Pathophysiological changes in the brain that are asso-ciated with psychiatric disorders or animal models of these conditions include gross differences in the sizes of specific brain regions, alterations in the morphology of subpopulations of neurons, neurochemical changes at the synaptic cleft, alterations in intracellular signalling and changes in the regulation of gene expression. Most psychiatric disorders share important features, including a substantial genetic predisposition1 and a contribution from environmental factors. Another common attribute of psychiatric conditions is long-lasting behavioural abnormalities. In most individuals, these illnesses develop gradually and show a chronic, remitting course, often over a lifetime. Likewise, the reversal of symptoms in response to treatment occurs over weeks or months. Psychiatric medications are virtually unique in their requirement for chronic administration to achieve their full clinical effect. Accordingly, an important challenge in psychiatric research has been to identify the molecular basis of stable changes in behaviour that account for both the symptoms of mental illness and their reversal during treatment.
The regulation of gene expression has been proposed as one molecular mechanism that could mediate stable adaptations and maladaptations in the brain2. Changes in mRNA levels have been documented in specific brain regions both in animal models of psychiatric illness and in human brains, and have been related to altered behaviour. However, it has been difficult to identify the molecular mec
hanisms that underlie such stable changes in gene expression; virtually all reported changes in transcription factors and other nuclear regu-latory proteins in animal models revert to normal within hours or days of chronic perturbation. One exception is the induction of ΔFOSB, a FOS family transcription factor, which accumulates in specific regions of the brain in response to many chronic stimuli (drugs of abuse, stress, antipsychotic drugs and so on), and persists for several weeks after the end of the stimulus3,4. But even the induction of ΔFOSB does not persist as long as the behavioural changes. Thus, the search continues for the molecular basis of particularly stable adaptations and maladaptations in the brain.
Recent research has raised the notion that epigenetic mechanisms, which exert lasting control over gene expression without altering the genetic code, could medi-ate stable changes in brain function. Historically, the field of epigenetics has focused on how cellular traits can be inherited without a change in DNA sequence. Studies of epigenetic mechanisms that underlie heritable transmis-sion have flourished in the fields of developmental and cancer biology, where the continuity of unique patterns of gene expression between parent and daughter cells is crucial. These studies have converged on a set of common enzymatic modifications to chromatin structure that can up- or downregulate gene expression in a manner that is transmissible to daughter cells. These mechanisms
also regulate gene expression in neurons, but, as most neurons do not divide, chromatin modifications are instead sustained within individual cells.
This review outlines recent discoveries involving the epigenetic regulation of neurobiological adapta-tions that are associated with long-lasting behaviours in animal models of psychiatric conditions and in the brains of humans with these disorders. After a brief overview of epigenetic mechanisms, we focus on a small number of conditions, including depression, addiction, schizophrenia and developmental disorders, for which the supporting evidence is best established.
Department of Psychiatry and Center for Basic Neuroscience, The University of T exas Southwestern Medical Center,
Dallas, T exas, USA. Correspondence to E.J.N.
e-mail:
doi:10.1038/nrn2132Epigenetic regulation in psychiatric disorders
Nadia T sankova, William Renthal, Arvind Kumar and Eric J. Nestler
Abstract | Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex ‘epigenetic’ mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.
Overview of epigenetic mechanisms
Chromatin is the complex of DNA, histones and non-histone proteins in the cell nucleus. Remodelling of chromatin is a dynamic process that modulates gene expression. The fundamental unit of chromatin is the nucleosome, which consists of ~147 base pairs of DNA wrapped around a core histone octamer (~1.65 turns). Each octamer contains two copies each of the histones H2A, H2B, H3 and H4 (FIG. 1a). The nucleosomal struc-ture of chromatin allows DNA to be tightly packaged into the nucleus by organized folding5. Intricate chroma-tin remodelling mechanisms ensure that DNA remains accessible to the transcriptional machinery. These epigenetic mechanisms alter gene activity by modulat-ing DNA–protein interactions without changing the genetic code.
In simplified terms, chromatin exists in an inac-tivated, condensed state, heterochromatin, which does not allow transcription of genes, and in an activated, open state, euchromatin, which allows individual genes to be transcribed (FIG. 1b). The opening of chroma-tin is associated with acetylation of nearby histones, although it remains unclear whether acetylation mediates or reflects chromatin decondensation. In reality, chromatin can exist in many states in between
Figure 1 | General scheme of chromatin remodelling.
a |Picture of a nucleosome showing a DNA strand wrapped around a histone octamer composed of two copies each of the histones H2A, H2B, H3 and H4. The amino (N) termini of the histones face outward from the nucleosome complex.
b | Chromatin can be conceptualized as existing in two primary structural states: as active, or open, euchromatin (top left) in which histone acetylation (A) is associated
with opening the nucleosome to allow binding of the basal transcriptional complex and other activators of transcription; or as inactive, or condensed, heterochromatin where all gene activity is permanently silenced (bottom left). In reality, chromatin exists in a continuum of several functional states (active; permissive (top right); repressed (bottom right); and inactive). Enrichment of histone modifications such as acetylation  and methylation (M) at histone N-terminal tails and related binding of transcription factors and co-activators (Co-Act) or repressors (Rep) to chromatin modulates the transcriptional state of the nucleosome. Recent evidence suggests that inactivated chromatin may in some cases be subject to reactivation in adult nerve cells, although this remains uncertain. c | Summary of common covalent modifications of H3, which include acetylation, methylation and phosphorylation (P) at several amino acid residues. H3 phosphoacetylation commonly involves phosphorylation of S10 and acetylation of K14. Acetylation is catalysed by histone acetyltransferases (HATs) and reversed by histo
ne deacetylases (HDACs); lysine methylation (which can be either activating or repressing) is catalysed by histone methyltransferases (HMTs) and reversed by histone demethylases (HDMs); and phosphorylation is catalysed by protein kinases (PK) and reversed by protein phosphatases (PP), which have not yet been identified with certainty. K, lysine residue; S, serine residue. Panels a,c modified, with permission, from Nature
Rev. Neurosci.REF. 62© (2005) Macmillan Publishers Ltd.
Histones
Highly basic proteins that comprise the major protein constituents of the nucleus. Octomeric complexes of histones, around which DNA is wrapped, form the nucleosome, the basic building block of chromatin.
Nucleosome
The basic building block of chromatin in which 147 base pairs of DNA are wrapped
(~1.65 turns) around a core histone octamer.
Heterochromatin
The inactivated state of chromatin, in which DNA is not accessible for transcription due to covalent modifications of histones, methylation of the DNA and the binding of numerous repressor proteins.
Euchromatin
The activated state of chromatin, in which sections of DNA are accessible to the transcriptional machinery.
Ubiquitylation
Covalent addition of a small protein, called ubiquitin, to many types of proteins. Addition of multiple ubiquitin groups, polyubiquitylation, targets proteins for degradation in the proteasome. By contrast, monoubiquitylation of histones and other regulatory proteins alters their functional properties.
SUMOylation
Covalent addition of SUMO, which are small ubiquitin-related modifier proteins, to histones and many other types of regulatory proteins, which alters those proteins’ function.
Nucleosome sliding
The movement of the core histone octamer relative to the DNA, which allows that DNA to be progressively transcribed into RNA.
SWI/SNF
Protein complex that partly mediates nucleosome sliding in an ATP-dependent manner. The name comes from genetic screens of yeast which identified proteins implicated in mating switching and sucrose non-fermentation. The proteins were later found to regulate nucleosome sliding.these two extremes (FIG. 1b). Portions of chromatin are
highly repressed, owing to DNA and histone methyla-
tion and the binding of repressor proteins, and might
never be accessible for transcription. Other portions of
chromatin are in repressed or permissive states; their
basal activity is low owing to histone methylation and
perhaps other modifications, but the genes are avail-
able for derepression and activation in response to
transcription factors and transcriptional co-activators.
Chromatin remodelling modulates gene expression
with high temporal and spatial resolution by permitting
small groups of nucleosomes to become more or less
open, which consequently enhances or inhibits access
of the transcriptional machinery to specific promoter
regions.
Experiments in yeast have yielded detailed infor-
mation about the molecular mechanisms that control
chromatin architecture to alter gene expression. Several
general mechanisms have emerged and it is generally
believed that their complex interactions determine the
appropriate expression of specific genes in eukaryotic
cells5,6.
By far the best characterized chromatin remodel-
ling mechanism in the brain is the post-translational,
covalent modification of histones at distinct amino
acid residues on their amino (N)-terminal tails. Such
modifications include acetylation, ubiquitylation or
SUMOylation at lysine (K) residues, methylation at lysine
or arginine (R) residues, phosphorylation at serine
(S) or threonine (T) residues, and ADP-ribosylation
at glutamate (E) residues (FIG. 1c). Hyperacetylation
is generally thought to promote decondensation of
chromatin and an increase in gene activity, whereas
hypoacetylation marks condensation and decreased
activity. It has also been proposed that increased gene
activity is best associated not with the level of acetyla-
tion, but with the dynamic cycling of acetylation
and deacetylation. In contrast to acetylation, histone
methylation can correlate with either gene activation
or repression, depending on the residue undergoing
methylation7. Phosphorylation of histones is also asso-
ciated with chromatin inhibition or activation6. The
roles of histone ubiquitylation, SUMOylation and ADP
ribosylation are less well understood8,9. The diversity
of histone modifications supports the ‘histone code
hypothesis’, which posits that the sum of modifications
at a particular promoter region defines a specific epige-
netic state of gene activation or silencing10.
The enzymes that mediate these covalent modifi-
cations are becoming increasingly understood. Many
histone acetyltransferases (HATs), which catalyse
acetylation, have been identified. Several transcrip-
tional activators contain intrinsic HAT activity10,11.
Histone deacetylases (HDACs) catalyse deacetylation;
they also associate with several transcriptional repres-
sors to further repress chromatin activity11(BOX 1). The
balance between the opposing activities of HATs and
HDACs maintains acetylation on core histones and is
thought to be an important determinant of transcription.
Methylation at lysine or arginine residues is mediated by
histone methyltransferases (HMTs). In general, histone
lysine methylation is regarded as a more stable modifica-
tion than other histone modifications, which seem to be
more readily reversible6,7, although the recent discovery
of histone demethylases (HDMs) indicates that even
methylation can be reversed12.
Several other general mechanisms of chromatin
remodelling have been described, although they
remain less well characterized in the nervous system.
Nucleosome sliding involves the movement of the histone
octamer along DNA and thereby allows the transcrip-
tional machinery to transcribe a gene5. This process is
facilitated by the SWI/SNF family of chromatin remod-
elling complexes, which use ATP-derived energy to
disrupt nucleosome structure non-covalently11. Histone
substitution, where canonical histones within a nucleo-
some are switched with naturally occurring histone
variants, is a further example of chromatin remodelling,
although its physiological function in the brain is poorly
understood6
.
Histone substitution
A type of chromatin remodelling where histone constituents of the nucleosome can be replaced by other naturally occurring histone variants.
X-chromosome inactivation Chromatin remodelling on a very large scale, whereby one of two X chromosomes in all cells of a female organism are inactivated by DNA hypermethylation. Once that chromosome is silenced, it remains inactive for the life of the organism.
Genetic imprinting
A process where only the maternal or paternal allele of a gene is expressed in the offspring. The other, inactivated allele is transcriptionally silenced through DNA methylation at CpG-rich domains.
DNA methylation is another important mechanism
documented evidence
of gene repression. It occurs by transfer of a methyl group
from S-adenosyl methionine (SAM) to cytosine residues
at the dinucleotide sequence CpG, and is catalysed by
DNA methyltransferases (DNMTs)6,7. Although CpG
sequences throughout the genome are usually heavily
methylated, those at the promoter regions of genes,
specifically at CpG clusters or islands, are methylated
to a much lesser extent, and the amount of DNA meth-
ylation at a promoter correlates with the extent of gene
inactivation. The functional significance of DNA meth-
ylation is best established in X chromosome inactivation
and genetic imprinting; abnormal imprinting can lead
to neurodevelopmental diseases (BOX 1; TABLE 1). More
recently, DNA methylation has been implicated in the
regulation of gene activity in the adult brain under
normal and pathological conditions (see below).
Patterns of DNA methylation are intricately linked to
patterns of histone modification. Methyl binding domain
proteins (MBDs), such as methyl-CpG-binding protein 2
(MeCP2), can be recruited to methylated DNA. MBDs
are associated with large protein complexes containing
HDACs and HMTs, which further repress gene transcrip-
tion7. Thus, DNA methylation and histone methylation
and deacetylation are intricately interconnected, each
representing epigenetic hallmarks of the silenced promoter.
Signalling pathways in chromatin remodelling
Although chromatin remodelling is best understood
for its influence on neural development (BOX 1), increas-
ing evidence suggests a role in regulating mature, fully
differentiated neurons. During synaptic transmission,
neurons respond to neurotransmitters by receptor-
mediated intracellular signal transduction events, which,
among other actions, activate or inhibit transcription
factors. The regulation of transcriptional activity by
transcription factor binding to DNA depends on interac-
tions of the transcription factors with many co-activators
or co-repressors and the underlying structure of chro-
matin. Chromatin remodelling is thus intimately linked
to activation or repression of genes by synaptic activity.
Such mechanisms regulate the expression of specific sets
of neuronal genes that are important for neural activ-
ity, survival, morphology and ultimately the integrated
regulation of complex behaviour.
We are beginning to understand how intracellular
signalling in the brain regulates chromatin remodelling.
The best-established mechanism involves the transcrip-
tion factor cyclic AMP (cAMP)-response element bind-
ing protein (CREB). The activation of several signalling
pathways involving cAMP, Ca2+ and extracellular signal
regulated kinase (ERK) leads to the phosphorylation of
CREB at Ser133 (FIG. 2). CREB phosphorylation triggers
Table 1 |
Examples of diseases of chromatin remodelling
mental retardation protein 1; MeCP2, methyl-CpG-binding protein 2; RSK2, ribosomal S6 kinase 2; SWI/SNF, mating switching and sucrose non-fermenting complex; UTR, untranslated region; XH2, X-linked helicase 2.
DNA is crosslinked to nearby proteins by light fixation, the material is sheared, then immunoprecipitated with an antibody to a particular protein of interest, and genes in the final immunoprecipitate are quantified by polymerase chain reaction.
Immediate-early genes Genes that are induced rapidly and transiently without the need for new protein synthesis. Many immediate-early genes, such as c-Fos, control the transcription of other genes, and thereby provide the early stages in the control of the production of llular mediators of these signals are poorly defined.
For example, cocaine and antipsychotic drugs induce
acetylation of histone H4 and phosphoacetylation
of histone H3 in the striatum (a brain region that is
important for the behavioural effects of these drugs;
see below)13–15. Among the genes that show the most
marked histone changes, which can be identified by
use of chromatin immunoprecipitation (ChIP) assays, are
immediate-early genes, such as c-Fos. c-Fos transcription
is induced rapidly in the brain by numerous stimuli,
including cocaine, antipsychotic drugs and seizures.
These stimuli trigger rapid and transient enrichment
of H4 acetylation and H3 phosphoacetylation at the
c-Fos promoter in neurons, in association with tran-
scriptional activation of c-Fos. However, the signalling
pathways through which these stimuli modify histones
cells, but their actions in the brain are unexplored17.
Therefore, although H3 phosphoacetylation has been
directly associated with c-Fos induction by acute stim-
uli, much work is needed to understand the underlying
molecular mechanisms involved.
Indeed, one of the main challenges in the field is to
elaborate the precise steps through which neural activ-
ity and synaptic transmission signal to the nucleus to
regulate the enzymes and other proteins that mediate
chromatin remodelling. Insight into these pathways has
come from studies of non-neural cells. The activation
of cellular Ca2+ pathways in muscle leads to the activa-
tion of CaMKs (calcium/calmodulin-activated protein
kinases), which phosphorylate class II HDACs. This
phosphorylation triggers the shuttling of the enzyme
out of the nucleus, and results in increased histone
acetylation (FIG. 2). This pathway has now been dem-onstrated in hippocampal cells18 and cerebellar granule neurons19, indicating that chromatin signalling mechanisms in different tissues overlap substantially.
It is unclear how histone acetylation can be regulated only at specific genes, but this is believed to involve multi-protein complexes. For example, class II HDACs can target specific genes for repression through N-terminal regulatory domains that mediate interactions between these HDACs and certain transcription factors, such as myocyte enhancing factor 2 (MEF2) (FIG. 2). Independent of histone deacetylation, class II HDACs can recruit cyclin-dependent kinase 5 (CDK5) to phosphorylate MEF2 and repress its transcriptional activity19,20. However, little is known about these regulatory mecha-nisms in the brain. Among neural genes, brain-derived neurotrophic factor (Bdnf) is one of the most studied for its regulation by chromatin remodelling (BOX 2).
The above studies underscore the importance of dynamic chromatin remodelling in the transcriptional response to acute stimuli in neuronal cells. However, much research on psychiatric disorders is focused on neuroadaptations that evolve slowly but can cause last-ing changes in brain circuitry. The next sections provide evidence for such stable neuronal regulation at the level of chromatin remodelling as it relates to the pathogenesis and maintenance of complex psychiatric disorders.Epigen
etic mechanisms in depression Depression is a common, chronic and debilitating disease. Although many patients benefit from anti-depressant medication, electroconvulsive seizures (ECS) or psychotherapy, only about half of depressed patients show a complete remission, which underscores the need for more effective agents21. The mechanisms that precipitate depression, such as stress, are incompletely understood. One mystery of the disease is its long-lasting nature and delayed response to antidepressant treatment. This persistence is thought to be mediated by slowly developing but stable adaptations, which might include epigenetic regulation.
To investigate such adaptations, one study examined changes in histone modifications after chronic ECS in the rat hippocampus22, a brain region implicated in the pathophysiology and treatment of depression23,24. Like antidepressant medications, ECS is effective only after repeated administration, indicating that long-term adap-tations at the level of gene expression might be involved. Chronic ECS upregulates the expression of Bdnf and Creb in the hippocampus, and such upregulation has been shown to mediate antidepressant activity in animal models25–27. Chronic ECS produced chromatin remod-elling changes that were very different from those seen after acute ECS, and that were detected at distinct Bdnf promoter regions. Chronic ECS increased H3 acetylation

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