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UNC-Chapel Hill Superfund Research ProgramAssessing biological responses to contaminantsAn introduction to epigenetics & the exposome
Same genes, different phenotypes
How?
Lesson: DNA Wrap-Packaging Matters
Learning Objectives
Define the make-up of chromatin Define epigenetics Describe DNA methylation as a
means of inhibiting transcription Evaluate impact of
environmental agent on gene expression (in mice)
Nucleotide(consists of a base, a 5-carbon sugar, and a phosphate group)
Hydrogen Bonds (between bases)
Phosphodiester Bond (between adjacent nucleotides)
Decondensed Chromatin
Condensed Chromatin
http://commons.wikimedia.org/wiki/File:Chromosome.gif
Genome vs epigenome
Genome Genes Hardware Static
Epigenome Accessibility to
genes Software Plastic
6
What is Epigenetics? Refers to changes in gene expression caused by
mechanisms other than changes in the underlying DNA sequence.
“The study of stable alterations in gene expression potential that arise during development and cell proliferation” (Nature).
Enables a cell/organism to respond to its dynamic external environment during development and throughout life!
The Epigenome at a Glance
Genetic Science Learning Center, University of Utah
Now it appears that our diets and lifestyles can change the expression of our genes. How? By
influencing a network of chemical switches within our cells collectively known as the epigenome.
NOVA’s Ghost in Your Genes (2006)
Epigenetic Mechanisms
1. DNA Methylation
2. Histone Modification
3. Small, non-coding RNAs (e.g., micro RNA)
10
2. DNA methylation The addition of methyl groups to DNA, mostly at
CpG sites, to convert cytosine to 5-methylcytosine.
SAMC G T A C A C G A C A C G A T
G C A T G T G C T G T G C T A
5’
5’
3’
3’
DNA methylation is preserved during DNA replication
DNA methylation leads to gene silencing
Promoter
TF
X Target gene not expressed
Target gene inactivated by DNA methylation
Promoter
TF Target gene expressed
Target gene expressed in normal cellNormal State
Epigenetic Modification
RNA pol
1) Changes to DNA Methylation leads to gene silencing
Promoter
TF
X Target gene not expressed
Target gene inactivated by hypermethylation
Promoter
TF Target gene expressed
Target gene expressed in normal cell e.g., tumor suppresor geneNorm
al State
Disease State arising from Epigenetic Modification
RNA pol
2) Changes to DNA Methylation leads to gene activation
Promoter
TF
X
Target gene expressed
Target gene activated by hypomethylation or demethylation
Promoter
TF
Target gene not expressed
Target gene silenced by methylation e.g., oncogeneNorm
al State
Disease State arising from Epigenetic Modification
RNA pol
HOW did these mice become different?
NOVA’s A Tale of Two MiceChapters 2 &3
In 2003, a research team at Duke discovered HOW changing the diet of Agouti yellow female
mice resulted in genetically identical offspring with altered
coat color distribution and disease susceptibility.
Agouti mouse model
?
Avy = Agouti Viable YellowDominant allele; paternally inheritedAllele is always expressed
a = mutant version of agouti gene
Genetically identical except for agouti gene
Environmental epigenomics and disease susceptibilityRandy L. Jirtle and Michael K. SkinnerNature Reviews Genetics 8, 253-262 (April 2007)http://www.nature.com/nrg/journal/v8/n4/fig_tab/nrg2045_F2.html
GeGenetically Identical Siblings
Epigenetic Variation
The most important effect of epigenetic marks – maybe their reason for existing – might be to wildly expand the number of
variant individuals in a population.
Michael Skinner, A New Kind of Inheritance (2014)
Environmental epigenomics and disease susceptibilityRandy L. Jirtle and Michael K. SkinnerNature Reviews Genetics 8, 253-262 (April 2007)http://www.nature.com/nrg/journal/v8/n4/fig_tab/nrg2045_F2.html
In this mouse model, a shift in coal color distribution indicates changes in epigenetic modifications.
TIME MAGAZINE, PERSON OF THE YEAR 2007
Dr. Jirtle's pioneering work in epigenetics and genomic
imprinting has uncovered a vast territory in which a gene
represents less of an inexorable sentence and more of an access
point for the environment to modify the genome.
Experiment: Does a maternal diet with soy influence expression of the agouti gene?
Female mice were fed genistein, the major phytoestrogen in soy, before and during pregnancy.
Shift in coat color distribution…
Genetically identical offspring exhibited varying coat colors.
Environmental epigenomics and disease susceptibilityRandy L. Jirtle and Michael K. SkinnerNature Reviews Genetics 8, 253-262 (April 2007)http://www.nature.com/nrg/journal/v8/n4/fig_tab/nrg2045_F2.html
50%
23%
Experimental results
Conclusions
Read the authors’ conclusions and with a partner discuss how these conclusions could be relevant for humans.
Genetic Science Learning Center, University of Utah
Conclusions
Our diet, especially during pregnancy, can influence our epigenome and ultimately determine our susceptibility to cancer and disease.
Genetic Science Learning Center, University of Utah
But nurture matters too. Many of the contingencies of life- what we eat,
what pollutants are in our environment, how often we are stressed –
affect how the genes operate.
Michael Skinner, A New Kind of Inheritance (2014)
30
Epigenetics and fetal development
“Epigenetics is being considered an important mechanism through which various stressors can operate. Many lines of evidence point to their being a special concern during rapid fetal development.”
Frederica Perera, Columbia Center for Children’s Environmental Health
Inheritance of Epigenetic modifications
Multigenerational
Inheritance from parent to progeny
Meiotic or transgenerational Inheritance by F3
offspring (rare; not documented in human studies to date)
Vinclozolin exposure and rats
To demonstrate transgenerational epigenetic inheritance researchers must:
Genetic Science Learning Center, University of Utah
• Rule out the possibility of genetic changes; and,
• Show that the epigenetic effect can pass through enough generations (F3 or great grandchild) to rule out the possibility of direct exposure.
Superfund Research ProgramUniversity of North Carolina at Chapel Hillhttp://www.sph.unc.edu/srp/Resources > For educators
Research Translation Core Dana [email protected](919) 843-5735
Contact Information
If time permits…
36
Imprinting
Genomic imprinting is a genetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner
It is an inheritance process independent of the classical Mendelian inheritance.
The first naturally occurring example of an imprinted gene was the discovery of imprinting in the IGF-2 gene in mice in 1991, and currently about ~150 imprinted genes have been identified in mice and humans.
37
DNA methylation & imprinting Imprinted genes
are inactive due to DNA methylation.
For imprinted genes, only one gene copy is active
http://learn.genetics.utah.edu
38
DNA methylation & imprinting Imprinted genes are protected from
reprogramming that occurs in zygote
http://learn.genetics.utah.edu
The Environment & Imprinted Genes
Environmental signals can affect the imprinting process during gamete development
Imprinted genes in the adult are sensitive to environmental signals (since only one gene copy is active)
Imprinting: an inheritance process independent of Mendelian inheritance
41
Why Imprint? The Genetic Conflict Hypothesis
Many imprinted genes are involved in growth and metabolism.
Often maternally and paternally imprinted genes work in the very same growth pathways. This conflict of interest sets up an epigenetic battle between the parents -- a sort of parental tug-of-war.
Randy L. Jirtle and Jennifer R. Weidman, 2007
Acetylation is the most highly studied
42
43
3. Non-protein coding RNAs short, non-coding RNAs
e.g., microRNAs
partially complementary to one or more mRNA molecules
post-transcriptional gene regulation, typically down regulation
44
1. Histone modification If the way that DNA is wrapped around the
histones changes, gene expression can change.
Histone Modification
http://ehp.niehs.nih.gov/wp-content/uploads/2012/09/WP_Focus_2_Title_web.png
Post-translational histone modifications