Although the role of histone acetylation in gene regulation has been the subject of many reviews, theirimpact on cell physiology and pathological states of proliferation, differentiation and genome stability ineukaryotic cells remain to be elucidated. Therefore, this review will discuss the molecular, physiological andbiochemical aspects of histone acetylation and focus on the interplay of histone acetyltransferases (HATs)and histone deacetylases (HDACs) in different disease states. Current treatment strategies are mostly limitedto enzyme inhibitors, though potential lies in targeting other imperative chromatin remodeling factorsinvolved in gene regulation.
Eukaryotic chromosomes are highly organized structures. Chroma-tin consists of DNA, histones and a plethora of different proteincomplexes that assist the dynamic changes occurring during DNAreplication, cell cycle progression, regulated-transcriptional and post-transcriptional events, DNA repair and recombination. The role ofreversible heritable changes in gene function that occur without achange in DNA nucleotide sequence has been explored in the lastdecade. Over the past fifteen years, it has been shown that geneexpression can be regulated by histone modulation [1,2]. Histoneproteins play structural and functional roles in all nuclear progressions.Although historically known as “packingmaterial” for nuclear DNA, theregulatory functions of histones were recently discovered in the early1990s. Nucleosomes are the basic structural units of chromatin and areevolutionarily conserved in all eukaryotes. The nucleosome coreparticles consist of two copies each of H2A, H2B, H3 and H4 histones,aroundwhich 146 base pairs of DNAarewrapped. TheH1 linker histonestabilizes the assembly of the octameric core into chromatin-specifichigher-order structures [3]. In addition to nucleosomes, the chromatinfiber contains a large variety of additional accessory proteins andnumerous histone variants that are not randomly distributed inchromatin but are expressed in developmentally constrained anddefinite cell type patterns [4].
Histonemodifications, including lysine acetylation andmethylation,serinephosphorylation and argininemethylation, playmajor regulatoryroles in transcriptional initiation and elongation, gene silencing andepigenetic cellular memory [5–7]. Such modifications provide a sourceof information that can be used as epigenetic marks for signaltransduction and cell dynamics.
Different combinations ofmodifications formulate a variety ofwordsendowedwithdifferent biologicalmeanings [8]. Apossible linkbetweenchromatin modifications and genetic regulation was acknowledged inearlier studies [9]. Moreover, evidence was reported that altered levelsof histone acetylation and methylation are allied with changes oftranscription rates [10–12].
Among these modifications, acetylation is well studied phenome-non [13]. The histones amino termini lysines undergo acetylation–deacetylation switches depending on the different physiologicalconditions [14]. The balance between these modifications is achievedthrough the action of enzymes dubbed histone acetyltransferases(HATs) and histone deacetyltransferases (HDACs). These specificenzymes catalyzes the transfer of an acetyl group from acetyl-CoAmolecules to the lysine″-amino groups on the N-terminal tails ofhistones [15]. Numerous activating factors possess a region dubbedbromodomain specifically interacting with acetylated lysine residues[16–19]. Histone acetylation supports the investiture of transcriptionfactors (TFs), and RNA polymerases to the promoter regions of gene[20] and initiate transcriptional activation. Following the discovery ofhistone acetylation [10], copious studies have shownvarious pattern ofmodification exists throughout thewhole eukaryotic genome [21–24].These studies also afford important support to the argument thatmechanisms, charge neutralization and recruitment of transactingfactors, are likely to be important [25]. The interplay between differentpatterns of modifications has been reviewed [26,27]. Nevertheless, thecausal relationship between residence in euchromatin and histoneacetylation has not yet been established.
2. Histone acetylation and transcriptional regulation
The perception of the molecular aspects of histone acetylation israpidly emerging. Acetylation of histones which occurs at lysineresidues and is catalyzed by HATs, is associated with activation ofgene transcription. Most HATs exist as multisubunit complexes invivo, as reviewed [28]. The complexes are typically more active thantheir respective catalytic subunits, the specificity of action being
ensured by their non-catalytic subunits [15]. These proteins aresupposed to be involved in other transcriptional function, particularlytheir large multiprotein complexes. These large complexes were alsoconsidered to guide the fate of the cell, either to proliferate ortransform into a specialized entity. The recruitment of HAT or HDACmultiprotein complexes on dimerization of Myc/Max or Mad/Max isresponsible for the regulation of cellular physiology by expression orrepression of growth stimulatory factors (Fig. 1), which further decidethe fate of the cell.
The acetylation state of different promoters is maintained byspecific combinations of HATs and HDACs; analyses accomplishedover large chromosomal domains indicating that the state ofacetylation is in a continuous genome-wide flux [29,30]. In terms ofcharge neutralization, acetylation and deacetylation, lysines regulatetranscription by manipulating the tightly packed heterochromatin tomore relaxed euchromatin state (Fig. 2). Acetylation of lysine residuesmight not merely alter chromatin structure but also provide uniquebinding surfaces for repressors and activators of transcription [22].Yeast and multicellular eukaryotes utilize similar molecular mechan-isms to link histone acetylation and transcriptional regulation butthey illustrate to contain a dissimilar ratio between permissive andrestrictive chromatin [31]. Deacetylation of histones, catalyzed byhistone deacetylases (HDACs), is also reported to be associated withgene silencing.
The very first indication of association between acetylation andtranscription came from the observation of Allfrey and co-workerswho proposed that in actively transcribed regions of chromatin,histones tend to be hyperacetylated, whereas in transcriptionallysilent regions histones are hypoacetylated [10]. Many additionalstudies have solidified this proposition by showing that hyperacety-lated core histones are associated with transcriptionally activechromatin [9,32,33]. Currently two independent lines of evidenceexist that suggest acetylation and transcription may be mechanisti-cally and physiologically related. First, altered patterns of transcrip-tion due to the mutation of H4 lysine residues have been reported inyeast. [34]. The other evidence is that the treatment of mammaliancells with effective inhibitors of histone deacetylase (trapoxin andtrichostatin A), resulted in over expression of a diversity of genes [35].However, after identification of the structure and function of a varietyof histone acetyltransferases and deacetylases the molecular mechan-isms of these processes became clearer. The interesting part of thesefindings is that numerous HATs and HDACs are proteins initiallycharacterized as being involved in transcriptional regulation. How-ever, it would be important to know whether the acetylation anddeacetylation of the H3 and H4 N-terminal tails help in mediatingbalance between cellular physiology. However, specific acetylationpatterns of histone tails may also help to recruit further modulators ofchromatin structure. If acetylation itself were to generate high-affinitybinding sites for HATs, propagation schemes could be envisaged[36,37].
3. Histone acetylation and its substrates
In spite of the fact that the various histone acetylases anddeacetylases can catalyze enzymatic reactions on histone substratesin vitro does not necessarily mean that histones are physiologicallyrelevant substrates in vivo. This issue is particularly imperative withrelevance to those enzymes that can acetylate non-histone proteins.P/CAF, TAF250, and p300 can efficiently acetylate the β subunit ofTFIIE, and both subunits of TFIIF can be acetylated by P/CAF and p300[38]. In addition, p300 can acetylate the p53 transcriptional activatorprotein, which results in a striking increase in specific DNA-bindingactivity [39]. In the case of these histone acetylases (and also ACTRand SRC-1), it has yet to be established, whether histones arephysiological substrates.
Fig. 1. Model depicting the role of histone acetylation in regulation of cellular development. (a).The heterodimerization of cell cycle regulatory factors Max with transcriptionalactivator Myc supports the formation of multiprotein complex and recruitment of histone acetyltransferase. Thereby, enhancing acetylation and accessibility of chromatin totranscription factors, which enhances the transcription. (b).The homodimerization of regulatory factor Max maintains the basal cellular transcription. (c).The association ofregulatory factor Max with Mad leads to the recruitment of HDAC complex, which deactylases the histones resulting in condense heterochromatin state and hence, the condensedform of chromatin could not provide accessibility to transcription factors and eventually, it represses the transcription.
Various studies on yeast Gcn5 and Rpd3 strongly suggests thathistones are physiologically relevant substrates for these enzymecomplexes, and that the histone acetylase and deacetylase activitiesare critical for transcriptional regulation. Two experimental reportsexplain detailed mutational analyses of Gcn5, leading to theconclusion that there is a strong correlation between histoneacetylase activity in vitro and transcriptional activity in vivo [40,41].In one of these studies [41], histone acetylation by the various Gcn5
Fig. 2. Histone acetylation and transition of heterochromatin to euchromatin. The figure dcharges/neutralization responsible for the interaction of histones with chromatin.
derivatives was performed in the context of the Ada and SAGAcomplexes on nucleosomal substrates. In the other study, additionalsubstantiation for physiological relevance was obtained by analyzingdirectly the acetylation state of chromatin in yeast cells [40].Acetylation of core histones found to be increased on over expressionof Gcn5. More interestingly, Gcn5 increases histone acetylation atpromoter regions in a manner that is correlatedwith Gcn5-dependenttranscriptional activation and histone acetylase activity in vitro.
epicts the molecular structure of acetylated and deacetylated lysine and the resultant
Interestingly, histones also serve as substrates for Rpd3 and Hda1histone deacetylases in yeast [41]. In accord with the enzymaticspecificities of these deacetylases, yeast strains lacking either Rpd3 orHda1 show increased acetylation at lysines 5 and 12 of histone H4.Furthermore, mutant derivatives of Rpd3 that abolish histonedeacetylase activity but do not affect Sin3–Rpd3 complex formationare defective for transcriptional repression in vivo [42]. Theseexperiments are consistent with and extend the observations inhuman cell lines that HDAC-dependent repression in vivo is sensitiveto histone deacetylase inhibitors. However, the ambiguity of whetherRpd3-dependent repression is associated with increased acetylationat the level of specific target genes still continues.
4. Histone acetyltransferases (HATs)
There have been five families of histone acetyltransferases reportedwhich contain more than twenty enzymes. All HATs contain anacetyltransferase domain (proven or suspected), but sequence com-parison divide them into subfamilies according to additional shareddomains. Among various HAT families the CBP/P300 family of enzymesis more efficient and has less substrate specificity than the other HATenzymes, since recombinant CBP/P300 has been shown to acetylate allfour histones in global-histone form aswell as in nucleosomes [43]. TheGNAT (Gcn5-related N-Acetyltransferases) can interact with p300/CBP[44], and involved in transcriptional regulation and cell cycle control.The MYST family of HAT proteins has diverse biological utility in cellcycle and growth control, transcription activation, positive transcrip-tional silencing (Sas2 and Sas3), formation of leukemic translocationproducts (MOZ and TIF2), dosage compensation in Drosophila (MOF),and DNA repair [9,45–48]. The MOZ (monocytic leukemia zinc fingerprotein) is a human protooncogene that has a homology with yeastSas3, which is the catalytic domain of the nucleosomal H3-specific HATcomplex, NuA3 [49]. The humanMOZ protein stimulates acute myeloidleukemia AML1-mediated transcription [50]. TAFII250 (TBP-associatedfactor) is a subunit of the TFIID complex, a general transcription factor(GTF) that provides a critical first step in transcription initiation. Itcontains an acetyl-CoA binding site and a bromodomain [51] its HATregion bears little similarity to other known acetyltransferases. Atemperature-sensitive TAFII250 mutant in the Syrian hamster cell linets13 has been reported to blocks cell cycle progression at thenonpermissive temperature [52], clearly demonstrating the essentialrole of TAFII250 gene.
5. HATs control on cell physiology
The impact of differential histone acetylation during developmenthas been documented in a number of organisms. Such as, studies in thesea urchin revealed a correlation between histone acetylation and thedegree of commitment to differentiation of specific cell types. In which,promyelocytic leukemia cells when treated with auroanofin incombination with retinoic acid, promotes cell differentiation byincreasing histone acetylation and the expression of differentiation-associated genes [53]. Chromatin remodeling is also complemented bygenome-wide commitment to euchromatin or heterochromatin duringmouse and human embryonic stem cell differentiation. Studies onchromatin dynamics indicate the presence of an essential locus formesoderm and endoderm differentiation [54–57]. Several reports havefurthermore investigated the interplay between cell lineage differenti-ation and global-histone acetylation. For example, treatment ofimmature chickens with estradiol leads to increased liver histoneacetylation and histone acetyltransferase activity varies over time indifferentiating chick myoblasts. Similarly, in rat skeletal muscleacetylation of chromosomal proteins decreases as developmentprogresses and recently identified Pitx2, as a previously unknownhomeodomain transcription factor functions to regulate the early stagesof smoothmuscle cell (SMC)by increasinghistoneacetylation level [58].
Several studies showed inhibition of deacetylases in human cancer cellsto an increase in differentiation-associated markers. Role of histone-modifying enzymes in development is reported extensively [59–61].The embryo grows rapidly after uterine implantation until gastrulation.During this developmental scheme, gene expression is temporally andspatially regulated in a highly coordinated manner by chromatin-modifying enzymes such as HATs and HDACs. Genetic studies in micehave demonstrated that the role of chromatin-modifying enzymes arenot only tissue-specific, but also illustrates dose-dependency pattern inthe developing embryos [62]. Consistently, mutations affecting histone-modifying activities lead to difficulty at or before embryo implantation,indicating a role for histone-modifying enzymes in regulation of specificgene expression during embryogenesis and development [62].
In eutherian species the inactivation of the second X chromosomeoccurs in the cells of female progeny. Though, the precise mechanismof this inactivation is not yet well defined, there is a compelling linkjoining the histone underacetylation and inactivation of the Xchromosome [63]. Also, in patients containing aberrant copy numbersof the X chromosome (polysomy X), incomplete deacetylation of all Xchromosomes was observed [64]. The syndrome of fragile X chromo-some thus provides another link between histone acetylation andhuman hereditary disorders and will be discussed below. Apart fromthese observations on the general acetylation state of chromosomalproteins, the role of specific histone acetyltransferases in developmentand differentiation has been well explored [65–67]. Substratespecificity of these reactions seems to be regulated by additionalcomponents of the large multimeric complexes containing HATs andHDACs. In this context, it is important to note that HAT substrates arenot restricted to histones, but also include a range of transcriptionfactors, such as p53, E2F-1, MyoD and GATA-1 [68–71]. Inappropriateacetylation states of transcription factors may therefore contribute todiseases provoked by unbalanced enzymatic activities.
6. Histone acetyltransferases and diseases
It is hypothesized that numerous diseases may be associated withthe hyperacetylation of chromosomal regions that are usually silencedor deacetylation of chromosomal regions that are actively transcribed;therefore, alterations of HATs at the genomic level disturbs theequilibrium of histone acetylation which in turn serves as a key factorin regulating gene expression. Review on some of the diseasesassociated with aberrant HAT activity can confirm this hypothesis.Mutations in the human CBP gene have been reported to be associatedwith Rubinstein–Taybi syndrome (RTS) which is a developmentalhaploinsufficiency disorder with an increased risk of cancer develop-ment [72]. In human cancer, spontaneously occurring mutations inthe P300 gene have been reported [73,74], which reinforce the ideathat p300/CBP activity can be under abnormal control in humandisease, particularly in cancer, which may inactivate a p300/CBPtumor suppressor-like activity. PCAF can interact with two importantcell cycle regulators: E2F and p53 [44,75] Transcription factor E2Finduces S-phase specific gene expression and is involved in promotingS-phase-entry. In contrast, p53 acts as a tumor suppressor protein byinhibiting cell cycle progression and S-phase entry. Induction of p53usually leads to posttranslational modifications of the protein. Severalreports have been shown that acetylation of the C-terminal regulatorydomain is involved in regulating activity of p53 [68,75,76]. Acetylationof this site is observed after DNA damage in vivo, induced p53 andcaused cell cycle arrest or apoptosis; therefore, over expression ofPCAF can cause growth arrest [68,77]. Alternatively, acetylation of E2Fincreases the transcriptional activity of E2F in vivo and stabilizes theE2F protein [68]. Therefore, PCAF can be involved in two opposingstates, promoting of cell cycle progression by activating E2F, and cellcycle arresting by activating p53. Thus, significant effects on cellularproliferation and tumor formation can be the result of PCAF mutation.
The identification of several histone deactylase (HDAC) enzymes,whose activities have been correlated with transcriptional repression,came almost in parallel to the discovery of HAT enzymes. The histonedeacetylases are mainly classified into three classes, with at least 11isozymes having been identified [78]. Class I contains HDAC 1–3 and 8,which are related to the yeast Rpd3 histone deacetylases [78]. Class IIcontains HDAC 4–7, 9 and 10 which are related to the yeast Hda1histone deacetylases . Whereas, Class IV contains only HDAC11 whichis expressed in the brain, heart, muscle, kidney and testis, but little isknown about its function [79,80]. It is composed of a deacetylasedomain that shows homology to class I and II HDAC domains, withsmall N- and C-terminal extensions. In addition to these classicalHDACs, mammalian genomes encode another group of deacetylases,the sirtuins, which are sometimes referred to as class III HDACs, whichis extensively reviewed by many workers [81–83].
8. HDAC and cellular physiology
Histone deacetylases (HDACs) are enzymes that modify keyresidues in histones to regulate chromatin architecture, and theyplay a vital role in cell survival, cell cycle progression, andtumorigenesis. HDAC1 null mice die prior to embryonic day 10.5and display severe proliferation defects and general growth retarda-tion. HDAC3 mutant mice die before embryonic day 9.5 and deletionof HDAC 3 reveals critical roles in S-phase progression and DNAdamage control [84,85]. Also, the loss of HDAC3 seems to beassociated with the defective DNA double-stranded break repairsystem [84]. Conditional deletion of HDAC3 has so far been describedfor liver and heart disorder. Role of HDAC4 in the formation ofskeleton has been reported. Studies revealed that global deletion ofHDAC4 led to premature mortality due to the ectopic ossification ofendochondrial cartilage. Mutants of HDAC5/9 show abnormalities innormal growth and maturation of cardiomyocytes. In addition, class IIHDACs are reported to modulate the activities of other transcriptionfactors involved in myocardial growth [86]. Likewise, hyperacetyla-tion of tubilin on HDAC6 deletion is reported to be associated with theregulation of cytoskeletal dynamics [87]. Disruption of the HDAC7gene in mice also results in embryonic lethality due to a defect inangiogenesis suggesting a role for HDAC and histone acetylationduring development of blood vessels [88]. HDAC7 also plays a key rolein T cell development [89]. It has shown to inhibit the expression ofNur77 (a member of the orphan nuclear receptor super-family) viathe transcription factor MEF2D. Triple mutant HDAC7 that is notexported from the nucleus in response to T cell receptor (TCR)activation suppresses TCR-mediated apoptosis. Furthermore, Inhibi-tion of HDAC7 expression by RNA interference causes increasedapoptosis in response to TCR activation. These results define the roleof HDAC7 in regulation of Nur77 and apoptosis in developingthymocytes. Class II HDACs (HDAC5 and HDAC9) also control thegrowth and function of cardiovascular system [90–92]. HDAC4 plays acentral role in formation of skeleton [93]. Numerous functions forClass II HDACs have been also described in skeletal muscle [94–96].
9. Histone deacetylases and diseases
Histone deacetylases (HDACs) are part of a vast family of enzymesthat have crucial roles in numerous biological processes, consistentwith the model of transcriptional activation through histone acety-lation, HDACs are in general associated with transcriptional repres-sion. Transcriptional repressors like YY1, Mad/Max or NCoR/Smarthave been shown to form complexes with histone deacetylases invitro and in vivo [97]. The expression of its isoforms in eukaryotic cellsraises questions about their specificity or redundancy, and theircontrol over global or specific programmes of gene expression. Recent
study on HDAC knockouts has revealed their highly specific functionsin development pathologies [98]. Similar to HATs, histone deacety-lases seem to be organized in multisubunit complexes which are notyet well analyzed. Recent findings on the importance of HDACs in cellcycle regulation and gene expression suggest a possible involvementin tumor formation. HDACs are known to be associated with twoimportant cell cycle regulators: Mad/Max and RB. Mad/Max hetero-dimers are essential for the repression of E-box-containing growthstimulatory genes during cellular differentiation [77]. Transcriptionalrepression by Mad/Max requires the assembly of a multisubunitrepressor complex that carries HDAC activity. Disruption of thisrepressor complex by overexpression of c-Myc or v-Ski results in re-induction of cell cycle progression and transformation [97]. Retino-blastoma (RB) tumor suppressor family proteins block cell prolifer-ation in part by repressing certain E2F-specific promoters. Disruptingthe Rb–Raf-1 interaction could inhibit cell proliferation in a multitudeof cancer cell lines as well as can prevent angiogenesis and tumorgrowth in vivo. Thus, the Rb–Raf-1 interaction is a promisingtherapeutic target for cancer. [99,100]. A recent study, suggests theloss of Rb phosphorylation led to transcription inhibition [101] anddepicts a relationship between cell cycle and Rb/Raf interaction.Recent studies have shown that deletion of a single HDAC is notsufficient to induce cell death, but that HDAC1 and 2 play redundantand essential roles in tumor cell survival. Their deletion leads tonuclear bridging, nuclear fragmentation, and mitotic catastrophe,mirroring the effects of HDACi on cancer cells [102]. Also the role forHDAC activity, E2F-1, and p53 in the regulation of Apaf-1 expressionin cell lines [103], proposed a link between apoptosis and HDACactivity.
10. Distinct specificity of HATs and HDACs
As indicated above, domain-wide and site-specific histone acety-lation are essential for transcription, but are not sufficient to establishfull accessibility of the chromatin. It was assumed that chromatinsubsists either in a transcriptionally active state in which histoneswere acetylated or in a repressed state in which histones were notacetylated. This inference became complicated by the observationsthat histone H4 isoforms acetylated at specific lysines are preciselyarranged on Drosophila chromosomes [104], and that lysine 12 ofhistone H4 is preferentially acetylated in yeast heterochromatin [105].Biochemical characterization of the various enzymes described abovemade realized levels of complexity in histone acetylation patterns.When assayed with a variety of substrates together with histone tailpeptides, isolated histones, or nucleosomes, the individual histoneacetylases and deacetylases exhibit distinct specificities. Someenzymes are relatively promiscuous in their action, whereas othersare quite specific in terms of the individual lysine residues andparticular histones they affect. For example, Gcn5 preferentiallyacetylates lysine 14 of histone H3 and lysines 8 and16 of histone H4[106], and HDAC/Rpd3 preferentially deacetylates lysines 5 and 12 ofhistone H4 [107]. Besides, histone acetylases differ in their ability toact on nucleosomal or free histones, and for which the recombinantform of the enzyme can differ dramatically from the histone acetylasecomplex that exists in cells. For example, recombinant Gcn5 can onlyacetylate free histones, whereas the Ada and SAGA complexes thatcontain Gcn5 can acetylate nucleosomes [108]. This suggests that theAda (and may be Spt) proteins are required for Gcn5 to utilizenucleosomal substrates. At present, the physiological roles of thesedistinct acetylation patterns are poorly understood, although it seemslikely this enzymatic specificity will be reflected in biologicalselectivity. In addition, the histone acetylases and deacetylases differwith respect to the individual lysine residues and specific histonesthat are affected, and there is limited information on how suchdifferences affect chromatin structure and protein accessibility invivo. These questions should be addressed in the near future, and it is
likely that the answerswill differ depending on the histone-modifyingactivity and the promoter. Although the effects of histone acetylationand deacetylation are typically viewed in terms of promoteraccessibility, it is also possible that acetylated or deacetylated histonescould serve as signals for interaction with proteins. For example, thetranscriptional repression domain of the Tup1 corepressor interactswith underacetylated forms of histones H3 and H4. Tertiary structureanalysis provides insight into the mode of specific recognition ofsubstrates by HAT proteins. The three-dimensional (3-D) crystalstructures of Gcn5/PCAF [109–111], Esa1 [112] and Hat1 [113]revealed that these HATs have a structurally conserved central coredomain and more divergent N- and C-terminal domains. The centralcore domain plays a particularly important role in histone substratecatalysis, while the N- and C-terminal domains are important inhistone substrate binding. The structures of a Gcn5/CoA/histone H3peptide (un-phosphorylated) complex and a Gcn5/CoA/histone H3peptide (phosphorylated at Ser10) complex revealed a mechanism bywhich phosphorylation of H3 Ser10 enhances acetylation of H3 Lys14by Gcn5. Phosphorylated H3 undergoes a significant structuralrearrangement, which promotes a stronger interaction betweenGcn5 and histone H3 [114]. Further structural analysis of complexeslike above described will validate and complement models based onbiochemistry or genetics, and lead to a better understanding of themolecular basis of HAT substrate specificity.
11. Other pathologies
11.1. Anti-inflammatory effect of histone hyperacetylation
To date, it is known that alteration in gene transcription is acommon mechanism of HDACi achieved by increasing the accumula-tion of hyperacetylated histones H3 and H4 which affects chromatinstructure and, thereby, the relationshipof the nucleosomeand the genepromoter elements [115]. It is also known thatHDACi is associatedwitha significant suppression of proinflammatory cytokines; therefore, itwas proposed to comprise an anti-inflammatory effect [116]. Suber-yolanilide hydroxamid acid (SAHA) has potent anti-inflammatoryactivities, both in vitro and in vivo [117]; and the anti-inflammatoryeffects of HDACi are until now limited just to SAHA and trichostatin A(TSA), bothmembers of the class of hydroxamic acids. Glauben R. et al.,found a dose dependent increase in histone H3 acetylation at the site ofinflammation under vaporic acid (VPA) treatment [115]. Therefore, in2006, role of histone hyperacetylation in amelioration of experimentalcolitis in mice was reported [118]. Though, this study demonstratedthat HDACi have significant anti-inflammatory effects in experimentalcolitis caused by hyperacetylation of H3, it is still to be identifiedwhether the anti-inflammatory efficacy would also reduce theincidence of gastrointestinal malignancies.
Diesel exhaust particulate matter (DEP) causes pulmonary inflam-mation and exacerbates asthma and is a potent inducer of inflammatoryresponses in human airway epithelial cells [119]. DEP induces theexpression of COX-2 in BEAS-2B cells at both the transcriptional andprotein levels. The induction of COX-2 gene expression is associatedwith HAT p300-mediated induction of histone H4 acetylation at thenative COX-2 promoter start site. Recent studies illustrate the role ofHDACs in maintaining TH1-like and TH2-like immunity in human T cells[120].
11.2. Effect of histone acetylation on allergies
HDAC/HAT activities might also be associated with severe steroid-insensitive asthma. Thus the suppression of LPS-induced cytokinerelease (monocyte chemoattractant protein 1, macrophage inflam-matory protein 1a, RANTES, TNF-a, IL-1b, IL-8, IFN-g, IL-6, IL-10, andGM-CSF) by dexamethasone from PBMCs of subjects with severesteroid-insensitive asthma was suppressed compared with that seen
in subjects with mild steroid-sensitive asthma [121]. Nuclear HDACand HAT activities were demised in patients with severe steroid-insensitive asthma compared with patients with mild steroid-sensitive asthma, and importantly, this reduction in HDAC activitycan be correlated directly with steroid insensitivity. In contrast, thereduction in HAT activity related to corticosteroid use rather thanasthma severity [122]. However, reduced HDAC2 expression has notbeen seen in all patients with severe steroid-insensitive asthma,perhaps reflecting the heterogeneity of the severe asthma phenotype[123]. HDAC2 expression and activity are also decreased in asthmaticsubjects, smokers, smoking asthmatic subjects and patients withchronic obstructive pulmonary disease (COPD) [124], all of whom areknown to be insensitive to the anti-inflammatory effects of gluco-corticoids. Overexpression of HDAC2, but not HDAC1, in primarymacrophages from patients with COPD restored dexamethasoneefficacy toward suppressing LPS-induced GM-CSF release to levelsseen in cells from healthy control subjects [124], which suggest theexistence of negative correlation between the repressive effect ofdexamethasone on cytokine production and total HDAC activity inalveolar macrophages from smokers and nonsmokers.
11.3. Chromatin remodeling and diabetes II
Evidence shows that high glucose (HG) conditions, mimickingdiabetes, can trigger the transcription of nuclear factor Kappa B (NF-κB) -regulated inflammatory genes [125]. It was demonstrated by invitro experiments with monocyte culture that high glucose (HG)conditions lead to the activation of the transcription factor NF-κB andconsiderably amplify the expression of a number of inflammatorychemokines and cytokines such as tumor necrosis factor-α (TNF-α),and monocyte chemoattractant protein-1 (MCP-1) [126,127]. NF-κBregulates expression of more than 100 genes including inflammatorygenes such as TNF-α, and cyclooxygenase-2 (COX-2). NF-κB is aheterodimer that consists of 65 and 50-kDa subunits (p65 and p50),which is bound to its inhibitor, IκB, in the cytoplasm. P65 is a keytranscription activating component of NF-κB. Recent studies by F.Miao et al (2004) have shown the occurrence of chromatinrearrangements at the promoters of inflammatory genes in vivo inmonocytes under diabetic conditions [125]. It was noted that HGculture of monocytes could specifically augment the recruitment ofp65 and coactivator HATs such as CBP and PCAF to the promoters ofinflammatory genes (TNF-α, COX-2) as well as an increase in theacetylation of nucleosomal factors histone H3 lysine 9 (K9), and lysine14 (K14) and H4 (K5, K8, and K12). In vivo relevance has beenelucidated by examining histone acetylation patterns in monocytes,from diabetic patients [126]. These results demonstrate high glucosecondition mimicking diabetes can have an effect on in vivo chromatinremodeling in both cell culture and in patients by increasingacetylation of specific lysine residue from histones 3 and 4 and byactivation of transcription factor NF-κB and HAT at the promoters ofinflammatory genes [126]. In addition, sugar-modified histones canundergo other transformations [128] to form advanced glycosylationend products (AGEs). AGE accumulation associated with histones andother proteins is implicated in the progression of aging and agerelated diseases like diabetes and Alzheimer [128,129].
11.4. Histone deacetylation and Fragile X syndrome
An illustration of a direct association between the levels of histoneacetylation and a severe hereditary disorder in humans is the fragile Xsyndrome. This syndrome is the most frequently encountered form ofinherited mental retardation in humans, distinguished by mutationsin the FMR-1 gene on the X chromosome [130], which leads tohypermethylation and transcriptional silencing [131]. In recentaccount, the mechanism of transcriptional silencing of the Xchromosome through cytosine methylation and histone deacetylation
was elucidated [132]. Considerable deacetylation of histones H3 andH4, and hypermethylation of the DNA were observed in the 5′-terminal end of FMR-1from fragile X-syndrome cells. Treatment of thecells with a methyltransferase inhibitor restored both methylationand histone acetylation of FMR-1 to near wild-type levels, andreactivated transcription of the gene. However, treatmentwith TSA, aninhibitor of deacetylases, did not lead to any detectable transcription ofthe FMR-1 locus, even though the acetylation of histone H4 wasrestored. Putting together, these data put forward a complexmechanism of transcriptional silencing in fragile X syndrome, wherehistone deacetylation may play an important role, albeit subordinateto DNA hypermethylation.
11.5. Histone acetylation and neurodegenerative diseases
McCampbell and colleagues demonstrated that the histoneacetyltransferase CBP is sequestered by polyglutamine nuclearinclusions in cell culture and animal models of polyglutamine disease,and in tissue from Kennedy's disease patients [133]. This observationhas since been extended to Huntington's disease (HD) and dentator-ubropallidoluysian atrophy (DRPLA) [134,135]. Steffan and co-work-ers demonstrated that physical interaction withmutant Huntington isdependent on the conserved acetyltransferase domain of CBP and thisinteraction results in reduced enzymatic activity in vitro [134].Functional depletion of CBP activity by expanded polyglutamine hasalso been observed in cell-culture-based transcription assays. More-over, polyglutamine toxicity in cell culture is mitigated by exogenousoverexpression of CBP [134,136]. In accordance with evidence ofreduced activity of CBP (and perhaps other acetyltransferases),polyglutamine toxicity in neuronal cell culture is associated with adeficiency in histone acetylation [136]. The altered acetylationhypothesis has emerged, which suggests that inappropriate interac-tion of expandedpolyglutamine-containingproteinswith componentsof the histone acetylation machinery leads to a deficiency in histoneacetylation. This hypothesis also predicts that the toxicity of expandedpolyglutamine would be reversed upon restoration of histoneacetylation, as has now been observed. In neuronal cell culture, thehistone acetylation defect is reversed upon treatment with the HDACisuch as suberoylanilide hydroxamic acid (SAHA) and TSA, and thisrestoration of histone acetylation is accompanied by a reduction inpolyglutamine-induced cell death [136]. Recently, Rai et al. [137]reported the possible efficacy of HDACi in reverting the pathologicalprocess in Friedreich ataxia, a so far incurable neurodegenerativedisease.
11.6. Obesity and histone acetylation: a current notion
Adipogenesis is reliant on the sequential activation of severaltranscription factors. VPA has been used for decades in the treatmentof epilepsy, and is also effective as a mood stabilizer and in migrainetherapy. As a histone deacetylase inhibitor (HDACi), VPA induceswidespread epigenetic reprogramming, which also involves demethy-lation of specific genes [138]. VPA inhibits mouse 3 T3 L1 and humanpre-adipocyte differentiation. TSA also inhibited adipogenesis, where-as the VPA analogue valpromide, which does not possess HDACinhibitory effects, did not prevent adipogenesis. These data highlightan interesting role for HDAC activity in adipogenesis that can beblocked by treatment with VPA and/or TSA [139].Central infusion of aHDAC inhibitor and TSA can reverse the acetylation state of histone,restoring or impairing the group differences in histone acetylation,NGFI-A binding, GR expression and hypothalamic–pituitary–adrenalcorresponding reactivity to stress in adult offspring [140]. Altogetherthis suggests a causal relationship among histone acetylation andstress responses in the adult offspring. This indirectly relates the foodhabit in stress conditions, and thereby histone acetylation in theseconditions. Despite the inherent permanence of the epigenomic
marks established early in life through behavioural programming,they are potentially reversible in the adult brain. Thus increase in oneamino acid (methionine) in the brain could alter DNA methylationand alter behaviour in adult brain [141]. The study performed withZucker obese rat model shows higher level of histone H3 acetylationat (K9, K14) and H4 acetylation at K5 in the obese animals liverhomogenate fraction [142]. In contrast, the nuclear level of H3 and H4acetylation at the same lysine residues was considerably higher in thelean and lower in the obese animals. This study also correlateshyperacetylation of histones in liver nuclei with amelioration ofhepatic steatotis as a result of obesity with hyperglycemia. Morespecifically H4 at lysine 5 and probably H3 at lysine 9 were reported tobe more affected in the process. Higher rates of intra abdominalobesity experiential after growth constraint may participate tohypertension and create atherothrombotic conditions leading to thedevelopment of cardiovascular diseases [143]. At every stage duringthe cascade of histone acetylation/deacetylation fluctuations (foetaldevelopment and ageing), the nutritional balance must be ‘optimal’.Moreover, environmental factors and nutrition may have greaterimpact on the patterns of these modifications which are maintainedthroughout life [144]. Understanding the drift in histone acetylationas a driving force in obesity and associated disorders (like cardiovas-cular diseases etc.) opens a new area of research on the mechanismsunderlying development in glucose homeostasis, epidemiology andrisk assessment.
11.7. Deviant HAT/HDAC activity and cancer
Anomalous regulation of gene transcription is hallmark of manyforms of cancer and there is increasing evidence that alterations inHAT and HDAC activity occur in several tumors [145]. In the first twocategories, abnormal activity of HATs and HDACs is involved, whichseems to be either due to mutations of genes encoding for theseenzymes or due to their binding and recruiting patterns. A significantimbalance of acetylation and deacetylation levels was observed intumors cells [146]. Histone acetylation plays many fundamental rolesin cellular processes, one of them being crucial to cell proliferation. Itis not surprising that mutations or chromosomal modificationsinvolving HATs result in the development of malignancies [147]. Ina recent comparative analysis of normal cells, primary tumors andcancer cell lines, an altered recruitment of the acetyltransferases MOZ,MOF and MORF was found in cancer cell lines and this correlates witha global loss of the otherwise normally acetylated H4-K16. This lastfeature was shown to be a common hallmark of human cancer and isusually accompanied by trimethylation at H4-K20 [148]. In addition,mutations of certain HATs also cause cancer, as observed inmice [149]and in several cases of human leukemia [150]. A biallelic mutation ofthe p300 locus was identified in human epithelial cancer [151].Specific alterations in genes coding for HDACs have not been reported.These complexes apparently act in cancer development with morethan one single mechanism [145,152]. On the basis of the availableliterature on acetylation and diseases, it is possible to differentiatebetween different deregulation mechanisms. Firstly, acetylationdisorders may be due to hyperacetylation and concomitant derepres-sion of normally repressed promoters, leading to the presence of a setof proteins at an inappropriate moment. Conversely, underacetylationof a set of promoters could have equally deleterious effects due todown regulation of genes necessary for maintenance of a certainphenotype. In each of these cases, both the phenomenon ofacetylation and deacetylation are disturbed which may lead to adiseased condition.
12. Current remedies
Many human diseases, including cancer, having an epigeneticaetiology have encouraged the development of a new therapeutic
option that might be called as ‘epigenetic therapy.’ Designing drugsagainst the epigenetics targets has become a new area of pharmacol-ogy. Many agents have been discovered that alter the modification ofhistones, and several of them are under clinical trials. Epigenetic driftsor defects, when compared to genetic defects, are thought to bereversible with pharmacological intervention [153,154]. In spite ofassurance as therapeutic agents, these drugs may also be able toprevent disease [155]. However, epigenetic therapy has its limitations,such as the fact that HDAC inhibitors may activate oncogenes due tolack of specificity, resulting in accelerated tumor progression [155].Moreover, the acetylation pattern once corrected may revert to theoriginal state because of the reversible nature of the histoneacetylation. Under the scope of the present review, the targets forthese drugs include enzymes such as histone acertyltransferases(HATs) and histone deacetylases (HDAC).
13. HAT inhibitors
There are not many reports on HATs inhibitors. Although, naturalinhibitor, curcumin (diferuloymethane) have been shown to have asignificant inhibitory effect of HAT. It specifically inhibits the p300/CREB-binding protein through the involvement of Reactive OxygenSpecies (ROS) [145]. Recently, curcumin was shown to repress bothHAT-dependent transcription and the acetylation of non-histoneproteins [156]. It also suppresses cellular transformation, prolifera-tion, and metastasis by inhibition of IKK (IKappaB Kinase complex)and activation of Akt leading to the subsequent inactivation of NF-kB[157]. In earlier study, a series of isothiazolone-based HAT inhibitorswere also identified [158]. Around thirty-five N-substituted analoguesshow inhibition of both p300/cyclic AMP-responsive element bindingprotein-binding protein-associated factor (PCAF) and p300 (1toN50 μmol/L, respectively) and the growth of a panel of humantumor cell lines (50% growth inhibition, 0.8 toN50 μmol/L). Theydecreased cellular acetylation in a time-dependent manner (2–48 h ofexposure) and a concentration-dependent manner (one to five times,72 h, 50% growth inhibition) in HCT116 and HT29 human colon tumorcell lines. As one of the first series of small-molecule inhibitors of HATactivity, further analogue synthesis is being pursued to examine thepotential scope for reducing chemical reactivity while maintainingHAT inhibition.
14. HDAC inhibitors (HDACi)
These drugs inhibit HDACs, which along with HATs, help tomaintain the acetylation status of histones. The currently availableHDACi are thought to inhibit the class I and class II HDACs [143].HDACi cause the induction of differentiation, growth arrest and/orapoptosis in a broad spectrum of transformed cells in culture andtumors in animals [159]. The anticancer effects of these drugs arethought to be due to the accumulation of acetylated histones leadingto the modulation of the transcription of specific genes whoseexpression causes inhibition of cancer cell growth [160]. Some HDACisuch as suberoylanilide hydroxamic acid [161] and depsipeptide [162]have been undergoing. HDACi can induce differentiation, growtharrest and/or apoptosis in transformed cells in culture and in tumors.The driving hypothesis is that accumulation of acetylated proteins,particularly histones, results in the induction of genes and theupregulation of others that have become epigenetically silenced. Inparticular, the gene encoding p21, which is a cell cycle kinaseinhibitor, is commonly upregulated in tumor cells, treated with theseagents in the absence of p53 [163]. The role of HDAC7 in autoimmunediseases has open new avenues and offer excellent proof of conceptdata to support the development of HDAC7 inhibitors as modulatorsof the T-cell repertoire. Different HDACi are being used intravenouslyor orally in several phase I and II clinical trials, in which changes inhistone acetylation have been documented. Because there are many
different HDACs, it will be important in the future to design therapiesthat can target individual enzymes and thus increase the precision ofthis approach.
15. Future perspectives
It is apparent that we are just at the beginning of understandingthe substantial contributions of epigenetics to human disease, andthere are probably many surprises ahead. As the finding that loss ofimprinting can be seen not only in normal colonic epithelium but alsoin the lymphocytes of colorectal patients was completely unforeseen[164]. Elucidating the whole and width of histone modification is anexhilarating challenge and will eventually lead to a better under-standing of the development of human disease and direct therapeuticconcepts into new directions. The possibility to obtain a global view ofhistone acetylation patterns in different cell types will advance ourunderstanding of the epigenetic code and its function in normal anddisease states as well as the role of the environment in human health.Irrespective of the pathological state or the genes/sequences involved,deciphering the histone acetylation patterns at stake should allow usto evaluate their potential reversibility. In the cases of non-histonesubstrates, it will be important to identify the proteins andunderstand how acetylation influences their actions. However, verylittle is known about the role of the complex machinery that catalyzesthe addition or removal of these modifications and how they areinvolved in orchestrating development. Future studies defining themolecular roles of these factors will provide a better understanding ofthe mechanisms governing these basic phenomena that regulateproper development and differentiation. Such studies would help todecipher the role of HATs and HDACs for human diseases associatedwith the misregulation of histone acetylation.
Technologies designed to examine epigenetic phenomena at thegenomic level have shown remarkable progress over the last fewyears. The possibility to obtain a global view of epigenetic marks indifferent cell types will advance our understanding of the epigeneticcode and its function in normal and disease states as well as the role ofthe environment in human health.
Acknowledgements
Author is grateful to Prof. Michael Hampsey, UMDNJ, USA for hiscritical comments to improve this review article. SNK acknowledgesDBT government of India for the fellowship.
References
[1] Mai A, Massa S, Rotili D, Cerbara I, Valente S, Pezzi R, et al. Histone deacetylationin epigenetics: an attractive target for anticancer therapy. Med Res Revs 2005;25:261–309.
[2] Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specificgenetic interference by double-stranded RNA in Caenorhabditis elegans. Nature1998;391:806–11.
[4] Parseghian MH, Newcomb RL, Winokur ST, Hamkalo BA. The distribution ofsomatic H1 subtypes is non-random on active vs. inactive chromatin: distributionin human fetal fibroblasts. Chromosome Res 2000;8:405–24.
[5] Strahl BD, Allis CD. The language of covalent histone modifications. Nature2000;403:41–5.
[6] Berger SL. Histone modifications in transcriptional regulation. Curr Opin GenetDev 2002;12:142–8.
[7] Turner BM. Cellular memory and the histone code. Cell 2002;111:285–91.[8] Fischle W, Wang Y, Allis CD. Binary switches and modification cassettes in
histone biology and beyond. Nature 2003;425:475–9.[9] Brownell JE, Zhou J, Ranalli T, Kobayashi R, Edmondson DG, Roth SY, et al.
Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linkinghistone acetylation to gene activation. Cell 1996;84:843–51.
[10] Allfrey VG, Faulkner R, Mirsky AE. Acetylation and methylation of histones andtheir possible role in the regulation of rna synthesis. Proc Natl Acad Sci USA1964;51:786–94.
[11] Khan AU, Krishnamurthy S. Histone modifications as key regulators oftranscription. Front Biosci 2005;10:866–72.
[12] Khan AU, Hampsey M. Connecting the DOTs: covalent histone modifications andthe formation of silent chromatin. Trends Genet 2002;18:387–9.
[13] Kurdistani SK, Grunstein M. Histone acetylation and deacetylation in yeast. NatRev Mol Cell Biol 2003;4(4):276–84.
[14] Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particleof the eukaryote chromosome. Cell 1999;98:285–94.
[15] Yang XJ. Lysine acetylation and bromodomain: a new partnership for signaling.Bioessays 2004;26:1076–87.
[16] Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM. Structure and ligandof a histone acetyltransferase bromodomain. Nature 1999;399:491–6.
[17] Hassan AH, Prochasson P, Neely KE, Galasinski SC, Chandy M, Carrozza MJ, et al.Function and selectivity of bromodomains in anchoring chromatin modifyingcomplexes to promoter nucleosomes. Cell 2002;111:369–79.
[18] Mujtaba S, He Y, Zeng L, Yan S, Plotnikova O. Sachchidanand Sanchez R, Zeleznik-Le NJ, Ronai Z and Zhou MM. Structural mechanism of the bromodomain of thecoactivator CBP in p53 transcriptional activation. Mol Cell 2004;13:251–63.
[19] Jacobson RH, Ladurner AG, King DS, Tjian R. Structure and function of a humanTAFII250 double bromodomain module. Science 2000;288:1422–5.
[20] Struhl K. Histone acetylation and transcriptional regulatory mechanisms. GenesDev 1998;12:599–606.
[21] Vogelauer M, Wu J, Suka N, Grunstein M. Global histone acetylation anddeacetylation in yeast. Nature 2000;408:495–8.
[22] Kurdistani SK, Tavazoie S, Grunstein M. Mapping global histone acetylationpatterns to gene expression. Cell 2004;117:721–33.
[24] Pokholok DK, Harbison CT, Levine S, Cole M, Hannett NM, Lee TI, et al. Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 2005;122:517–27.
[25] Schubeler D, Turner BM. A new map for navigating the yeast epigenome. Cell2005;122:489–92.
[26] FischleW,Wang Y, Allis CD. Histone and chromatin cross-talk. Curr Opin Cell Biol2003;15:172–83.
[27] Davie JR. Covalent modifications of histones: expression from chromatintemplates. Curr Opin Genet Dev 1998;8:173–8.
[28] Verdone L, Caserta M, Di Mauro E. Role of histone acetylation in the control ofgene expression. Biochem Cell Biol 2005;83:344–53.
[29] Waterborg JH. Dynamics of histone acetylation in Saccharomyces cerevisiae.Biochemistry 2001;40:2599–605.
[30] Katan-Khaykovich Y, Struhl K. Dynamics of global histone acetylation anddeacetylation in vivo: rapid restoration of normal histone acetylation status uponremoval of activators and repressors. Genes Dev 2002;16:743–52.
[31] Deckert J, Struhl K. Histone acetylation at promoters is differentially affected byspecific activators and repressors. Mol Cell 2001;21:2726–35.
[32] Hebbes TR, Clayton AL, Thorne AW, Crane-Robinson C. Core histone hyperace-tylation co-maps with generalized DNase I sensitivity in the chicken beta-globinchromosomal domain. EMBO J 1994;13:1823–30.
[33] Vettese-Dadey M, Grant PA, Hebbes TR, Crane-Robinson C, Allis CD, Workman JL.Acetylation of histone H4 plays a primary role in enhancing transcription factorbinding to nucleosomal DNA in vitro. EMBO J 1996;15:2508–18.
[34] Durrin LK, Mann RK, Kayne PS, Grunstein M. Yeast histone H4 N-terminalsequence is required for promoter activation in vivo. Cell 1991;65:1023–31.
[35] Yoshida M, Horinouchi S, Beppu T. Trichostatin A and trapoxin: novel chemicalprobes for the role of histone acetylation in chromatin structure and function.Bioessays 1995;17:423–30.
[36] Schübeler D, Francastel C, Cimbora DM, Reik A, Martin DI, Groudine M. Nuclearlocalization and histone acetylation: a pathway for chromatin opening andtranscriptional activation of the human β-globin locus. Genes Dev 2000;14:940–50.
[37] Forsberg EC, Bresnick EH. Histone acetylation beyond promoters: long-rangeacetylation patterns in the chromatin world. Bioessays 2001;23:820–30.
[38] Imhof A, Becker PB. Modifications of the histone N-terminal domains. Evidencefor an “epigenetic code”? Mol Biotechnol 2001;17:1–13.
[39] GuW, Roeder RG. Activation of p53 sequence specific DNA binding by acetylationof the p53 C-terminal domain. Cell 1997;90:595–606.
[40] Kuo MH, Zhou J, Jambeck P, Churchill ME, Allis CD. Histone acetyltransferaseactivity of yeast Gcn5p is required for the activation of target genes in vivo. GenesDev 1998;12:627–39.
[41] Rundlett SE, Carmen AA, Kobayashi R, Bavykin S. Turner BM and Grunstein MHDA1 and RPD3 are members of distinct yeast histone deacetylase complexes.Proc Natl Acad Sci 1996;93:14503–8.
[42] Kadosh D, Struhl K. Repression by Ume6 involves recruitment of a complexcontaining Sin3 corepressor and Rpd3 histone deacetylase to target promoters.Cell 1997;89:365–71.
[43] Timmermann S, Lehrmann H, Polesskaya A, Harel-Bellan A. Histone acetylationand disease. Cell Mol Life Sci 2001;58:728–36.
[44] Hupp TR, Meek DW, Midgley CA, Lane DP. Regulation of the specific DNA bindingfunction of p53. Cell 1992;71:875–86.
[45] Borrow J, Stanton Jr VP, Andresen JM, Becher R, Behm FG, Chaganti RS, et al. Thetranslocation t(8;l6)(p11, p13) of acute myeloid leukaemia fuses a putativeacetyltransferase to the CREB-binding protein. Nat Genet 1996;14:33–41.
[46] Carapeti M, Aguiar RC, Watmore AE, Goldman JM, Cross NC. Consistent fusion ofMOZ and TIF2 in AML with inv (8) (p11q13). Cancer Genet Cytogenet 1999;113:70–2.
[47] Hilfiker A, Hilfiker-Kleiner D, Pannuti A, Lucchesi JC. mof a putative acetyltransferase gene related to the TIP60 andMOZ human genes and to the SAS genes
of yeast, is required for dosage compensation in Drosophila. EMBO J 1997;16:2054–60.
[48] Carrozza MJ, Utley RT, Workman JL, Cote J. The diverse functions of histoneacetyltransferase complexes. Trends Genet 2003;19:321–9.
[49] Creaven M, Hans F, Mutskov V, Col E, Caron C, Dimitrov S, et al. Control of thehistone acetyltransferase activity of Tip60 by the HIV-1 transactivator protein,Tat. Biochemistry 1999;38:8826–30.
[50] Brady ME, Ozanne DM, Gaughan L, Waite I, Cook S, Neal DE, et al. Tip60 is anuclear hormone receptor coactivator. J Biol Chem 1999;274(25):17599–604.
[51] Mizzen CA, Yang XJ, Kokubo T, Brownell JE, Bannister AJ, Owen-Hughes T, et al.The TAF(II)250 subunit of TFIID has histone acetyltransferase activity. Cell1996;87:1261–70.
[52] Wang EH, Tjian R. Promoter-selective transcriptional defect in cell cycle mutantts13 rescued by hTAFII250. Science 1994;263:811–4.
[53] Park SJ, Kim M, Kim NH, Oh MK, Cho JK, Jin JY, et al. Auranofin promotes retinoicacid- or dihydroxyvitamin D(3)-mediated cell differentiation of promyelocyticleukaemia cells by increasing histone acetylation. Br J Pharmacol 2008;154:1196–205.
[54] Golob JL, Paige SL, Muskheli V, Pabon L, Murry CE. Chromatin remodeling duringmouse and human embryonic stem cell differentiation. Dev Dyn 2008;237:1389–98.
[55] Chen G, Zhu J, Lv T, Wu G, Sun H, Huang X, et al. Spatiotemporal expression ofhistone acetyltransferases, p300 and CBP, in developing embryonic hearts. JBiomed Sci 2009;16:24–34.
[56] Creppe C, Malinouskaya L, Volvert ML, Gillard M, Close P, Malaise O, et al.Elongator controls the migration and differentiation of cortical neurons throughacetylation of alpha-tubulin. Cell 2009;136:551–64.
[57] Zhong X, Jin Y. Critical roles of coactivator p300 in mouse embryonic stem celldifferentiation and Nanog expression. J Biol Chem 2009;284:9168–75.
[58] Shang Y, Yoshida T, Amendt BA, Martin JF, Owens GK. Pitx2 is functionallyimportant in the early stages of vascular smooth muscle cell differentiation. J CellBiol 2008;181:461–73.
[59] Bhaumik SR, Smith E, Shilatifard A. Covalent modifications of histones duringdevelopment and disease pathogenesis. Nat Struct Mol Biol 2007;14:1008–16.
[60] Gomez RA, Pentz ES, Jin X, Sequeira Lopez ML. CBP and p300 are essential forrenin cell identity and morphological integrity of the kidney. Am J Physiol HeartCirc Physiol 2009;296:H1255–62.
[61] Guelman S, Kozuka K, Mao Y, Pham V, Solloway MJ, Wang J, et al. The double-histone-acetyltransferase complex ATAC is essential for mammalian develop-ment. Mol Cell Biol 2009;29:1176–88.
[62] Lin W, Dent SY. Functions of histone-modifying enzymes in development. CurrOpin Genet Dev 2006;16:137–42.
[63] Brinkman AB, Roelofsen T, Pennings SW, Martens JH, Jenuwein T, StunnenbergHG. Histone modification patterns associated with the human X chromosome.EMBO Rep 2006;7:628–34.
[64] Leal CA, Ayala-Madrigal ML, Figuera LE, Medina C. Histone H4 acetylationanalyses in patients with polysomy X: implications for the mechanism of Xinactivation. Hum Genet 1998;103:29–33.
[65] Thomas T, Dixon MP, Kueh AJ, Voss AK. Mof (MYST1 or KAT8) is essential forprogression of embryonic development past the blastocyst stage and required fornormal chromatin architecture. Mol Cell Biol 2008;28:5093–105.
[66] Rowland BD, Roig MB, Nishino T, Kurze A, Uluocak P, Mishra A, et al. Buildingsister chromatid cohesion: smc3 acetylation counteracts an antiestablishmentactivity. Mol Cell 2009;33:763–74.
[67] Keenen B, de la Serna IL. Chromatin remodeling in embryonic stem cells:regulating the balance between pluripotency and differentiation. J Cell Physiol2009;219:1–7.
[68] GuW, Roeder RG. Activation of p53 sequence specific DNA binding by acetylationof the p53 C-terminal domain. Cell 1997;90:595–606.
[69] Martinez-Balbas MA, Bauer UM, Nielsen SJ, Brehm A, Kouzarides T. Regulation ofE2F1 activity by acetylation. EMBO J 2000;19:662–71.
[70] Sartorelli V, Puri PL, Hamamori Y, Ogryzko V, Chung G, Nakatani Y, et al.Acetylation of MyoD directed by PCAF is necessary for the execution of themuscle program. Mol Cell 1999;4:725–34.
[71] Cho Y, Song SH, Lee JJ, Choi N, Kim CG, Dean A, et al. The role of transcriptionalactivator GATA-1 at human beta-globin HS2. Nucleic Acids Res 2008;36:4521–8.
[72] Roelfsema JH, Peters DJ. Rubinstein-Taybi syndrome: clinical and molecularoverview. Expert Rev Mol Med 2007;9:1–16.
[73] Bundy JG, Iyer NG, Gentile MS, Hu DE, Kettunen M, Maia AT, et al. Metabolicconsequences of p300 gene deletion in human colon cancer cells. Cancer Res2006;66:7606–14.
[74] Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin SF, et al. Mutationstruncating the EP300 acetylase in human cancers. Nat Genet 2000;24:300–3.
[75] Grossman SR. p300/CBP/p53 interaction and regulation of the p53 response. Eur JBiochem 2001;268:2773–8.
[76] Liu L, Scolnick DM, Trievel RC, Zhang HB, Marmorstein R, Halazonetis TD, et al.p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in responseto DNA damage. Mol Cell Biol 1999;19:1202–9.
[77] Sears R, Ohtani K, Nevins JR. Identification of positively and negatively actingelements regulating expression of the E2F2 gene in response to cell growthsignals. Mol Cell Biol 1997;17:5227–35.
[78] Gray SG, Ekstrom TJ. The human histone deacetylse family. Exp Cell Res 2006;262(2):75–83.
[79] Gao L, Cueto MA, Asselbergs F, Atadja P. Cloning and functional characterizationof HDAC11, a novel member of the human histone deacetylase family. J Biol Chem2002;277:25748–55.
[80] Liu H, Hu Q, Kaufman A, D'Ercole AJ, Ye P. Developmental expression of histonedeacetylase 11 in the murine brain. J Neurosci Res 2008;86:537–43.
[81] Schwer B, Verdin E. Conserved metabolic regulatory functions of sirtuins. CellMetab 2008;7:104–12.
[82] Longo VD, Kennedy BK. Sirtuins in aging and age-related disease. Cell 2006;126:257–68.
[83] Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature2006;444:868–74.
[84] Bhaskara S, Chyla BJ, Amann JM, Knutson SK, Cortez D, Sun ZW, et al. Deletion ofhistone deacetylase 3 reveals critical roles in S phase progression and DNAdamage control. Mol Cell 2008;30:61–72.
[85] Montgomery RL, Potthoff MJ, Haberland M, Qi X, Matsuzaki S, Humphries KM,et al. Maintenance of cardiac energy metabolism by histone deacetylase 3 inmice. J Clin Invest 2008;118:3588–97.
[86] Song K, Backs J, McAnally J, Qi X, Gerard RD, Richardson JA, et al. Thetranscriptional coactivator CAMTA2 stimulates cardiac growth by opposingclass II histone deacetylases. Cell 2006;125:453–66.
[87] Zhang Y, Kwon S, Yamaguchi T, Cubizolles F, Rousseaux S, Kneissel M, et al. Micelacking histone deacetylase 6 have hyperacetylated tubulin but are viable anddevelop normally. Mol Cell Biol 2008;28:1688–701.
[88] Chang S, Young BD, Li S, Qi X, Richardson JA, Olson EN. Histone deacetylase 7maintains vascular integrity by repressing matrix metalloproteinase 10. Cell2006;126:321–34.
[89] Kasler HG, Verdin E. Histone deacetylase 7 functions as a key regulator of genesinvolved in both positive and negative selection of thymocytes. Mol Cell Biol2007;27:5184–200.
[90] Chang S, McKinsey TA, Zhang CL, Richardson JA, Hill JA, Olson EN. Histonedeacetylases 5 and 9 govern responsiveness of the heart to a subset of stresssignals and play redundant roles in heart development. Mol Cell Biol 2004;24:8467–76.
[91] Backs J, Song K, Bezprozvannaya S, Chang S, Olson EN. CaM kinase II selectivelysignals to histone deacetylase 4 during cardiomyocyte hypertrophy. J Clin Invest2006;116:1853–64.
[92] Oka SI, Ago T, Kitazono T, Zablocki D, Sadoshima J. The role of redox modulationof class II histone deacetylases in mediating pathological cardiac hypertrophy. JMol Med 2009;87:785–91.
[93] Vega RB, Matsuda K, Oh J, Barbosa AC, Yang X, Meadows E, et al. Histonedeacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell2004;119:555–66.
[95] Potthoff MJ, Wu H, Arnold MA, Shelton JM, Backs J, McAnally J, et al. Histonedeacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers. J Clin Invest 2007;117:2459–67.
[96] Méjat A, Ramond F, Bassel-Duby R, Khochbin S, Olson EN, Schaeffer L. Histonedeacetylase 9 couples neuronal activity to muscle chromatin acetylation andgene expression. Nat Neurosci 2005;8:313–21.
[97] Kurland JF, Tansey WP. Myc-mediated transcriptional repression by recruitmentof histone deacetylase. Cancer Res 2008;68:3624–9.
[98] Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylasesin development and physiology: implications for disease and therapy. Nat RevGenet 2009;10:32–42.
[99] Dasgupta P, Sun J, Wang S, Fusaro G, Betts V, Padmanabhan J, et al. Disruption ofthe Rb–Raf-1 interaction inhibits tumor growth and angiogenesis. Mol Cell Biol2004;24(21):9527–41.
[100] Davis RK, Chellappan S. Disrupting the Rb-Raf-1 interaction: a potentialtherapeutic target for cancer. Drug News Perspect 2008;21:331–5.
[101] Hahm ER, Singh SV. Honokiol causes G0–G1 phase cell cycle arrest in humanprostate cancer cells in association with suppression of retinoblastoma proteinlevel/phosphorylation and inhibition of E2F1 transcriptional activity. Mol CancerTher 2007;6:2686–95.
[102] Haberland M, Johnson A, Mokalled MH, Montgomery RL, Olson EN. Geneticdissection of histone deacetylase requirement in tumor cells. Proc Natl Acad SciUSA 2009;106:7751–5.
[103] Wallace DM, Cotter TG. Histone deacetylase activity in conjunction with E2F-1and p53 regulates Apaf-1 expression in 661 W cells and the retina. J Neurosci Res2009;87:887–905.
[104] Turner BM, Birley AJ, Lavender J. Histone H4 isoforms acetylated at specific lysineresidues define individual chromosomes and chromatin domains in Drosophilapolytene nuclei. Cell 1992;69:375–84.
[105] Braunstein M, Sobel RE, Allis CD, Turner BM, Broach JR. Efficient transcriptionalsilencing in Saccharomyces cerevisiae requires a heterochromatin histoneacetylation pattern. Mol Cell Biol 1996;16:4349–56.
[106] Kuo MH, Brownell JE, Sobel RE, Ranalli TA, Cook RG, Edmonson DG, et al.Transcription-linked acetylation by GCN5p of histones H3 and H4 at specificlysines. Nature 1996;383:269–72.
[107] Rundlett SE, Carmen AA, Kobayashi R, Bavykin S, Turner BM, Grunstein M. HDA1and RPD3 are members of distinct yeast histone deacetylase complexes. ProcNatl Acad Sci 1996;93:14503–8.
[108] Grant PA, Duggan L, Cote J, Roberts SM, Brownell JE, Candau R, et al. Yeast Gcn5functions in two multisubunit complexes to acetylate nucleosomal histones:characterization of an Ada complex and the SAGA (Spt/Ada) complexs. GenesDev 1997;11:1640–50.
[109] Rojas JR, Trievel RC, Zhou J, Mo Y, Li X, Berger SL, et al. Structure ofTetrahymena GCN5 bound to coenzyme A and a histone H3 peptide. Nature1999;401:93–8.
[110] Trievel RC, Rojas JR, Sterner DE, Venkataramani RN, Wang L, Zhou J, et al. Crystalstructure and mechanism of histone acetylation of the yeast GCN5 transcrip-tional coactivator. Proc Natl Acad Sci USA 1999;96:8931–6.
[111] Clements A, Rojas JR, Trievel RC, Wang L, Berger SL, Marmorstein R. Crystalstructure of the histone acetyltransferase domain of the human PCAFtranscriptional regulator bound to coenzyme A. EMBO J 1999;18:3521–32.
[112] Yan Y, Barlev NA, Haley RH, Berger SL, Marmorstein R. Crystal structure of yeastEsa1 suggests a unifiedmechanism for catalysis and substrate binding by histoneacetyltransferases. Mol Cell 2000;6:1195–205.
[113] Dutnall RN, Tafrov ST, Sternglanz R, Ramakrishnan V. Structure of the histoneacetyltransferase Hat1: a paradigm for the GCN5-related N-acetyltransferasesuperfamily. Cell 1998;94:427–38.
[114] Clements A, Poux AN, Lo WS, Pillus L, Berger SL, Marmorstein R. Structural basisfor histone and phosphohistone binding by the GCN5 histone acetyltransferase.Mol Cell 2003;12:461–73.
[115] Glauben R, Batra A, Fedke I, Zeitz M, Lehr HA, Leoni F, et al. Histonehyperacetylation is associated with amelioration of experimental colitis inmice. J Immunol 2003;176:5015–22.
[116] Glauben R, Siegmund B. Molecular basis of histone deacetylase inhibitors as newdrugs for the treatment of inflammatory diseases and cancer. Meth Mol Biol2009;512:365–76.
[117] Leoni F, Zaliani A, Bertolini G, Porro G, Pagani P, Pozzi P, et al. The antitumorhistone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiin-flammatory properties via suppression of cytokines. Proc Natl Acad Sci USA2002;99:2995–3000.
[118] Glauben R, Batra A, Fedke I, Zeitz M, Lehr HA, Leoni F, et al. Histonehyperacetylation is associated with amelioration of experimental colitis inmice. Immunol 2006;176:5015–22.
[119] Cao D, Bromberg PA, Samet JM. COX-2 expression induced by diesel particlesinvolves chromatinmodification and degradation of HDAC1. Am J Respir Cell MolBiol 2007;37:232–9.
[120] Su RC, Becker AB, Kozyrskyj AL, Hayglass KT. Epigenetic regulation of establishedhuman type 1 versus type 2 cytokine responses. J Allergy Clin Immunol2007;121:57–63.
[121] Hew M, Bhavsar P, Torrego A, Meah S, Khorasani N, Barnes PJ, et al. Relativecorticosteroid insensitivity of peripheral blood mononuclear cells in severeasthma. Am J Respir Crit Care Med 2006;174:134–41.
[122] Bergeron C, Fukakusa M, Olivenstein R, Lemiere C, Shannon J, Ernst P, et al.Increased glucocorticoid receptor-beta expression, but not decreased histonedeacetylase 2, in severe asthma. J Allergy Clin Immunol 2006;117:703–5.
[123] Kelly A, Bowen H, Jee YK, Mahfiche N, Soh C, Lee T, et al. The glucocorticoidreceptor beta isoform can mediate transcriptional repression by recruitinghistone deacetylases. J Allergy Clin Immunol 2007;121:203–8.
[124] Ito K, Yamamura S, Essilfie-Quaye S, Cosio B, Ito M, Barnes PJ, et al. Histonedeacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappa B suppression. J Exp Med 2006;203:7–13.
[125] Miao F, Gonzalo IG, Lanting L, Natarajan R. In vivo chromatin remodeling eventsleading to inflammatory gene transcription under diabetic Conditions. J BiolChem 2004;279:18091–7.
[126] Guha M, Bai W, Nadler JL, Natarajan R. Molecular mechanisms of tumor necrosisfactor alpha gene expression in monocytic cells via hyperglycemia-inducedoxidant stress-dependent and -independent pathways. J Biol Chem 2000;275:17728–39.
[127] Shanmugam N, Reddy MA, Guha M, Natarajan R. High glucose-inducedexpression of proinflammatory cytokine and chemokine genes in monocyticcells. Diabetes 2003;52:1256–64.
[128] Cervantes-Laurean D, Jacobson EL, Jacobson MK. Glycation and glycoxidation ofhistones by ADP-ribose. J Biol Chem 1996;271:10461–9.
[129] Gugliucci A, Bendayan M. Histones from diabetic rats contain increased levels ofadvanced glycation end products. BiochemBiophys Res Commun 1995;212:56–62.
[130] Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, et al. Identification ofa gene (FMR-1) containing a CGG repeat coincident with a breakpoint clusterregion exhibiting length variation in fragile X syndrome. Cell 1991;65:905–14.
[131] Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, et al. Absence ofexpression of the FMR-1 gene in fragile X syndrome. Cell 1991;66:817–22.
[132] Coffee B, Zhang F, Warren ST, Reines D. Acetylated histones are associatedwith FMR1 in normal but not fragile X-syndrome cells. Nat Genet 1999;22:98–101.
[133] McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, et al. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet2000;9:2197–202.
[134] Steffan JS, Kazantsev A, Spasic-Boskovic O, Greenwald M, Zhu YZ, Gohler H, et al.The Huntington's disease protein interacts with p53 and CREB-binding proteinand represses transcription. Proc Natl Acad Sci USA 2000;97:6763–8.
[135] Nucifora Jr FC, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, et al.Interference by huntingtin and atrophin-1 with CBP-mediated transcriptionleading to cellular toxicity. Science 2001;291:2423–8.
[137] Rai M, Soragni E, Jenssen K, Burnett R, Herman D, Coppola G, et al. HDAC inhibitorscorrect frataxin deficiency in a Friedreich ataxia mouse model. PLoSONE 2008;3:e1958.
[138] Milutinovic S, D'Alessio AC, Detich N, Szyf M. Valproate induces widespreadepigenetic reprogramming which involves demethylation of specific genes.Carcinogenesis 2006;28:560–71.
[139] Lagace DC, Nachtigal MW. Inhibition of histone deacetylase activity by valproicacid blocks adipogenesis. J Biol Chem 2004;279:18851–60.
[140] Weaver IC, Meaney MJ, Szyf M. Maternal care effects on the hippocampaltranscriptome and anxiety-mediated behaviors in the offspring that arereversible in adulthood. Proc Natl Acad Sci USA 2006;103:3480–5.
[141] Weaver IC, Champagne FA, Brown SE, Dymov S, Sharma S, Meaney MJ, et al.Reversal of maternal programming of stress responses in adult offspring throughmethyl supplementation: altering epigenetic marking later in life. J Neurosci2005;25:11045–54.
[142] Naahidi S. In vivo epigenetic study of histone acetylation associated with obesity,masters' dissertation. Ontario, Canada: Waterloo; 2007.
[143] Remacle C, Bieswal F, Reusens B. Programming of obesity and cardiovasculardisease. Int J Obes Relat Metab Disord 2004;28:S46–53.
[144] Feil R. Environmental and nutritional effects on the epigenetic regulation ofgenes. Mutat Res 2006;600:46–57.
[145] Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999;21:163–7.[146] Kang J, Chen J, Shi Y, Jia J, Zhang Y. Curcumin-induced histone hypoacetylation:
the role of reactive oxygen species. Biochem Pharmacol 2005;69:1205–13.[147] Santos-Rosa H, Caldas C. Chromatin modifier enzymes, the histone code and
cancer. Eur J Cancer 2005;41:2381–402.[148] Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, et al.
Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is acommon hallmark of human cancer. Nat Genet 2005;37:391–400.
[149] Kung AL, Rebel VI, Bronson RT, Ch'ng LE, Sieff CA, Livingston DM, et al. Genedosedependent control of hematopoiesis and hematologic tumor suppression byCBP. Genes Dev 2000;14:272–7.
[150] Shigeno K, Yoshida H, Pan L, Luo JM, Fujisawa S, Naito K, et al. Disease-relatedpotential of mutations in transcriptional cofactors CREB-binding protein andp300 in leukemias. Cancer Lett 2004;213:11–20.
[151] Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin SF, et al. Mutationstruncating the EP300 acetylase in human cancers. Nat Genet 2000;24:300–3.
[152] UrnovFD, Yee J, Sachs L, CollingwoodTN,BauerA, BeugH, et al. TargetingofN-CoRandhistone deacetylase 3 by the oncoprotein v-erbA yields a chromatin infrastructure-dependent transcriptional repression pathway. EMBO J 2000;19:4074–90.
[153] Zelent A, Waxman S, Carducci M, Wright J, Zweibel J, Gore SD. State of thetranslational science: summary of Baltimore workshop on gene re-expression asa therapeutic target in cancer January 2003. Clin Cancer Res 2004;10:4622–9.
[154] Miyamoto K, Ushijima T. Diagnostic and therapeutic applications of epigenitics.Jpn J Clin Oncol 2005;35:293–301.
[155] Gilbert J, Gore SD, Herman JG, Carducci MA. The clinical application of targetingcancer through histone acetylation and hypomethylation. Clin Cancer Res2004;10:4589–96.
[156] Maitra A, Fukushima N, van Heek NT, Matsubayashi H, Iacobuzio-Donahue CA,Rosty C, et al. Frequent hypomethylation of multiple genes overexpressed inpancreatic ductal adenocarcinoma. Cancer Res 2003;63:4158–66.
[157] Bramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, Ranga U, et al.Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltrans-ferase, represses the acetylation of histone/non histone proteins and histoneacetyltransferasedependent chromatin transcription. J Biol Chem 2004;279:51163–71.
[158] Al S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. Curcumin(diferuloylmethane) down-regulates expression of cell proliferation and anti-apoptotic and metastatic gene products through suppression of Ikappa B alphakinase and Akt activation. Mol Pharmacol 2006;69:195–206.
[159] Stimson L, Rowlands MG, Newbatt YM, Smith NF, Raynaud FI, Rogers P, et al.Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity.Mol Cancer Ther 2005;4:1521–32.
[160] Yan L, Nass SJ, Smith D, Nelson WG, Herman JG, Davidson NE. Specific inhibitionof DNMT1 by antisense oligonucleotides induces re-expression of estrogenreceptoralpha (ER) in ER-negative human breast cancer cell lines. Cancer BiolTher 2003;2:552–6.
[161] Marks PA, Miller T, Richon VM. Histone deacetylases. Curr Opin Pharmacol2003;3:344–51.
[162] Kelly WK, Richon VM, O'Connor O, Curley T, MacGregor-Curtelli B, Tong W, et al.Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamicacid administered intravenously. Clin Cancer Res 2003;9:3578–88.
[163] Byrd JC, Marcucci G, Parthun MR, Xiao JJ, Klisovic RB, Moran M, et al. A phase 1and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocyticleukemia and acute myeloid leukemia. Blood 2005;105:959–67.
[164] Xiao H, Hasegawa T, Isobe K. Both Sp1 and Sp3 are responsible for p21waf1promoter activity induced by histone deacetylase inhibitor in NIH3T3 cells. J CellBiochem 1999;73:291–302.
