Gavin Epigenetic Post-transcriptional Dysregulation 2012

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Epigenetic Post-transcriptional Dysregulation
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  Review Epigenetic and post-transcriptional dysregulation of gene expression inschizophrenia and related disease David P. Gavin  a, ⁎ , Schahram Akbarian  b a The Psychiatric Institute, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612, USA b Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester MA 01604, USA a b s t r a c ta r t i c l e i n f o  Article history: Received 1 September 2011Revised 10 November 2011Accepted 4 December 2011Available online 13 December 2011 Keywords: MethylationAcetylationBipolar disorderDemethylation5-hydroxymethylcytosineGABAGlutamateCpG islandHistone deacetylaseBDNF Cortical and subcortical dysfunction in schizophrenia includes altered expression of RNA and proteins in-volved in neurotransmission, metabolism, myelination and other functions. The molecular mechanisms un-derlying this type of alteration remain largely unknown. Here, we summarize  󿬁 ndings from postmortembrain studies and argue that transcriptional dysregulation, including changes in DNA and histone modi 󿬁 ca-tions involved in epigenetic control of gene expression, as well as microRNA-mediated post-transcriptionalmechanisms contribute to the neurobiology of schizophrenia.© 2011 Elsevier Inc. All rights reserved. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255DNA methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256DNA methylation abnormalities and schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2565-methylcytosine is not reliably measurable at the single nucleotide level using bisul 󿬁 te sequencing . . . . . . . . . . . . . . . . . . . . 2565-methylcytosine may not be most relevant in terms of transcription when located at a gene's promoter . . . . . . . . . . . . . . . . . . 257There is signi 󿬁 cant 5-methylcytosine turnover in post-mitotic neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257Histone modi 󿬁 cation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258Abnormalities in the postmortem brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258Comparisons to other disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Histone deacetylase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Histone demethylase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259DNMT inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Epigenetic and microRNA-mediated  󿬁 ne tuning of gene expression in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 Introduction Schizophrenia, a psychiatric disorder characterized by hallucina-tions and delusions, social withdrawal, disorganized speech andother symptoms typically is not associated with clear cut structural Neurobiology of Disease 46 (2012) 255 – 262 ⁎  Corresponding author. Fax: +1 312 413 4569. E-mail address:  dgavin@psych.uic.edu (D.P. Gavin).  Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$  –  see front matter © 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.nbd.2011.12.008 Contents lists available at SciVerse ScienceDirect Neurobiology of Disease  journal homepage: www.elsevier.com/locate/ynbdi  brain pathology (Harrison, 1999; Iritani, 2007). However, there ap-pears to be a select set of RNAs and proteins that are expressed at al-tered levels in at least a subset of patients. The list of misexpressedgenes in the cerebral cortex and other brain regions of individualswith schizophrenia includes transcripts involved in inhibitory or ex-citatory neurotransmission, myelination and metabolism, amongothers (Akbarian and Huang, 2009; Bauer et al., 2008; Connor andAkbarian, 2008; Curley et al., 2011; Davis and Haroutunian, 2003;Fatemi et al., 2005; Hof et al., 2002; Kristiansen et al., 2007;Maldonado-Aviles et al., 2009; Sodhi et al., 2011). These disease phe-notypes likely re 󿬂 ect a complex and diverse pathophysiology. Twodifferent approaches are gaining increasing prominence in the  󿬁 eld.The  󿬁 rst, which is the major focus of this review, is epigenetic dysre-gulation of gene expression, an approach aimed at linking changes inchromatin structure and function to alterations in gene expressionand RNA levels. The second is covered by several timely reviews inthis issue of   Neurobiology of Disease , relates to the role of microRNAsand other small RNAs involved in post-transcriptional regulation, in-cluding stability of the target RNA and expression of correspondingprotein. We argue that while there is no evidence that a speci 󿬁 c epi-genetic marking or microRNA species is consistently affected inschizophrenia, further exploration of these mechanisms potentiallycould pave the way for novel treatments and almost certainly shoulddeepen our insights into the neurobiology of psychosis.Epigenetic mechanisms provide a platform whereby genetic andenvironmental factors can be studied and understood in relation todisease. Genetic polymorphisms, as well as environmental factorssuch as, malnutrition, infections, drugs of abuse, chemical exposures,psychosocial and stochastic factors can all alter epigenetic marksresulting in inherited developmental diseases (Abdolmaleky et al.,2008; Szyf, 2009). The study of GAD1 provides an example of this in-tersection. Polymorphisms in the GAD1 gene have been associatedwith schizophrenia (Addington et al., 2005; Straub et al., 2007). Sev-eral of these polymorphisms have been associated with signs of  ‘ closed ’  chromatin at GAD1 and reduced expression (Huang et al.,2007). Poor maternal care in rats can also lead to restrictive histonemodi 󿬁 cationsandincreasedDNAmethylationreducingGAD1expres-sion (Zhang et al., 2010). These  󿬁 ndings indicate that epigeneticmechanisms provide a common pathway through which the effectsof genetic mutation and environmental factors on gene expressioncan be measured. DNA methylation Over the last decade exciting examinations have been conductedregardingDNAmethylationabnormalitiesinschizophrenia.However,within the last two years several discoveries regarding the DNAmethyl mark have shed additional light on the nature of this impor-tant modi 󿬁 cation. Until recently it has been thought that: 1) 5-methylcytosine (5MC) is reliably measurable at the single nucleotidelevel using bisul 󿬁 te sequencing; 2) 5MC is most relevant in terms of transcription when located at a gene's promoter; and 3) there islow to insigni 󿬁 cant 5MC turnover in post-mitotic neurons. Each of these three assumptions, however, can now be considered outdated.In this review, we will discuss the previous literature implicatingDNA methylation abnormalities in psychosis then speci 󿬁 cally addresshow recent studies have provided additional insight into itscharacteristics. DNA methylation abnormalities and schizophrenia The hypothesis that abnormalities in one-carbon metabolism con-tribute to schizophrenia pathophysiology date back to the 1960s and1970s when investigators noted that patients treated with  L  -methio-nineexhibitedaworseningofsymptoms(Wyattetal.,1971).Thishy-pothesis has been resurrected over the last several years when ahypermethylating milieu in inhibitory, GABAergic neurons was pos-tulated (Veldic et al., 2004) to contribute to the highly replicated re-ductions in gene expression of GAD1 and reelin (RELN) in thecerebral cortex of subjects with schizophrenia (Akbarian and Huang,2006; Akbarian et al., 1995; Fatemi et al., 2005; Guidotti et al., 2000;Hashimoto et al., 2008). These de 󿬁 cits in expression of genes with akey role for inhibitory neurotransmission are thought to contributetothebreakdownof orderlysynchronizedactivity ofneuronalassem-blies thatarethoughttobe partofthediseaseprocessofatleastsomesubjects with schizophrenia (Uhlhaas and Singer, 2010; Yoon et al.,2010) (Fig. 1). The importance of DNA methylation in regulating GAD1 and RELNhas been well-established using cell cultures and animal models(Chen et al., 2002; Noh et al., 2005; Tremolizzo et al., 2002, 2005).In postmortem experiments, two separate groups reported increasedpromoter methylation at the RELN promoter with likely consequentreduced gene expression in schizophrenia,  although there is no con-sensus yet exactly which portion of the promoter is affected (Abdolmaleky et al.,2005; Graysonetal., 2005). In addition, increasesin the mediators of DNA methylation have been reported in the post-mortem brain in schizophrenia including the methyl donor S-adenosylmethionine (Guidotti et al., 2007), and the DNA methyl-transferases DNMT1 (Veldic et al., 2004; Veldic et al., 2005) andDNMT3a(Zhubietal.,2009). DNMT1 wasalsoshowntobenegativelycorrelated in postmortem brain samples with GAD1 expression(Veldic et al., 2007) (Fig. 1). However, since these initial reports other studies have indicated areduction in gene promoter methylation, such as at COMT(Abdolmaleky et al., 2006), reduced DNA methylation associatedwith a repressive histone mark at GAD1 (Huang and Akbarian,2007), and overall degraded DNA methylation network modules,characterized by increases and decreases in methylation at individualpromoters (Mill et al., 2008). Finally, subsequent studies have notbeen able to replicate the increased methylation at the RELN promot-er or reduced methylation at the COMT promoter (Dempster et al.,2006; Mill et al., 2008; Tochigi et al., 2008). These inconsistenciespoint to substantial heterogeneity in the manifestation of thesetypes of molecular pathology between disease cases. Thus, if one as-sumes that these and other epigenetic alterations could be limitedto only a subset of cases, larger scale studies with perhaps hundredsof postmortem specimens may be necessary to uncover a disease-associated signal as opposed to random variation. 5-methylcytosine is not reliably measurable at the single nucleotide levelusing bisul  󿬁 te sequencing  Although 5-hydroxymethylcytosine (5HMC) was srcinally de-scribed in 1952 in bacteriophages (Wyatt and Cohen, 1952), its rolein mammalian gene regulation, has only recently been recognized(Kriaucionis and Heintz, 2009). 5HMC is particularly abundant inthe brain, accounting for approximately 14% of all methylcytosinesin the cortex (Globisch et al., 2010; Munzel et al., 2010). 5MC is con-verted to 5HMC by the TET family of enzymes (TET1, TET2, TET3) (Itoet al., 2010). Studies indicate that 5HMC is abundantly proximal totranscription start sites (TSS) ( Jin et al., 2011), in exons (Ficz et al., 2011; Xu et al., 2011), CpG islands (Ficz et al., 2011; Xu et al.,2011), and LINE elements (Ficz et al., 2011). The role of the 5HMC modi 󿬁 cation in transcriptional regulation is currently under activeexploration, with some evidence indicating that it is a facilitativemark (Ficz et al., 2011; Jin et al., 2011), likely as a result of its inabilityto bind methyl-CpG binding domain (MBD) proteins associated withrepressive chromatinremodeling(Valinlucket al.,2004). However,incertain tissues, including embryonic stem cells, 5HMC was also foundto exert negative effects on gene expression (Pastor et al., 2011;Robertson et al., 2011). 256  D.P. Gavin, S. Akbarian / Neurobiology of Disease 46 (2012) 255 –  262  In addition to 5HMC, several other cytosine modi 󿬁 cations have re-cently been identi 󿬁 ed in the brain, including 5-hydroxymethyluracil(5HMU), 5-formylcytosine (5FC), and 5-carboxylcytosine (5CaC)(He et al., 2011; Ito et al., 2011). In the cortex, 5MC is thought to ac-count for approximately 4.5% of cytosines (Globisch et al., 2010),5HMC 0.65% (Globisch et al., 2010), 5FC 0.0015%, and 5CaC is 50-fold less abundant than 5FC (Ito et al., 2011).Prior studies have mostly utilized bisul 󿬁 te sequencing to measureDNA methylation site-speci 󿬁 cally in the genome. However, the factthat bisul 󿬁 te sequencing is unable to discriminate 5HMC from 5MCand 5CaC from unmethylated cytosine may affect interpretation of prior animal and human postmortem studies conducted using thismethod. Assuming 5MC and 5HMC are functionally different modi 󿬁 -cations, a shift in a genomic region from 5MC to 5HMC or vice versamay be as important in terms of gene expression as the overall levelof methylcytosines (combined 5MC and 5HMC) that is measured bybisul 󿬁 te sequencing. This lack of assay speci 󿬁 city may also contributeto non-replication in prior postmortem gene promoter DNA methyla-tion studies. 5-methylcytosine may not be most relevant in terms of transcriptionwhen located at a gene's promoter  Another aspect of DNA methylation that has added to the com-plexity of studying this modi 󿬁 cation is discerning the gene regionmost relevant in terms of its impact on transcription. Most prior in-vestigations examine genomic locations within several hundredbases of the in silico predicted transcription start site (TSS). The es-tablishment of a gene's TSS in itself is not always well-de 󿬁 ned. A re-cent study demonstrated that the in silico predicted TSS does notalways agree with experimental veri 󿬁 cation in cell lines (Chen et al.,2011). However, it should also be noted that a gene's TSS can differdepending on tissue-type. Therefore, identi 󿬁 cation of a gene's TSS ina cell line may not correspond to its TSS in neurons in vivo. Addition-ally, several studies indicate that the areas that surround CpG islands,or  “ CpG island shores, ”  even if they are located 1 kb from the pre-dicted TSS, are more important for gene expression than CpG islandsor methylation sites near gene promoters (Doi et al., 2009; Irizarry etal., 2009). However, recently intragenic CpG island methylation, rath-er than  ‘ shores ’  have been implicated as key transcriptional regulato-ry regions (Deaton et al., 2011). On the other hand, numerous cellculture (Chen et al., 2011; Martinowich et al., 2003), animal (Dennis and Levitt, 2005; Levenson et al., 2006; Miller et al., 2008; Weaveret al., 2004), and even postmortem brain studies (Abdolmaleky etal., 2005; Grayson et al., 2005; Lintas and Persico, 2010) con 󿬁 rm therepressive effects of promoter methylation on gene expression. Con-sidering even a single methylated CpG can silence gene expression,determining methylcytosine locations most relevant to transcriptionis essential for future DNA methylation studies (Sharma et al., 2010). There is signi  󿬁 cant 5-methylcytosine turnover in post-mitotic neurons The stability of the covalent bond linking a methyl group to cyto-sine had been thought to prevent active DNA demethylation (as op-posed to its passive removal that occurs without maintenance DNAmethylation in dividing cells) in non-dividing cells, such as most neu-rons (Ooi and Bestor, 2008). Emerging data indicate that the DNAmethylation status of a given gene promoter is the consequence of adynamic equilibrium between DNA methylation and putative de-methylation activity (Cortellino et al., 2011; Guidotti et al., 2011;Szyf, 2010). There is increasing support for a means of active DNA de-methylation that involves  󿬁 rst deaminating 5MC or 5HMC to formthymine or 5HMU, respectively (Guo et al., 2011; Morgan et al.,2004; Popp et al., 2010). The resultant TpG:methyl-CpG or Fig. 1.  Hypothetical molecular model of dynamic chromatin state changes. 1) In normal brains, the promoter region of brain-derived neurotrophic factor (BDNF) or glutamic aciddecarboxylase (GAD1) genes are unmethylated which allows for active gene expression. However, in schizophrenia brain overexpression of DNA methyltransferase (DNMT) en-zymes increase gene promoter methylation leading to a reduction in gene expression. 2) Subsequently, a positive feedback loop of gene repression occurs. Methyl-CpG bindingdomain (MBD) proteins bind to 5-methylcytosine (5MC) which can recruit enzymes that produce restrictive histone modi 󿬁 cations such as those that methylate lysine 27 or lysine9 of histone 3 (KMTs) and deacetylate histones, such as histone deacetylases (HDACs) (Fuks et al., 2003b; Jones et al., 1998). DNMTs also can recruit KMTs and HDACs (Bachman et al.,2001; Fuks etal.,2000, 2001, 2003a; Robertson et al.,2000; Rountree etal., 2000), and KMTs canrecruitDNMTs(Epsztejn-Litman etal.,2008). Heterochromatin protein-1 (HP1) binds methylated lysine 9, further condensing chromatin and can recruit DNMTs as well (Fuks et al., 2003a; Jacobs and Khorasanizadeh, 2002; Lehnertz et al., 2003; Wallace andOrr-Weaver, 2005). The combination of these factors results in long-term gene silencing, and prevent binding of a DNA demethylating protein (GADD45). In schizophrenia the re-versal of this state may require powerful chromatin altering medications, capable of inhibiting KMTs or DNMTs. On the other hand, animal models of depression suggest that in-creased KMT expression at certain gene promoters (e.g., NR2B) can have an antidepressant effect ( Jiang et al., 2010). The inhibition of KMTs and DNMTs may alter the balance to astate more conducive to DNA demethylation. 3) Tet enzymes (orange) convert 5-methylcytosine (5MC) to 5-hydroxymethylcytosine (5HMC), which may be a necessary interme-diary in DNA demethylation. It has been suggested that 5HMC allows promoter regions to remain poised for activation (Pastor et al., 2011). 4a and 4b) GADD45 recruits a cytidinedeaminase (CD) (blue), which converts 5MC to thymine or 5HMC to 5-hydroxymethyluracil (5HMU) resulting in a TpG:methyl-CpG or 5HMUpG:methyl-CpG mismatch, respec-tively (Cortellino et al., 2011; Guo et al., 2011; Rai et al., 2008). 5a and 5b) GADD45 recruits a thymidine glycosylase (TG) (purple) to remove either thymine or 5HMU, which isthen replaced by a non-methylated cytosine (Cortellino et al., 2011; Rai et al., 2008). 6) The gene is now no longer methylated and is reactivated long-term.257 D.P. Gavin, S. Akbarian / Neurobiology of Disease 46 (2012) 255 –  262  5HMUpG:methyl-CpGmismatchis thenexcised using a DNA glycosy-lase (Boland and Christman, 2008; Cortellino et al., 2011; Hendrich etal., 1999). The GADD45 proteins (Barreto et al., 2007; Ma et al., 2009;Schmitz et al., 2009) are thought to be master coordinators of thisprocess by recruiting deaminases and glycosylases to promoter re-gions (Cortellino et al., 2011; Rai et al., 2008). Recently, Guo et al. (2011)indicatedthathydroxylationof5MCto5HMC,followedbyde-amination to 5HMU, are necessary intervening steps for electrocon-vulsive shock (a type of treatment often used for severe forms of depression)-induced demethylation in the mouse brain (Guo et al.,2011).We recently reported decreased GADD45b promoter binding inthe cerebral cortex of patients with major psychosis (i.e., combinedbipolar with psychotic features and schizophrenia patients) at thebrain-derived neurotrophic factor ( BDNF  ) (encoding a nerve growthfactor protein and key regulator of GABAergic signaling in the brain(Marty et al., 1997)) promoter. This decrease in binding was associat-ed with a decrease in BDNF expression and promoter hypermethyla-tion (Gavin et al., 2012). Decreased binding could not be explained bydecreased gene expression as we also report an increase in GADD45bmRNA and protein in these same patients. It is possible that the ob-served increase in expression is compensatory to decreased binding.One explanation for lower GADD45b promoter binding in psychosisis that restrictive histone modi 󿬁 cations, which have been reportedin psychosis, limit GADD45b promoter access (Benes et al., 2007;Gavin et al., 2008, 2009b; Huang et al., 2007; Sharma et al., 2008).This is supported by the fact that the sister protein of GADD45b,GADD45a, avidly binds to acetylated histones, and does not signi 󿬁 -cantly bind to either nonacetylated histones or naked DNA (Carrieret al., 1999). Whether GADD45b has similar properties has yet to beestablished.Recent discoveries regarding the nature of DNA methylation mayhave implications for both the interpretation of prior studies and fu-ture investigations. If one in seven methylcytosines measured via bi-sul 󿬁 te sequencing is a 5HMC, which may be functionally opposite of the repressive modi 󿬁 cation 5MC, then studies utilizing this methodneed to be viewed with that consideration in mind. Additionally,while 5MC was thought to be a nearly permanent modi 󿬁 cation innondividing cells recent studies indicate that its removal does occurin post-mitoticneurons.Therefore,at timesmeasuresof DNAmethyl-ationatpromotersmaybesnapshots,ratherthanare 󿬂 ectionofaper-manent state. These recent discoveries are expected to have atremendous impact on the  󿬁 eld moving forward as they are increas-ingly taken into account. Histone modi 󿬁 cation  Abnormalities in the postmortem brain Chromatin is essentially a chain of nucleosomes connected bynon-nucleosomal (linker) DNA. Each nucleosome is comprised of 146 bp of DNA wrapped around an octamer of small proteins, thecore histones H3/H4/H2A/H2B. It is thought that there are up to 70(amino acid) residue speci 󿬁 c modi 󿬁 cations, including methylationand acetylation, as well as ubiquitinylation or SUMOylation or poly-ADP ribosylation of speci 󿬁 c lysine residues, and phosphorylation of serine, threonine and tyrosine residues, arginine methylation andother types of post-translational histone modi 󿬁 cations (PTMs)(Taverna et al., 2007; Weake and Workman, 2008). Many of thesePTMs play an important role for chromatin remodeling complexes in-volved in the regulation of gene expression and chromatin structures(Taverna et al., 2007; Zhou and Zhou, 2011). Of note, multiple groupsreported that site-speci 󿬁 c PTMs are suf  󿬁 ciently maintained to allowquanti 󿬁 cation in healthy and diseased (postmortem) brain via chro-matin immunoprecipitation followed by qPCR to map the epigeneticstatus at speci 󿬁 c loci (Al-Mahdawi et al., 2008; Ernst et al., 2009;Huang et al., 2006), or massively parallel sequencing and other tech-niques for genome-wide coverage (Cheung et al., 2010; Maunakea etal., 2010). To date, however, very little is known about histone PTMchanges in schizophrenia brain. For example, methylated arginine17 of histone H3 (H3R17me), which in cortical neurons is expressedat much higher levels than in their surrounding non-neuronal cells,is associated with reduced metabolic gene expression in prefrontalcortex of a subset of subjects with schizophrenia (Akbarian et al.,2005). There are also complex shifts in open and repressivechromatin-associated histone and DNA methylation changesat a sub-set of GABAergic gene promoters (Huang and Akbarian, 2007; Huanget al., 2007; Mellios et al., 2009). Comparisons to other disorders Complex shifts in histone PTMs and DNA methylation are a sharedfeature of unipolar depression. In rodent models, low maternal carehas been shown to lead to restrictive histone PTMs and increasedDNA methylation of a gene encoding a negative regulator of theHPA axis (Weaver et al., 2004, 2005, 2006). Changes at this samegene were also found in postmortem brains of suicide victims whowere abused as children, and in cord blood samples of infants bornto depressed mothers (McGowan et al., 2009; Oberlander et al.,2008). Animal models have also demonstrated that low maternalcare and maltreatment of pups also lead to epigenetically-mediateddownregulation of GAD1 and BDNF (Roth et al., 2009; Zhang et al.,2010). In genome-wide scans of repressive histone PTMs in mice ex-posed to either social defeat or social isolation the vast majority of genes exhibited an increase in repressive marks that were reversiblewith imipramine (Wilkinson et al., 2009). In agreement with repres-sive chromatin being associated with depression, histonedeacetylase-5 (HDAC5) overexpression, a state repressive to tran-scription, prevents the imipramine-mediated reversal of chronic de-feat stress (Tsankova et al., 2006).By contrast, several studies have indicated that decreasing repres-sive histone PTMs may promote depression, while increasing particu-lar histone PTMs may in fact have antidepressant actions. Renthal etal. (2007) reported that HDAC5 knockout mice are hypersensitive tochronic defeat stress (Renthal et al., 2007). Similarly, when HDAC in-hibitors (HDACi) are administered alone to mice it increases mea-sures of behavioral despair (Schroeder et al., 2007). In a paper by Jiang et al. (2010) mice that overexpress Setdb1, a histone H3-lysine9 methyltransferase (HMT) which induces a restrictive chromatinstate, display decreased levels of learned helplessness compared towildtypemice.Thesemicealsoshowincreasedsucroseconsumption,and decreased immobility in tail suspension and forced swim tests( Jiang et al., 2010). These data indicate that at least for depressionits association with chromatin state is not simply dependent uponmore or less restrictive chromatin increasing the likelihood of devel-opingdepression.Rather,it appears thatmoresubtle differencesexistthat may be re 󿬂 ected as different outcomes depending on the para-digms used to assess animal depression models, the speci 󿬁 c chroma-tin remodeling complexes involved, and the target genes examined.To date there have been few studies aimed at discerning epigenet-ic changesuniquetoparticularmentaldisorders.Infact,manystudiescombine patients with schizophrenia and bipolar disorder with psy-chotic features in order to increase power based on genetic and epi-demiological evidence suggesting these are pathogenetically relateddisorders (Connor and Akbarian, 2008; Craddock et al., 2006;Guidotti et al., 2007; Mill et al., 2008; Pope and Yurgelun-Todd,1990; Reichenberg et al., 2009; Tsuang, 1991; Veldic et al., 2005).Generally, authors note no differences between these diagnoses. Inone of the few studies comparing two mental disorders, we reportedlower peripheral blood cell acetylated histone H3 in patients with bi-polar disorder compared to those with schizophrenia at baseline andsmaller increases in acetylated histone 3 or 4 in schizophrenia 258  D.P. Gavin, S. Akbarian / Neurobiology of Disease 46 (2012) 255 –  262
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