesis underlies progeroid phenotypes in polg mutator mice. Ahlqvist KJ, Hämäläinen RH, Yatsuga S, Uutela M, Terzioglu M, Götz A, Forsström S, Salven P, Angers-Loustau A, Kopra OH, Tyynismaa H, Larsson NG, Wartiovaara K, Prolla T, Trifunovic A, Suomalainen A. Cell Metab 2012;15:100–109.

Cell-autonomous FGF signaling regulates anteroposterior pat-terning and neuronal differentiation in the mesodiencephalic do-paminergic progenitor domain. Lahti L, Peltopuro P, Piepponen TP, Partanen J. Development 2012;139:894–905.

Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin. Bespalov MM, Sidorova YA, Tumova S, Ahonen-Bishopp A, Magalhães AC, Kulesskiy E, Paveliev M, Rivera C, Rauvala H, Saarma M. J Cell Biol 2011;192:153–169.

DirectorPetra Sipilä, PhD, docentEmail: [email protected] GM mouse Unit Viikki

Laboratory Animal CenterUniversity of Helsinki

More informationWeb site: http://www.helsinki.fi/kek/KEK%20eng/index.htm

Email: [email protected]

Spermatozoa bound to the oocytePronucleus injection

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Core Facilities

Light Microscopy Unit (LMU)Imaging technologies and services– Confocal and multiphoton imaging of live and fixed samples– Wide field and TIRF imaging of live samples– Confocal and wide field high content imaging– FRET imaging (homoFRET and FLIM-FRET)– Diffusion analysis (FRAP and FCS)– Image analysis– Workstations, software, data storage and user training

The light microscopy unit provides high-end microscopy sys-tems together with related training, consultation and support services. All the equipment is available to all scientific and commercial users and the access to the instruments is provid-ed after initial user training. Larger projects, for example set-ting up new imaging or analysis methods, are accomplished ei-ther as scientific collaborations or provided with fee for service principle. LMU aims to be a facility for high-end data acquisi-

tion with a wide range of supported applications and to keep pace with developing imaging technologies.

The available instruments include a multiphoton and con-focal Leica SP5 microscope with lifetime imaging and fluores-cence correlation spectroscopy capability, two conventional (Leica SP2 & SP5) confocal microscopes as well as one high content capable Leica SP5 system. Additionally, a 3I Marianas TIRF microscope, a TILL imaging system, two Cell-IQ continu-ous cell culturing platforms, Cellomics CellInsight personal cell imager and four image analysis workstations are available. All microscopes are equipped for live cell imaging; further details can be found on our web page. We also provide backed-up data storage and cell culture facilities for our users.

The unit is a part of National Imaging Infrastructure Network of Biocenter Finland and a member of Helsinki Functional Im-aging Center, which is the umbrella organization for nonmedi-cal imaging in greater Helsinki area and European Light Micros-copy Initiative.

Selected publications using the core services

Active maintenance of nuclear actin by importin 9 supports tran-scription. Dopie J, Skarp KP, Rajakylä EK, Tanhuanpää K, Vartiainen MK. P Natl Acad Sci USA 2012;109(9):E544–552.

Callose Biosynthesis Regulates Symplastic Trafficking during Root Development. Vatén A, Dettmer J, Wu S, Stierhof YD, Miyashima S, Yadav SR, Roberts CJ, Campilho A, Bulone V, Lichtenberger R, Lehes-ranta S, Mähönen AP, Kim JY, Jokitalo E, Sauer N, Scheres B, Nakajima K, Carlsbecker A, Gallagher KL, Helariutta Y. Dev Cell 2011;21:1144–1155.

Pinkbar is an epithelial-specific BAR domain protein that gener-ates planar membrane structures. Pykäläinen A, Boczkowska M, Zhao H, Saarikangas J, Rebowski G, Jansen M, Hakanen J, Koskela EV, Peränen J, Vihinen H, Jokitalo E, Salminen M, Ikonen E, Dominguez R, Lappalainen P. Nat Struct Mol Biol 2011;18:902–907.

Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin. Bespalov MM, Sidorova YA, Tumova S, Ahonen-Bishopp A, Magalhães AC, Kulesskiy E, Paveliev M, Rivera C, Rauvala H, Saarma M. J Cell Biol 2011;192:153–169.

Directors

Kimmo Tanhuanpää, docent [email protected]

Maria Vartiainen, docent [email protected]

Cell Biology Program, Institute of Biotechnology

More informationWebsite: www.biocenter.helsinki.fi/bi/lmu/General contacts: [email protected] of the core: Biocenter 1C5, Viikki campus

Maria VartiainenKimmo Tanhuanpää

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Core Facilities

Meilahti Clinical Proteomics Core Facility

T he BCH Unit at the Meilahti Medical Campus Area of the University of Helsinki in is a state-of-the-art core facility de-

voted to basic – and clinically oriented proteomics. With strong support of its staff being trained to work within clinical prot-eomics and patient samples, its ideal location in the heart of the largest Medical Campus in the Country with over 800 sci-entists devoted to work almost entirely in medical research, the Unit provides all necessary support for clinical proteomics projects from bedside to the laboratory. In addition to compre-hensive proteome analyses the Unit provides consultation and project planning linked to medical sample collection and anal-ysis for the national and international research community and industry. The Unit provides large scale services in liquid chro-matography-mass spectrometry (LC-MS/MS) analysis on 1D – and 2D – LC platform as well as sophisticated gel electropho-resis technologies. Label free and isotope labeled quantitation is also offered. Mass spectrometry Imaging (IMS) technology is one of the new special services offered for comprehensive spatial proteome/peptidome/lipidome tissue analysis. The Unit is a member of three COST (European Cooperation in Sci-ence and Technology) actions for MS-Imaging, protein synthe-sis and kidney – and urine proteomics, providing constant and ongoing education to the Unit personnel. In the end of 2011 the Unit finished its own software development for fully auto-mated glycoproteomics analysis which will be used in 2012 in

the new Biocenter Finland funded clinical glycoproteomics ser-vice and technology platform. The Unit provides in addition to technical services education to seven national (or local) gradu-ate schools (The Finnish National Graduate School for Neuro-sciences, The Helsinki Biomedical Graduate School, The Helsin-ki Graduate School for Biotechnology and Molecular Biology, The Viikki Graduate School for Molecular Biosciences, The Na-tional Graduate School for Nanosciences, The National Gradu-ate School for Material Sciences and the National Glycoscience Graduate School). Four lecture – and hands-on courses for na-tional - and international students are organized by the Clinical Proteomics Unit and 8 lectures are given on courses organized by third parties on the yearly basis. International courses are organized e.g. on glycoproteomics and IMS technology. A new training school has been initiated in 2011 for the International Master Program for Medicine at the Medical Faculty, University of Helsinki.

Selected publications using the core services

Caloric restriction ameliorates angiotensin II-induced mitochon-drial remodeling andcardiac hypertrophy. Finckenberg P, Eriksson O, Baumann M, Merasto S, Lalowski MM, Levijoki J,Haasio K, Kytö V, Muller DN, Luft FC, Oresic M, Mervaala E. Hypertension 2012;59:76-84.

Recognition of Porphyromonas gingivalis Gingipain Epitopes by Natural IgM Binding to Malondialdehyde Modified Low-density Lipoprotein. Turunen P, Kummu O, Harila K, Veneskoski M, Soliymani R, Baumann M, Pussinen P, Hörkkö S. PLoS ONE 2012;10.1371/journal.pone.0034910

Analysis of myotilin turnover provides mechanistic insight on the role of myotilinopathy-causing mutations. Von Nandelstadh P, Soli-ymani R, Baumann M, Carpen O. Biochem J 2011;15;436:113-121.

Identification of proteins associated with ligand-activated estro-gen receptor alpha in human breast cancer cell nuclei by tandem affinity purification and nanoLC-MS/MS. Tarallo R, Bamundo A, Nassa G, Nola E, Paris O, Ambrosino C, Facchiano A, Baumann M, Ny-man T, Weisz A. Proteomics 2011;11:172–179.

Marc Baumann, Director Institute of Biomedicine/Biochemistry Biomedicum Helsinki Research Center Medical Faculty, University of Helsinki

Tel: +358919125200, Fax: +358919125206 Mobile: +358505671980

Email: [email protected] Website: http://research.med.helsinki.fi/corefacilities/proteinchem/default2.htm

Imaging (IMS) technology is one of the new special services offered for comprehensive spatial proteome/peptidome/lipidome tissue analysis.

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Core Facilities

Proteomics Unit

F or the past three decades the Protein Chemistry Core Facil-ity, under the supervision of Dr. Nisse Kalkkinen (retired June

2011), provided analyses for a large number of academic and industrial researchers and research groups.

In 2011, Dr. Markku Varjosalo was selected as a new Sys-tems Biology Research Group Leader as well as a Director of the Institute of Biotechnology (BI) Proteomics Unit. 

The unit operates under the national Biocenter Finland in-frastructure network of Proteomics and Metabolomics and is supported by both Biocentrum Helsinki and Biocenter Finland. In 2011, BI Proteomics Unit had customers from over 100 differ-ent research groups from University of Helsinki, other Biocenter Finland Universities, Helsinki University Central Hospital, re-search institutes as well as non-academic companies.

The main instrumentation of the Protemics Unit consists of:– 1D- and 2D-gel electrophoretic separation systems– Multiple different types of liquid chromatographic systems

(HPLC) with different protein and peptide separation parameters and columns

– An Applied Biosystems Procise 494 HT protein/peptide sequencer for N-terminal sequencing

– A MALDI-TOF/TOF mass spectrometer (Ultraflex TOF/TOF, Bruker Daltonics),

– Nano LC-ESI Q-TOF mass spectrometer (Applied Biosystems Qstar Elite, Applied Biosystems/Sciex)

– Top of the line, high performance nano LC-(H)ESI Orbitrap Elite Hybrid Mass Spectrometer (Thermo Scientific)

ServicesThe Proteomics Unit, that is located in Biocenter 3 in Viikki campus of University of Helsinki, continues to offer standard protein purifications, identifications and characterizations, but will also heavily focus on developing state-of-the-art omics-scale proteomic analyses. During the fall 2011, the Proteom-ics unit underwent major upgrades to the instrumentation and analysis software. The purchase of an Orbitrap Elite Hybrid Mass Spectrometer and label-free mass spectrometry data analysis softwares (e.g Progenesis, Nonlinear Dynamic) in-creases the sensitivity and specificity of our analyses and ena-bles us to offer a wide variety of completely new proteomics services.

Selected publications using the core services

Production and characterization of virus-like particles and the P domain protein of GII.4 norovirus. Koho T, Huhti L, Blazevic V, Nur-minen K, Butcher SJ, Laurinmäki P, Kalkkinen N, Rönnholm G, Vesikari T, Hytönen VP, Kulomaa MS. J Virol Methods 2012;179:1–7.

Nucleolar proteins with altered expression in leukemic cell lines. Teittinen KJ, Kärkkäinen P, Salonen J, Rönnholm G, Korkeamäki H, Vi-hinen M, Kalkkinen N, Lohi O. Leuk Res 2012;36:232–236.

Structural determinants of vascular endothelial growth factor-D receptor binding and specificity. Leppänen VM, Jeltsch M, Anisi-mov A, Tvorogov D, Aho K, Kalkkinen N, Toivanen P, Ylä-Herttuala S, Ballmer-Hofer K, Alitalo K. Blood 2011;117:1507–1515.

Proteomics and transcriptomics characterization of bile stress response in probiotic Lactobacillus rhamnosus GG. Koskenniemi

K, Laakso K, Koponen J, Kankainen M, Greco D, Auvinen P, Savijoki K, Nyman TA, Surakka A, Salusjärvi T, de Vos WM, Tynkkynen S, Kalk-kinen N, Varmanen P. Mol Cell Proteomics 2011;10:M110.002741.

Director, Markku Varjosalo, PhD Institute of Biotechnology

Website: http://www.biocenter.helsinki.fi/bi/protein/index.htmContact persons: Markku Varjosalo and Salla KeskitaloEmail: [email protected], [email protected]

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Core Facilities

Systems Biology Unit (SBU)

S ystems biology unit focuses on bioinformatics, experi-mental design, data analysis and interpretation. SBU is lo-

cated in Biomedicum Helsinki and it works closely with other cores, such as Biomedicum Functional Genomics Unit (coor-dinated by Juha Klefström and Outi Monni) and Genome Biol-ogy Unit (coordinated by Tea Vallenius). SBU is coordinated by Dr. Sampsa Hautaniemi, who is the coordinator for Biocenter Finland bioinformatics technology platform, which provides a large variety of bioinformatics services to the bioscience com-munity in Finland. Full list of services provided by SBU and bioinformatics network is available at http://www.biocenter.fi/index.php?page=bioinformatics. SBU also maintains and coor-dinates the bioinformatics helpdesk (http://bioinformatics.bio-center.fi/), which is the contact point for the Finnish research community in all matters concerning bioinformatics services.

Data analysis services– SNP, aCGH, gene, exon, methylation microarray data

analysis– Mass spectrometry data management & analysis– ChIP-seq, RNA-seq, exome/whole-seq data analysis– Image analysis

ServicesSystems biology unit (SBU) offers a wide variety of bioinfor-matics and computational analysis related services. These include high-throughput data analysis services (e.g., gene, exon, SNP, array-CGH, protein microarrays, mass spectrometry, high-throughput imaging, ChIP-seq and RNA-seq) and a data analysis infrastructure (Anduril; http://csbi.ltdk.helsinki.fi/an-duril/). The Anduril infrastructure is freely available for the Finn-ish research community (with training). The SBU also conducts customized projects such as identifying motifs, building web services, consultation in hiring bioinformaticians to groups be-longing to BCH.

Selected publications and patent for SBU services

Method for detection of autoimmune disease. Harri Salo, Jarno Honkanen, Outi Vaarala. US patent PCT/FI2009/050966.

Identification of a c-Jun N-terminal kinase 2 dependent signal amplification cascade that regulates c-Myc levels in Ras trans-formation. Mathiasen D, Egebjerg C, Khanna A, Daugaard M, Rafn B, Bøttzauw T, Friberg C, Tuomela S, Valo E, Willumsen B, Hautan-iemi S, Lahesmaa R, Westermarck J, Jäättelä M, Kallunki T. Oncogene 2012;31:390–401.

KSHV-Initiated Notch Activation Leads to Membrane-Type-1Ma-trixMetalloproteinase-Dependent Lymphatic Endothelial-to-Mes-enchymal Transition. Cheng F, Pekkonen P, Laurinavicius S, Sugiyama N, Henderson S, Gunther T, Rantanen V, Kaivanto E, Aavikko M, Sarek G, Hautaniemi S, Biberfeld P, Aaltonen LA, Grundhoff A, Boshoff C, Ali-talo K, Lehti K, and Ojala P. Cell Host & Microbe 2011;10:577–590.

NAV3 copy number changes and target genes in basal and squa-mous cell cancers. Maliniemi P, Carlsson E, Kaukola A, Ovaska K, Ni-iranen K, Saksela O, Jeskanen L, Hautaniemi S, Ranki A. Exp Dermatol 2011;20:926–931.

DirectorSampsa Hautaniemi, DTech, DocentAcademy of Science ResearcherGenome-Scale Biology Research Program

Email: [email protected]: http://www.ltdk.helsinki.fi/sysbio/

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Biocentrum Helsinki Viikki Metabolomics Unit (ViMU)

B iocentrum Helsinki Viikki Metabolomics unit (ViMU) is an established and functional service unit at Viikki campus of

the University of Helsinki. ViMU was initially established 2004 as a core facility by faculties of Biological and environmental sciences, and Pharmacy to provide metabolic profiling services for groups working on Viikki campus. The unit became an offi-cial core facility of BCH from beginning of 2008 with BCH fund-ing for personnel providing analytic services for the research community in Helsinki and nationwide. ViMU is specialized in plant metabolic profiling and provides services for the plant research community in Finland and abroad. Additionally the unit provides services for targeted and non-targeted analysis of microbial metabolites and analysis of drug metabolites. ViMU provides education in plant and microbial metabolomics both for the graduate students and researchers. The unit is located in Biocenter 2 building at Dept of Biosciences. ViMU is part of the Biocenter Finland ProtMet national infrastructure network supported by Biocentrum Helsinki and Biocenter Finland. In 2011 the number of academic groups using the services was 16, of these 14 from University of Helsinki, and 2 other domes-tic.

ServicesBCH Viikki Metabolomics unit has new state of the art equip-ment including QTOF (Waters Synapt G2, UPLC-QTOF/MS) and a GC-MS (Agilent 7890A GC – 7000 triple Quad MS) that be-came operational in March and April 2011, respectively. Thus, ViMU can provide a wide range of analytical services related to plant metabolic profiling initially focused on targeted profiling of central plant metabolites and hormones as well as both tar-geted and non-targeted analysis of microbial metabolites.

Analytical services available include UPLC-QTOF/MS analysis of:– Glucosinolates– Phenolic compounds– Cytokinins– Steroids– Synthesis productsGC-MS analysis of:– Plant hormones: auxin, jasmonic acid, abscisic acid, salicylic acid, gibberellic

acid and ethylene– Fatty acids– Sugars and sugar derivatives– Organic acids– Amino acids– Waxes

Selected publications from academic groups using Metabolomics unit services

Biotin deficiency causes spontaneous cell death and activation of defense signaling. Li J, Brader G, Helenius E, Kariola T, Palva ET. Plant J 2012 doi: 10.1111/j.1365–313X.2011.04871.x

Apoplastic reactive oxygen species transiently decrease auxin signaling and cause stress-induced morphogenic response in Arabidopsis. Blomster T, Salojärvi J, Sipari N, Brosché M, Ahlfors R, Keinänen M, Overmyer K, Kangasjärvi J. Plant Physiol 2011;157:1866–1883.

Regulatory subunit B’γ of protein phosphatase 2A prevents un-necessary defense reactions under low light in Arabidopsis thali-ana. Trotta A, Wrzaczek M, Scharte J, Tikkanen M, Konert G, Rahikainen M, Holmström M, Hiltunen H-M, Rips S, Sipari N, Mulo P, Weis E, von Schaewen A, Aro E-M, Kangasjarvi S. Plant Physiol 2011;156:1464–1480.

Determination of  steroids and their intact glucuronide conju-gates in mouse brain by capillary liquid chromatography-tandem mass spectrometry. Jäntti SE, Tammimäki A, Raattamaa H, Piep-Jäntti SE, Tammimäki A, Raattamaa H, Piep-ponen P, Kostiainen R, Ketola RA. Anal Chem 2010;82:3168–3175.

Directors

Professor Tapio Palva Department of Biosciences (09) 191 59600 [email protected] http://www.helsinki.fi/bioscience/plantgenetics/groupleader.htm

Professor Risto Kostiainen Division of Pharmaceutical Chemistry (09) 191 59134 [email protected] http://www.helsinki.fi/farmasia/pharmchemistry/index_eng.htm

More informationWebsite: http://www.helsinki.fi/bioscience/metabolomics/Contact person: [email protected]

Core Facilities

Tapio Palva Risto Kostiainen

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Biocentrum Helsinki in 2012 | 53

The graduate students in GPBM organized the FinBioNet International PhD Symposium

"5 Senses & Science" in November 2011

Helsinki Graduate Program in Biotechnology and Molecular Biology – GPBM

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G PBM is the international Ph.D. training program of Biocen-trum Helsinki. The research interests of the program cover

nearly all aspects of modern molecular biology ranging from molecular medicine and developmental biology to biophys-ics and systems biology. The graduate program is intended for four years of theoretical and practical studies culminating in academic dissertation. Students receive salary from the gradu-ate program, which also organizes courses and symposia. All teaching in these courses is in English. The student’s progress in his/her research project is closely monitored by a three-member thesis committee. The lectures and practical training courses aim at providing most up-to-date knowledge of mo-lecular biology, cell biology and biotechnology. A broad based training is purported to provide the students with a wide per-spective of their research area and enables them to utilize their training not only in academic science, but opens other pos-sibilities in career development, including industry and other biotechnological applications.

PhD Students and SupervisorsThe students are from different backgrounds of Biomedical and Life Sciences. The competition for admission is tough; the se-lection is carried out on the basis of previous merits of the stu-

dents, along with their dedication and enthusiasm towards sci-ence. There are currently some 50 graduate students enrolled in GPBM representing 13 different nationalities.

National CoordinationGPBM coordinates the Finnish Life Science Network of Gradu-ate Schools (FinBioNet), a national network of ~30 doctoral programs in seven universities. FinBioNet maintains job board for young scientists and coordinates research training collabo-ration between all Biocenters in Finland.

2011 HighlightsThe graduate students in GPBM organized the FinBioNet In-ternational PhD Symposium “5 Senses & Science” in Novem-ber 2011. Top international speakers with backgrounds in medicine, biology and technology covered different aspects on hearing, smell, sight, touch and taste.

The BiotechClub@GPBM student organisation linking sci-ence and industry organized a series of events for industry-curious students including a visit to Caltch BiotechCLub at the Californian institute of Technology,USA and biotech companies in San Diego. More about the club at: www.biotechclub.fi

More information at www.helsinki.fi/gpbm

Communications Officer Anita TienhaaraInstitute of Biotechnology

tel. +358-9-191 [email protected]

Scientific Coordinator Erkki RauloInstitute of Biotechnologytel. +358-9-191 [email protected]

Director Pekka Lappalainen

Institute of Biotechnologytel. +358-9-191 59499

[email protected]

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Biocentrum Helsinki in 2012 | 55

I was asked to write a few words about the Biocentrum Hel-sinki (BCH) start-up grant that, among others, I received this

year. I will start by thanking the Board of Biocentrum Helsinki for believing in me, and my research. My research is focused on discovering the essential cellular signaling networks medi-ated by protein kinases and phosphatases using systems bi-ology tools, proteomics and genomics. With the BCH support I could hire a graduate student and kick-start the project. We have now already mapped interacting partners for human pro-tein phosphatases and expect to get a first manuscript ready for submission to Nature by the end of the two-year BCH sup-port period.

For young group leaders, starting their own research group after their postdoctoral period abroad, these kind of funding in-struments are a necessity, and one cannot emphasize enough their importance. Unlike with many other research grants the Biocentrum Helsinki start-up grant funding decision comes ex-tremely fast and allows the research to start immediately. Eve-

ryone can understand that waiting as long as 18 months after applying funding can kill the career of any young scientist. This is especially a big problem for a scientist returning to Finland. Therefore there is a great demand for grants focusing on this highly important group of people, and getting them back.

Personally, I feel that an even bigger threat to Finnish sci-ence is that fewer and fewer people want to do their postdoc-toral period abroad. These visits should be encouraged more and more as the skills and contacts acquired during them are key to why Finnish science is so competitive. We need to get young people out of their comfort zone and out into the big world. This can be a bit frightening (I admit it was for me), but the rewards are also big. I learned so many things that I could not have learned in Finland and made new friends, many for life. And please remember, you can ALWAYS come back to Fin-land, and get funded by Biocentrum Helsinki.

Markku Varjosalo

Biocentrum Helsinki start-up grant recipients (2011–)

Ari Löytynoja PhDInstitute of BiotechnologyComputational Methods for Evolutionary and Comparative Sequence Analysis

Mikko AiravaaraPhD

Institute of BiotechnologyPhysiological and Therapeutic

Actions of Neurotrophic Factors in Ischemic Brain Injury

Henna Tyynismaa PhDBiomedicum Helsinki 1, Research Program of Molecular NeurologyMechanisms and Consequences of Mitochondrial Translation Defects

Tero-Pekka Alastalo MD, PhD

Biomedicum Helsinki 2, Pediatric Research Laboratory

Molecular Mechanisms Underlying the Pathogenesis of Pulmonary

Arterial Hypertension

Markku Varjosalo PhDInstitute of BiotechnologySystems Biology of the Kinome and Phosphatome

Bogac Kaynak PhD

Institute of BiotechnologyRegulation and Patterning of

Cardiac Chamber Morphogenesis

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Administration and Funding

Director Academy Professor Lauri Aaltonen, MD, PhD

The governing Board of Biocentrum HelsinkiThe governing Board has been appointed by the Rectors of the University and Aalto University until December 31, 2013, and it consists of the following members:

Chair:Academy Professor Lauri Aaltonen,

Faculty of Medicine

Vice-Chair:Academy Professor Mart Saarma,

Institute of Biotechnology

Other members:Professor Sarah Butcher,

Institute of Biotechnology

Academy Professor Elina Ikonen, Faculty of Medicine

Professor Jaakko Kangasjärvi, Faculty of Biological and Environmental Sciences

Professor Samuel Kaski, Aalto University

Professor Hannes Lohi, Faculty of Medicine and Faculty of Veterinary Medicine

Professor Heikki Mannila, Aalto University (Until 29th of February, 2012)

Professor Kaarina Sivonen, Faculty of Agriculture and Forestry

Professor Anu Wartiovaara, Faculty of Medicine

Administration

Funding of Biocentrum Helsinki in 2011–2012 Funding from the University of Helsinki 2 199 604 € in 2011 and 2 177 608 € in 2012

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Biocentrum Helsinki AdministrationCoordinatorHeli Lehtonen (until May 31, 2012)

Administration secretary Riitta-Smahl-El Hamraui

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Biocentrum Helsinki P.O.Box 63,

FI-00014 University of Helsinki, Finland

www.helsinki.fi/biocentrum, e-meil: [email protected]

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