Neurobiology of Disease 46 (2012) 255262

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Neurobiology of Disease
journal homepage: www.elsevier.com/locate/ynbdi

Review

Epigenetic and post-transcriptional dysregulation of gene expression in

schizophrenia 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 r t i c l e i n f o a b s t r a c t

Article history: Cortical and subcortical dysfunction in schizophrenia includes altered expression of RNA and proteins in-
Received 1 September 2011 volved in neurotransmission, metabolism, myelination and other functions. The molecular mechanisms un-
Revised 10 November 2011 derlying this type of alteration remain largely unknown. Here, we summarize ndings from postmortem
Accepted 4 December 2011
brain studies and argue that transcriptional dysregulation, including changes in DNA and histone modica-
Available online 13 December 2011
tions involved in epigenetic control of gene expression, as well as microRNA-mediated post-transcriptional
Keywords:
mechanisms contribute to the neurobiology of schizophrenia.
Methylation 2011 Elsevier Inc. All rights reserved.
Acetylation
Bipolar disorder
Demethylation
5-hydroxymethylcytosine
GABA
Glutamate
CpG island
Histone deacetylase
BDNF

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
DNA methylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
DNA methylation abnormalities and schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
5-methylcytosine is not reliably measurable at the single nucleotide level using bisulte sequencing . . . . . . . . . . . . . . . . . . . . 256
5-methylcytosine may not be most relevant in terms of transcription when located at a gene's promoter . . . . . . . . . . . . . . . . . . 257
There is signicant 5-methylcytosine turnover in post-mitotic neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Histone modication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Abnormalities in the postmortem brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Comparisons to other disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Histone deacetylase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Histone demethylase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
DNMT inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Epigenetic and microRNA-mediated ne tuning of gene expression in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

Introduction

Corresponding author. Fax: + 1 312 413 4569.

Schizophrenia, a psychiatric disorder characterized by hallucina-
E-mail address: dgavin@psych.uic.edu (D.P. Gavin). tions and delusions, social withdrawal, disorganized speech and
Available online on ScienceDirect (www.sciencedirect.com). other symptoms typically is not associated with clear cut structural

0969-9961/$ see front matter 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.nbd.2011.12.008
256 D.P. Gavin, S. Akbarian / Neurobiology of Disease 46 (2012) 255262
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 misexpressed
genes in the cerebral cortex and other brain regions of individuals
with schizophrenia includes transcripts involved in inhibitory or ex-
citatory neurotransmission, myelination and metabolism, among
others (Akbarian and Huang, 2009; Bauer et al., 2008; Connor and
Akbarian, 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 reect a complex and diverse pathophysiology. Two
different 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 in
chromatin structure and function to alterations in gene expression
and RNA levels. The second is covered by several timely reviews in
this issue of Neurobiology of Disease, relates to the role of microRNAs
and other small RNAs involved in post-transcriptional regulation, in-
cluding stability of the target RNA and expression of corresponding
protein. We argue that while there is no evidence that a specic epi-
genetic marking or microRNA species is consistently affected in
schizophrenia, further exploration of these mechanisms potentially
could pave the way for novel treatments and almost certainly should
deepen our insights into the neurobiology of psychosis.
Epigenetic mechanisms provide a platform whereby genetic and
environmental factors can be studied and understood in relation to
disease. Genetic polymorphisms, as well as environmental factors
such as, malnutrition, infections, drugs of abuse, chemical exposures,
psychosocial and stochastic factors can all alter epigenetic marks
resulting 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 associated
with 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 histone
modications and increased DNA methylation reducing GAD1 expres-
sion (Zhang et al., 2010). These ndings indicate that epigenetic
mechanisms provide a common pathway through which the effects
of genetic mutation and environmental factors on gene expression
can be measured.
DNA methylation
Over the last decade exciting examinations have been conducted
regarding DNA methylation abnormalities in schizophrenia. However,
within the last two years several discoveries regarding the DNA
methyl mark have shed additional light on the nature of this impor-
tant modication. Until recently it has been thought that: 1) 5-
methylcytosine (5MC) is reliably measurable at the single nucleotide
level using bisulte sequencing; 2) 5MC is most relevant in terms of
transcription when located at a gene's promoter; and 3) there is
low to insignicant 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 implicating
DNA methylation abnormalities in psychosis then specically address
how recent studies have provided additional insight into its
characteristics.
DNA methylation abnormalities and schizophrenia
The hypothesis that abnormalities in one-carbon metabolism con-
tribute to schizophrenia pathophysiology date back to the 1960s and
1970s when investigators noted that patients treated with L-methio-
nine exhibited a worsening of symptoms (Wyatt et al., 1971). This hy-
pothesis has been resurrected over the last several years when a
hypermethylating 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 the
cerebral 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 decits in expression of genes with a
key role for inhibitory neurotransmission are thought to contribute
to the breakdown of orderly synchronized activity of neuronal assem-
blies that are thought to be part of the disease process of at least some
subjects with schizophrenia (Uhlhaas and Singer, 2010; Yoon et al.,
2010) (Fig. 1).
The importance of DNA methylation in regulating GAD1 and RELN
has 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 increased
promoter methylation at the RELN promoter with likely consequent
reduced gene expression in schizophrenia, although there is no con-
sensus yet exactly which portion of the promoter is affected
(Abdolmaleky et al., 2005; Grayson et al., 2005). In addition, increases
in 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) and
DNMT3a (Zhubi et al., 2009). DNMT1 was also shown to be negatively
correlated in postmortem brain samples with GAD1 expression
(Veldic et al., 2007) (Fig. 1).
However, since these initial reports other studies have indicated a
reduction in gene promoter methylation, such as at COMT
(Abdolmaleky et al., 2006), reduced DNA methylation associated
with 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 individual
promoters (Mill et al., 2008). Finally, subsequent studies have not
been 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 inconsistencies
point to substantial heterogeneity in the manifestation of these
types of molecular pathology between disease cases. Thus, if one as-
sumes that these and other epigenetic alterations could be limited
to only a subset of cases, larger scale studies with perhaps hundreds
of 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 level
using bisulte sequencing
Although 5-hydroxymethylcytosine (5HMC) was originally de-
scribed in 1952 in bacteriophages (Wyatt and Cohen, 1952), its role
in mammalian gene regulation, has only recently been recognized
(Kriaucionis and Heintz, 2009). 5HMC is particularly abundant in
the brain, accounting for approximately 14% of all methylcytosines
in 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) (Ito
et al., 2010). Studies indicate that 5HMC is abundantly proximal to
transcription 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
modication in transcriptional regulation is currently under active
exploration, with some evidence indicating that it is a facilitative
mark (Ficz et al., 2011; Jin et al., 2011), likely as a result of its inability
to bind methyl-CpG binding domain (MBD) proteins associated with
repressive chromatin remodeling (Valinluck et al., 2004). However, in
certain tissues, including embryonic stem cells, 5HMC was also found
to exert negative effects on gene expression (Pastor et al., 2011;
Robertson et al., 2011).
 D.P. Gavin, S. Akbarian / Neurobiology of Disease 46 (2012) 255262 257

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 acid
decarboxylase (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 binding
domain (MBD) proteins bind to 5-methylcytosine (5MC) which can recruit enzymes that produce restrictive histone modications such as those that methylate lysine 27 or lysine
9 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 et al., 2000, 2001, 2003a; Robertson et al., 2000; Rountree et al., 2000), and KMTs can recruit DNMTs (Epsztejn-Litman et al., 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 and
Orr-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 a
state 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 cytidine
deaminase (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 is
then 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.

In addition to 5HMC, several other cytosine modications have re-
cently been identied 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 bisulte sequencing to measure
DNA methylation site-specically in the genome. However, the fact
that bisulte sequencing is unable to discriminate 5HMC from 5MC
and 5CaC from unmethylated cytosine may affect interpretation of
prior animal and human postmortem studies conducted using this
method. Assuming 5MC and 5HMC are functionally different modi-
cations, a shift in a genomic region from 5MC to 5HMC or vice versa
may be as important in terms of gene expression as the overall level
of methylcytosines (combined 5MC and 5HMC) that is measured by
bisulte sequencing. This lack of assay specicity may also contribute
to non-replication in prior postmortem gene promoter DNA methyla-
tion studies.
depending on tissue-type. Therefore, identication of a gene's TSS in
a 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 islands
or methylation sites near gene promoters (Doi et al., 2009; Irizarry et
al., 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 cell
culture (Chen et al., 2011; Martinowich et al., 2003), animal (Dennis
and Levitt, 2005; Levenson et al., 2006; Miller et al., 2008; Weaver
et al., 2004), and even postmortem brain studies (Abdolmaleky et
al., 2005; Grayson et al., 2005; Lintas and Persico, 2010) conrm the
repressive effects of promoter methylation on gene expression. Con-
sidering even a single methylated CpG can silence gene expression,
determining methylcytosine locations most relevant to transcription
is essential for future DNA methylation studies (Sharma et al., 2010).
There is signicant 5-methylcytosine turnover in post-mitotic neurons

5-methylcytosine may not be most relevant in terms of transcription
when located at a gene's promoter
Another aspect of DNA methylation that has added to the com-
plexity of studying this modication is discerning the gene region
most relevant in terms of its impact on transcription. Most prior in-
vestigations examine genomic locations within several hundred
bases of the in silico predicted transcription start site (TSS). The es-
tablishment of a gene's TSS in itself is not always well-dened. A re-
cent study demonstrated that the in silico predicted TSS does not
always agree with experimental verication in cell lines (Chen et al.,
2011). However, it should also be noted that a gene's TSS can differ
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 DNA
methylation in dividing cells) in non-dividing cells, such as most neu-
rons (Ooi and Bestor, 2008). Emerging data indicate that the DNA
methylation status of a given gene promoter is the consequence of a
dynamic 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 form
thymine or 5HMU, respectively (Guo et al., 2011; Morgan et al.,
2004; Popp et al., 2010). The resultant TpG:methyl-CpG or
258 D.P. Gavin, S. Akbarian / Neurobiology of Disease 46 (2012) 255262
5HMUpG:methyl-CpG mismatch is then excised using a DNA glycosy-
lase (Boland and Christman, 2008; Cortellino et al., 2011; Hendrich et
al., 1999). The GADD45 proteins (Barreto et al., 2007; Ma et al., 2009;
Schmitz et al., 2009) are thought to be master coordinators of this
process by recruiting deaminases and glycosylases to promoter re-
gions (Cortellino et al., 2011; Rai et al., 2008). Recently, Guo et al.
(2011) indicated that hydroxylation of 5MC to 5HMC, followed by de-
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 in
the cerebral cortex of patients with major psychosis (i.e., combined
bipolar with psychotic features and schizophrenia patients) at the
brain-derived neurotrophic factor (BDNF) (encoding a nerve growth
factor 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 by
decreased gene expression as we also report an increase in GADD45b
mRNA 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 psychosis
is that restrictive histone modications, which have been reported
in 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 (Carrier
et al., 1999). Whether GADD45b has similar properties has yet to be
established.
Recent discoveries regarding the nature of DNA methylation may
have implications for both the interpretation of prior studies and fu-
ture investigations. If one in seven methylcytosines measured via bi-
sulte sequencing is a 5HMC, which may be functionally opposite of
the repressive modication 5MC, then studies utilizing this method
need to be viewed with that consideration in mind. Additionally,
while 5MC was thought to be a nearly permanent modication in
nondividing cells recent studies indicate that its removal does occur
in post-mitotic neurons. Therefore, at times measures of DNA methyl-
ation at promoters may be snapshots, rather than a reection of a per-
manent state. These recent discoveries are expected to have a
tremendous impact on the eld moving forward as they are increas-
ingly taken into account.
Histone modication
Abnormalities in the postmortem brain
Chromatin is essentially a chain of nucleosomes connected by
non-nucleosomal (linker) DNA. Each nucleosome is comprised of
146 bp of DNA wrapped around an octamer of small proteins, the
core histones H3/H4/H2A/H2B. It is thought that there are up to 70
(amino acid) residue specic modications, including methylation
and acetylation, as well as ubiquitinylation or SUMOylation or poly-
ADP ribosylation of specic lysine residues, and phosphorylation of
serine, threonine and tyrosine residues, arginine methylation and
other types of post-translational histone modications (PTMs)
(Taverna et al., 2007; Weake and Workman, 2008). Many of these
PTMs 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 groups
reported that site-specic PTMs are sufciently maintained to allow
quantication in healthy and diseased (postmortem) brain via chro-
matin immunoprecipitation followed by qPCR to map the epigenetic
status at specic 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 et
al., 2010). To date, however, very little is known about histone PTM
changes in schizophrenia brain. For example, methylated arginine
17 of histone H3 (H3R17me), which in cortical neurons is expressed
at much higher levels than in their surrounding non-neuronal cells,
is associated with reduced metabolic gene expression in prefrontal
cortex of a subset of subjects with schizophrenia (Akbarian et al.,
2005). There are also complex shifts in open and repressive
chromatin-associated histone and DNA methylation changes at a sub-
set of GABAergic gene promoters (Huang and Akbarian, 2007; Huang
et al., 2007; Mellios et al., 2009).
Comparisons to other disorders
Complex shifts in histone PTMs and DNA methylation are a shared
feature of unipolar depression. In rodent models, low maternal care
has been shown to lead to restrictive histone PTMs and increased
DNA methylation of a gene encoding a negative regulator of the
HPA axis (Weaver et al., 2004, 2005, 2006). Changes at this same
gene were also found in postmortem brains of suicide victims who
were abused as children, and in cord blood samples of infants born
to depressed mothers (McGowan et al., 2009; Oberlander et al.,
2008). Animal models have also demonstrated that low maternal
care and maltreatment of pups also lead to epigenetically-mediated
downregulation 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 reversible
with imipramine (Wilkinson et al., 2009). In agreement with repres-
sive chromatin being associated with depression, histone
deacetylase-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 et
al. (2007) reported that HDAC5 knockout mice are hypersensitive to
chronic 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-lysine
9 methyltransferase (HMT) which induces a restrictive chromatin
state, display decreased levels of learned helplessness compared to
wild type mice. These mice also show increased sucrose consumption,
and decreased immobility in tail suspension and forced swim tests
(Jiang et al., 2010). These data indicate that at least for depression
its association with chromatin state is not simply dependent upon
more or less restrictive chromatin increasing the likelihood of devel-
oping depression. Rather, it appears that more subtle differences exist
that may be reected as different outcomes depending on the para-
digms used to assess animal depression models, the specic chroma-
tin remodeling complexes involved, and the target genes examined.
To date there have been few studies aimed at discerning epigenet-
ic changes unique to particular mental disorders. In fact, many studies
combine 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 related
disorders (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. In
one of the few studies comparing two mental disorders, we reported
lower peripheral blood cell acetylated histone H3 in patients with bi-
polar disorder compared to those with schizophrenia at baseline and
smaller increases in acetylated histone 3 or 4 in schizophrenia
 D.P. Gavin, S. Akbarian / Neurobiology of Disease 46 (2012) 255262
compared to bipolar patients when they were either clinically treated
with the HDACi valproic acid (VPA) or their blood cells were cultured
with the more potent HDACi Trichostatin A (TSA) (Gavin et al., 2009a;
Sharma et al., 2006). These studies suggest that at baseline bipolar pa-
tient chromatin is more open and that it is also more plastic com-
pared to schizophrenia. A genome-wide study of DNA methylation
also using blood cells found a number of genes with similar DNA
methylation abnormalities shared by both disorders, as well as sever-
al sites in which differences from controls were in opposite directions
(Dempster et al., 2011). Interestingly, a study by Higuchi et al., 2011
showed that changes in blood cell DNMT enzyme expression varies
based on mood state with similar changes in depressed bipolar pa-
tients and unipolar depression. Taken together, it is tempting to spec-
ulate that shared aspects of mental disorders have common
epigenetic gene regulatory abnormalities, while other aspects may
be unique to particular disorders.
Therapeutics
Histone deacetylase inhibitors
In recent years there has been a great deal of interest in the use of
HDACi as treatments for numerous psychiatric and neurological dis-
orders. Valproic acid (VPA) is a nonspecic HDACi, and has proven ef-
fectiveness for bipolar disorder. It is thought to mediate this effect
through enhancing GABA transmission by increasing GAD (including
GAD1) expression and inhibition of GSK-3 signaling. Both these ef-
fects are mediated in part by its HDAC inhibitory effects (Phiel et al.,
2001). However, while several clinical studies indicate VPA may in
some instances serve as a useful adjunct to antipsychotic treatment
it has not been shown to be reliably effective in schizophrenia
(Schwarz et al., 2008). These clinical characteristics may correspond
to differences in epigenetic state between bipolar disorder and
schizophrenia. In support of this hypothesis we reported that bipolar
patients show signicantly greater increases in peripheral blood cell
acetylated histone H3 when either clinically treated with VPA or
when their blood cells are cultured with the more potent TSA. This
may lead to a greater ability among bipolar patients to increase
genes, such as GAD1, a gene implicated in both disorders (Guidotti
et al., 2000; Huang and Akbarian, 2007; Thompson Ray et al., 2011).
Possible explanations for the inability of HDACi to increase histone
acetylation in schizophrenia are abnormalities in more stable epige-
netic factors, such as histone or DNA methylation. For example, a re-
duction in (open chromatin-associated) H3K4 methylation and
increases in repressive H3K9 methylation have been reported in
schizophrenia (Gavin et al., 2009b; Huang et al., 2007). If schizophre-
nia is characterized by abnormalities in other histone marks then
HDACi may not be effective in schizophrenia. In addition, abnormali-
ties in DNA methylation have been shown to be present in schizo-
phrenia postmortem brain studies (Veldic et al., 2004). The reported
over-expression of DNA methylating enzymes may reduce respon-
siveness to HDACi. However, it should be noted that differences in
VPA's effectiveness may not be a result of epigenetic differences, but
rather a result of the fact that VPA like lithium, inhibits GSK-3 and
other important signaling pathways operating outside of the cell nu-
cleus. These are pathways more highly implicated in bipolar disorder
than schizophrenia. Resolving whether HDACi have more therapeutic
potential for bipolar disorder compared to schizophrenia based on
differences in epigenetic factors or because VPA inhibits GSK-3 path-
ways would require clinical trials of novel HDACi with larger cohorts
than those reported in the previous studies.
Histone demethylase inhibitors
Some of the monoamine oxidase inhibitors acting as powerful an-
tidepressants primarily by upregulating effective brain catecholamine
259
levels, including tranylcypromine and phenelzine, also block histone
demethylase activity targeted at H3K4 and H3K9 lysines (Peter and
Akbarian, 2011). Whether this mechanism of action plays some role
in the drugs' clinical prole, or whether clinically unrealistic doses
are necessary to achieve histone demethylase blockade is unknown
in humans (Sun et al., 2010).
DNMT inhibitors
DNMT inhibitors include agents such as doxorubicin, 5-aza-2-
deoxycytidine (AZA), zebularine (ZEB), and procainamide. These
drugs have been shown to increase the expression of GAD1 and
RELN in cultured cell lines while decreasing the expression of
DNMT1 (Kundakovic et al., 2007). Unfortunately, AZA and ZEB are
the most potent DNMT1 inhibitors, but do not cross the blood brain
barrier (Yoo et al., 2004).
Satta et al. (2008) reported that nicotine decreases DNMT1 ex-
pression in GABAergic mouse neurons leading to decreased methyla-
tion at the GAD1 promoter and increased GAD1 protein expression
(Satta et al., 2008). This effect was found to occur as a result of nico-
tinic receptor agonism. The specic pathways from the nicotinic re-
ceptor to the inhibition at the level of the DNMT1 receptor have yet
to be established. It is tempting to speculate that this epigenetic effect
has some connection with the fact that 80% of schizophrenia patients
use tobacco (de Leon, 1996), and the benecial effects of an alpha7-
nicotine receptor agonist in small clinical studies (Olincy et al.,
2006). However, it should be stated that it is possible that nicotine af-
fects a variety of neurotransmitter pathways, including glutamate,
GABA, and dopamine which may provide its benecial effects outside
of epigenetic changes.
Clozapine and quetiapine, but not haloperidol or risperidone have
also been shown to decrease DNA methylation (Guidotti et al., 2011).
The metabotropic glutamate agonist LY379268 and clozapine have
been recently shown to induce the expression of GADD45b, and
LY379268 increases GADD45b binding to BDNF, RELN, and GAD1 pro-
moters perhaps leading to decreased promoter methylation and in-
crease social interaction in mice (Matrisciano et al., 2011). The
mechanisms of these effects remain unknown. One possibility is
that this is a downstream effect of neurotransmitter receptor binding.
However, Huang et al. demonstrated that clozapine and not haloper-
idol is able to increase H3K4 methylation outside of its effects on D2
and D3 dopamine receptors (Huang et al., 2007). Clearly, clozapine
and quetiapine affect a large number of neurotransmitter receptors
besides D2 and D3, which may account for their therapeutic effects
outside of DNA methylation. A better understanding of these path-
ways may lead to novel therapeutics that more efciently target spe-
cic pathways in the brain.
Epigenetic and microRNA-mediated ne tuning of gene expression
in the brain
As indicated in the introductory chapter, it is likely that multiple
layers of regulation govern the expression of specic gene products
in the brain. In addition to the epigenetic mechanisms discussed
above, microRNAs ne-tune expression via post-transcriptional
mechanisms (mainly involving RNA stability and protein translation).
They are derived from longer precursor molecules, are incorporated
to the RNA-induced silencing complex (RISC) and interact with com-
plementary regions within the 3 untranslated region (3-UTR) and
other portions of their target mRNAs (Bartel, 2004). It is likely that
chromatin- and microRNA-mediated mechanisms operate in parallel,
or sequentially during development, to govern expression of the
same gene. A case in point is BDNF, a member of the neurotrophin
family of molecules that plays a prominent role during cortical devel-
opment and maturation (An et al., 2008; Baquet et al., 2005) and in a
variety of neuropsychiatric diseases, including depression and
260 D.P. Gavin, S. Akbarian / Neurobiology of Disease 46 (2012) 255262
schizophrenia (Buckley et al., 2007; Duman and Monteggia, 2006;
Krishnan and Nestler, 2010). A recent postmortem study on human
prefrontal cortex presented evidence that gene expression activity
at the BDNF locus progressively increases from prenatal period to
early adolescence and puberty, with parallel changes in both BDNF
transcript and open chromatin-associated histone H3-lysine 4 (tri)
methylation at multiple BDNF gene promoters (Mellios et al., 2008).
While this type of developmentally regulated chromatin remodeling
plays an important role for the rising levels of BDNF expression dur-
ing childhood and adolescence, post-transcriptional regulation of
BDNF via microRNA-mediated mechanisms operating at the gene's
3-UTR is thought to be particularly important in the mature cortex
(Mellios et al., 2008). These ndings highlight the potential complex-
ities of gene regulation across the lifespan of the human brain, with
expression and ne-tuning of specic genes under control of different
mechanisms that each operate during limited period of development.
A microRNA-mediated downregulation of BDNF protein expression in
prefrontal cortex of subjects with schizophrenia may also contribute
to decits in BDNF-dependent expression of neuropeptides and sig-
naling molecules of GABAergic inhibitory interneurons (Mellios et
al., 2009), a type of molecular alteration frequently observed in this
disorder (Lewis et al., 2011; Lisman et al., 2008).
Conclusion
In summary, multiple lines of evidence suggest epigenetic abnor-
malities in schizophrenia. These include studies from animal and
human postmortem studies indicating abnormal DNA methylation
and histone post-translational modications. Recent studies indicate
a far more complex system than previously thought. For example,
within the last two years the potential importance of four additional
cytosine modications in the brain has been identied (i.e., 5HMC,
5HMU, 5CaC, 5FC) (Globisch et al., 2010; Guo et al., 2011; He et al.,
2011; Ito et al., 2011). This discovery, among others, sheds light on
previous epigenetic studies utilizing clinical cohorts, and indicates
additional considerations for future studies. There is little doubt that
future studies of DNA methylation, histone modications, and micro-
RNA as well as the interplay between these systems in human post-
mortem brain and in preclinical models will make crucial
contributions to a deeper understanding of the molecular neurobiol-
ogy of schizophrenia and related disease.
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