chromatin remodeling in neural development and plasticity

Chromatin remodeling in neural development and plasticityJenny Hsieh1 and Fred H Gage2

Neural stem cells generate distinct cell types for tissue

formation and cell replacement during development and

throughout adulthood. Neural development and plasticity are

determined by both extrinsic and intrinsic factors that interface

to regulate gene programs for controlling neuronal cell fate and

function. Recent reports have shown that chromatin

remodeling and epigenetic gene regulation play an important

role in such diverse areas as neural cell fate specification and

synaptic development and function. These epigenetic

mechanisms include cell-type-specific transcriptional

regulators, histone modifications and chromatin remodeling

enzymes, and the activity of retrotransposons.

Addresses1Department of Molecular Biology and Cecil H and Ida Green

Center for Reproductive Biology Sciences, UT Southwestern Medical

Center, 6001 Forest Park Road, Dallas, Texas 75390, USA2 Laboratory of Genetics, The Salk Institute, 10010 North Torrey

Pines Road, La Jolla, California 92037, USA

Corresponding authors: Gage, Fred H ([email protected]) and Hsieh,

Jenny ([email protected])

Current Opinion in Cell Biology 2005, 17:664–671

This review comes from a themed issue on

Cell differentiation

Edited by Andrea H Brand and Rick Livesey

Available online 13th October 2005

0955-0674/$ – see front matter

# 2005 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.ceb.2005.09.002

IntroductionRecently, we published a review describing how different

epigenetic mechanisms contribute to neural cell fate

specification [1]. We focused on the role of DNA methy-

lation, histone modifications (such as acetylation and

methylation) and regulatory noncoding RNAs. In this

review, we expand on the idea that chromatin remodeling

and epigenetic mechanisms may regulate rapid changes

in brain function, which is particularly important during

the postnatal period when infants explore their world.

Postnatal and adult neurogenesis can be divided into

three stages: first, self-renewal, fate specification (into

neurons and glia) and survival of neural precursor cells;

second, migration and connection of newborn neurons

with pre-existing neurons; and third, reorganization in the

synaptic connectivity between newborn and pre-existing

neurons driven by sensory experience. Epigenetic altera-

tions leading to chromatin remodeling could provide a

coordinated system of regulating gene expression at each


stage of neurogenesis. Interestingly, disruption of epige-

neticmechanisms leading to dysregulation of gene expres-

sion results in a number of syndromes associated with

mental retardation (e.g. ATR-X, Fragile X, Rett, Rubin-

stein-Taybi, ICFandAngelman; reviewed in [2]).Why the

development and function of the CNS seem to be parti-

cularly sensitive to epigenetic changes and the exact

connection between epigenetic regulation and brain func-

tion remain obscure. Here we discuss new insights regard-

ing chromatin-based mechanisms of neural development

and plasticity in both normal and disease states.

Chromatin structure and the role ofhistone modificationsMany studies in recent years have focused on the role of

chromatin structure, particularly the covalent modifica-

tions that take place on histones, in controlling cellular

identity and mediating heritable changes in gene expres-

sion (reviewed in [3]). One of the best-characterized

histone modifications to date is lysine acetylation, which

is mediated by two groups of enzymes, histone acetyl-

transferases (HATs) and histone deacetylases (HDACs)

(Figure 1). HATs induce acetylation of N-terminal his-

tone tails, which decreases the interaction of the posi-

tively charged histone tails with the negatively charged

phosphate backbone of DNA and hence results in relaxa-

tion of the nucleosomes. HDACs catalyze the reverse

reaction; in the deacetylated state, histones package the

DNA into more condensed chromatin, which prevents

access of transcriptional activators to their target sites,

resulting in transcriptional repression. There have been at

least 11HDACs characterized to date in human. They fall

into two classes: the class I HDACs (1, 2, 3 and 8) are

widely expressed, and the class II HDACs (4, 5, 6, 7, 9 and

10) have cell-type-restricted patterns of expression

(reviewed in [4,5]). A third class of HDACs — a group

of proteins related to the yeast transcriptional repressor

Sir2 and called sirtuin deacetylases — will not be dis-

cussed. Following on from extensive studies of histone

acetylation and deacetylation in cultured cells, the char-

acterization of specific HDACs in vivo has revealed that

they have essential functions in chondrocyte develop-

ment, cardiac signaling and skeletal muscle physiology

[6�,7,8��]. This finding is consistent with the observation

that class II HDACs display their highest expression

levels in striated muscle and brain. In terms of brain

function, although changes in histone modifications have

been observed during oligodendrocyte differentiation in

the developing corpus callosum [9] and after acute and

chronic electroconvulsive seizures in the hippocampus

[10], the role of cell-type-specific HDACs in neural

development remains to be determined.

www.sciencedirect.com

Chromatin remodeling in neural development and plasticity Hsieh and Gage 665

Figure 1

Changes in histone modifications convert chromatin from repressive to active to allow gene transcription. Histone acetylation (red circles) and

histone methylation of histone H3 lysine 4 (K4) (purple circles) allows relaxation of chromatin and enables cell-type-specific regulator proteins

and RNA polymerase complex to access DNA and start transcription. Histone deacetylation and histone methylation of histone H3 lysine 9 (K9)

(purple circles) is involved in the formation of repressive chromatin. Ac, acetylation; HAT, histone acetyltransferase; HDAC, histone deacetylase;

HDMT, histone demethylase; HMT, histone methyltransferase; TAF, TBP-associated factor; TBP, TATA-binding protein. Modified from [1] with

permission.

Despite a lack of understanding of the specific HDACs in

the CNS, a great deal of attention has focused on a class of

small molecules that can inhibit HDAC activity, called

HDAC inhibitors [11,12]. HDAC inhibitors can prefer-

entially mediate the neuronal differentiation of both

embryonic-day-18 cortical cells and adult hippocampal

neural progenitor cells [13,14]. In addition to inducing

neuronal differentiation, HDAC inbibitors suppress glial

differentiation and the proliferation of neural progenitors

[14,15]. Furthermore, HDAC inhibitors appear to have

beneficial effects in the CNS, including having the ability

to attenuate neurodegeneration and motor deficits in

animal models of Huntington’s disease and to normalize

gene expression in a mouse model of schizophrenia-

related neuropathology [16–18]. Currently, several

HDAC inhibitors are being tested in Phase I/II clinical

trials as anticancer agents (reviewed in [19]). The future

use of HDAC inhibitors for the treatment of CNS dis-

orders remains an exciting possibility.

In contrast to acetylation, which appears to be reversible

and dynamic and is most often associated with the

expression of individual genes, epigenetic regulation

by histone methylation is stable and may be involved

in the long-term maintenance of certain regions of the

genome (reviewed in [20,21]) (Figure 1). Lysine methy-


lation has been directly linked to epigenetic inheritance;

histone H3 methylation at lysine 4 (K4) leads to tran-

scriptional activation, whereas histone H3 methylation at

lysine 9 (K9) is associated with transcriptional silencing

(reviewed in [2]). A recent paper by Shi and colleagues,

identifying histone H3 K4 demethylase, raises the ques-

tion of whether histone methylation, like acetylation, is

reversible and dynamic [22]. In fact, one study looking at

changes in histone methylation revealed that there were

elevated levels of histone H3 trimethyl K9 and histone

H4 monomethyl K20 in proliferating cells of the neural

tube, while histone H4 K20 trimethyl derivatives were

enriched in differentiating neurons. This inverse relation-

ship between monomethyl and dimethyl histone H4 K20

was even more striking during skeletal and cardiac myo-

genesis, suggesting that there may be a highly dynamic

common histone ‘code’ (reviewed in [3]) to control tissue

patterning in both CNS and muscle. What these distinct

dynamics and distributions of the various histone methyl-

lysine derivatives in the CNS actually mean in terms of

cell fate specification remains elusive.

Although these global studies of histone modifications

and HDAC inhibitors in neural development are infor-

mative, detailed studies are needed to understand how

specific genes are regulated to control neurogenesis. The


666 Cell differentiation

mechanism for regulating HDAC activity in the cell

usually involves a shuttling process to sequester HDACs

outside the nucleus [23,24] or, more commonly, the

recruitment of HDACs to gene-specific promoters by

association with DNA binding factors (reviewed in [4]),

a process that will be discussed in the next section.

Context-dependent gene regulation by theNRSF complexDuring development, telencephalic neuroepithelial cells

first undergo limited expansion, mostly through sym-

metric divisions, and then undergo neurogenesis, chiefly

involving asymmetric divisions (reviewed in [25]).

Toward the end of neurogenesis, cortical progenitors

switch back to symmetric divisions and give rise to

astrocytes and oligodendrocytes. A vast array of transcrip-

tional repressors and activators underlies the sequential

stages of neuronal and glial fate specification (reviewed in

[26,27]). Many of these factors have been studied indi-

vidually; however, a unifyingmechanism that controls the

process of neural cell fate specification throughout

maturation has not been found. A good candidate for

providing this unification is the transcriptional regulator

NRSF (neuron-restrictive silencing factor, also called

REST) [28,29]. Dozens of papers over the past decade

have implicated NRSF as a repressor of neuronal genes in

non-neuronal cells. NRSF is a zinc finger protein that

binds to a conserved 21–23-bp motif known as NRSE

(neuron-restrictive silencing element, also called RE1).

The NRSE sequence is found in a large number of

neuronal genes, including ion channels, neurotransmitter

receptors and guidance/migration molecules. NRSF can

mediate repression through association with the mSin3A/

B complex [30], with N-CoR [31] or with the novel

corepressor complex CoREST/HDAC2 [32], suggesting

the context-dependent nature of its repressor activities.

CoREST can recruit the assembly of other silencing

machinery at NRSF target genes, including the methyl

DNA-binding proteinMeCP2, heterochromatin protein 1

and suppressor of variegation 39H1, a histone lysine

methyltransferase [33]. In this model, some target genes

(e.g. otoferlin) are HDAC-dependent and can be reacti-

vated with treatment of the HDAC inhibitor trichostatin

A (TSA), whereas other genes (e.g. SMARCe) are

silenced by HDAC- and DNA-methylation-dependent

mechanisms and are only reactivated upon stimulation

with both TSA and the DNA demethylating reagent 5-

aza-cytidine.

Although NRSF is expressed mainly in non-neuronal

cells [28,29], some studies have shown that it is also

expressed in certain mature neurons in adults [34,35],

suggesting that it might have a more complex role than

was previously appreciated. Furthermore, studies of

dominant-negative forms, different splice variants and

recombinant activator forms of NRSF have led to the

proposal that NRSF modulates the expression of NRSE-


containing genes in mature neurons and plays a role in

synaptic plasticity [34–36]. A set of recent papers adds

further intrigue regarding the true function of NRSF

(Figure 2). Kuwabara and colleagues (2004) identified a

small noncoding double-stranded RNA (dsRNA) match-

ing the NRSE sequence and showed that the RNA was

co-expressed with NRSF in neuronal progenitors of the

adult hippocampus [37]. When dsRNA was expressed,

NRSF was converted from a repressor to an activator

complex, leading to the activation of neuron-specific

genes for the induction of neurogenesis. One model of

how dsRNA acts is to directly associate with NRSF,

altering its activity perhaps through a conformational

change and preventing the interaction with co-repressor

proteins. Alternatively, dsRNA could convert NRSF

from a repressor to an activator through the action of

an unknown protein(s). Ballas and colleagues (2005)

described a dual regulatory mechanism of NRSF during

neural development that operates at the level of protein

and mRNA [38�]. Using a model of neuronal differentia-

tion from mouse embryonic stem (ES) cells, they found

that NRSF is post-translationally degraded when ES cells

transition into neural progenitor cells. The NRSF gene is

actively transcribed in ES and neural progenitor cells;

however, when the cell exits the cell cycle and differ-

entiates into mature neurons, NRSF is repressed by the

unliganded RA receptor (RAR) repressor complex.

Furthermore, the authors found that there is a release

of NRSF from neuronal gene chromatin as progenitors

differentiate into cortical neurons and NRSE-containing

genes are activated. This finding conflicts with the

observation that NRSF and co-activators remain asso-

ciated with neuronal gene chromatin in adult hippocam-

pal neurons [37]. Since a cross-comparison between

developmental and adult stages is lacking, the question

remains whether NRSF functions as a stage-specific

activator/repressor of neuronal gene expression and

whether the regulation of NRSF mRNA, protein and/

or activity by dsRNA is critical for proper development of

the CNS.

As previously mentioned, many NRSF target genes are

required long after progenitor cells initially choose their

fates, so how are the long-lasting changes in gene expres-

sion that occur during neural plasticity and maturation

influenced? The answer may lie in DNA methylation, an

epigenetic modification that has been implicated in

diverse gene regulatory processes, such as genomic

imprinting and X-chromosome inactivation [39]. Ballas

and colleagues recently discovered that the activation of

neuronal genes in post-mitotic neurons depends on the

release of NRSF from the NRSE site; however, the

different neuronal genes can be divided into two classes

on the basis of the mechanisms by which they are regu-

lated [38�] (Figure 2). The removal of the NRSF repres-

sor complex is sufficient for derepression of Class I gene

expression. Class II genes, such as brain-derived neuro-



Figure 2

Context-dependent gene regulation by the NRSF complex. (a) Neuronal gene expression is low in embryonic stem (ES) cells as a result of

maximal levels of NRSF mRNA. NRSF mRNA levels are still high but protein levels are low, as NRSF is post-translationally degraded (dark purple

nuclei to light purple nuclei) when ES cells transition into neural progenitors; the degradation of NRSF allows neuronal gene expression to be

‘primed’ for activation. In cortical neurons, NRSF mRNA is repressed by the unliganded RAR receptor (RAR) complex binding to the retinoic

acid receptor element (RARE) and neuronal gene expression is high (large red arrow). (b) Two classes of neuronal genes mediated by two

different mechanisms of NRSF-mediated repression. Class I neuronal genes are repressed by the NRSF repressor complex in neural progenitor

cells. Upon neuronal differentiation, displacement of NRSF complex occurs, allowing derepression of neuronal genes. Class II neuronal genes

are repressed by both the NRSF repressor complex and MeCP2/mSin3 complex at nearby CpGs (red ‘Me’ circles) in neural progenitor cells.

Upon neuronal differentiation, NRSF is displaced (as for class I genes); however, neuronal gene expression is still repressed by MeCP2/mSin3

(smaller green arrow). When neurons are depolarized upon stimulation, MeCP2 is phosphorylated and released from CoREST, allowing neuronal

gene activation (larger green arrow). (c) NRSF represses neuronal genes in adult neural stem cells. Neuronal induction triggers the production

of NRSE double-stranded RNA (NRSE dsRNA) and NRSF is converted from a repressor to an activator allowing activation of neuronal gene

expression. In glia, NRSE-containing genes remain repressed as a result of the presence of the NRSF repressor complex. Me: DNA

methylation. Modified with permission from [38�].

www.sciencedirect.com Current Opinion in Cell Biology 2005, 17:664–671


trophic factor (BDNF) and Calbindin, are repressed by

both NRSF at the NRSE site and CoREST/MeCP2

complexes on adjacent methylated CpGs (mCpGs).

Interestingly, upon membrane depolarization, MeCP2

becomes phosphorylated and, along with HDAC and

mSin3, dissociates from neuronal chromatin to allow gene

expression, consistent with other recent findings regard-

ing MeCP2 phosphorylation in the regulation of BDNF

[40,41]. In addition to neuronal gene regulation by the

NRSF complex, recent evidence suggests that SWI/SNF

complexes, consisting of one or more catalytic subunits—

Brahma (Brm), Brahma-related gene 1 (Brg1), or Breast-

ovarian cancer susceptibility gene 1 (Brca1) — and poly-

comb repressors (Bmi-1) have roles in neural develop-

ment and stem cell biology.

An emerging role for SWI/SNF chromatinremodeling complexes in neurogenesisOne of the first chromatin remodeling complexes identi-

fied, the SWI/SNF family of chromatin remodeling pro-

teins, uses ATP hydrolysis to disrupt histone–DNA

associations (reviewed in [42]). SWI/SNF complexes

interact with HATs or HDACs and/or sequence-specific

transcription factors to activate or repress target genes.

Chromodomain proteins, which possess the ATPase

domain found in SWI/SNF proteins, are also recruited

by polycomb repressors, and are involved in silencing

gene expression from clusters of homeotic genes to con-

trol tissue patterning. Kondo and Raff (2004) showed that

the conversion of oligodendrocyte precursor cells to

neural-stem-like cells is associated with the recruitment

of Brca1 and Brm to the promoter of a key transcription

factor involved in maintaining the proliferation of neural

stem-like cells (NSLCs), the SRY-related, HMG-box-

containing protein Sox2 [43]. This conversion was asso-

ciated with the replacement of histone H3 K9 with K4

methylation and acetylation of K9 at the Sox2 promoter,

consistent with the upregulation of Sox2 in NSLCs. Brg1

was also discovered to be required for Xenopus neurogen-esis; loss of Brg1 correlated with an increase in proliferat-

ing neural progenitors and an expansion of Sox2-positive

cells in embryos at a later stage of neurogenesis (early

neural induction and cell fate determination appeared

normal) [44]. In addition, there was decreased neuronal

differentiation when Brg1 activity was reduced. Interest-

ingly, Brg1 was found to be associated with two proneural

bHLH proteins, Neurogenin-related-1 and NeuroD, and

was required for the ability of these proneural genes to

drive neurogenesis. Furthermore, the polycomb family

transcriptional repressor Bmi-1 is required for the self-

renewal of stem cells in the PNS and CNS; lack of Bmi-1

leads to their postnatal depletion, which may explain why

mice lacking Bmi-1 expererience neurological defects

[45–47]. Bmi-1 is also required for long-term hematopoi-

esis [48,49]. Together, these data suggest that neurogen-

esis might be a process that requires extensive chromatin

remodeling. Although it has been suggested that cell


cycle genes (including the cyclin-dependent-kinase inhi-

bitors p16 and p19) are targets of SWI/SNF and polycomb

in neural cells [45,46], less is known about the role of

homeotic selector genes in neural fate specification. It was

recently discovered that HoxB4, a homeotic gene, plays a

role in the self-renewal of hematopoetic stem cells, mak-

ing it likely that Hox genes also play roles in neural stem

cell biology [50].

Epigenetic control of neural plasticity,learning and memoryEpigenetic mechanisms spanning diverse areas, such as

histone modifications, polyADP-ribosylation, DNA

methylation and even retrotransposition, have been

linked with changes in neural plasticity and long-term

memory (reviewed in [51]). Previously, studies of long-

term plasticity in Aplysia sensory-motor synapses have

revealed a role for HDAC5 and histone acetylation at the

promoter of the immediate early gene C/EBP when

stimuli producing long-term facilitation or long-term

depression were applied [52]. A recent study of learning

in Aplysia neurons found that the enzyme that catalyzes

polyADP-ribosylation, polyADP-ribose polymerase-1,

becomes activated when neurons are stimulated by phy-

siological activity and is required for long-term memory

[53�]. Furthermore, two different mouse models for

Rubinstein–Taybi syndrome (RTS) were used to demon-

strate that histone acetylation — particularly that carried

out by the HAT activity of CREB-binding protein (CBP)

— is required for long-term potentiation, learning and

memory [54,55��]. In one of the mouse models, CBP

heterozygotes exhibited normal levels of short-term

memory (although their motor learning was abnormal,

probably as a result of skeletal defects); instead, the major

memory defect detected was in long-term memory, as

determined in contextual and cued fear conditioning and

novel object recognition tasks [54]. When the HDAC

inhibitor suberoylanilide hydroxamic acid was infused

into the ventricle of CBP heterozygotes, the mice showed

improvement in contextual fear conditioning. In a second

mouse model, bearing a hippocampal CA1- and dentate-

gyrus-specific inducible form of mutant CBP lacking

HAT activity, there were also deficits in long-term but

not short-term recognition memory [55��]. Interestingly,when the transgene was shut off or when the HDAC

inhibitor Trichostatin A was used, there was rescue of the

memory deficit, suggesting that pharmacological manip-

ulation of HAT activity might be a potential therapeutic

approach to treat RTS. In another set of studies, MeCP2

was found to be highly enriched in postmitotic neurons;

mutations inMeCP2 have been linked to the neurological

disorder Rett syndrome [56,57]. RTS and Rett syndrome

are two examples of cognitive disorders linked to chro-

matin remodeling and transcriptional regulation

(Figure 3). Many more examples of neurodevelopmental

disorders linked to transcriptional regulators have already

been described (reviewed in [58�]).



Figure 3

Chromatin remodeling in neural plasticity, learning and memory. In the starting state, a silencing complex consisting of DNA methyltransferases

(DNMT), histone deacetylases (HDAC1/2), histone methyltranferases (HMT) and transcriptional co-repressors (Sin3A) keeps the local chromatin

repressed and transcriptionally inactive at neural plasticity gene promoters (i.e. BDNF). Upon neuronal activity and calcium signaling, several

kinases for MeCP2, CREB and CBP become active that induce the release of the MeCP2 silencing complex. CBP is recruited to phosphorylated

CREB and the basal transcriptional machinery is recruited to neural plasticity gene promoters. Furthermore, the histone acetyltransferase

activity of CBP opens up local chromatin, an event which is important for long-term plasticity and memory. Mutations in MeCP2, CBP, RSK2

(a kinase that phosphorylates CREB), and CACNA1C (an L-type voltage-gated calcium channel) lead to Rett, Rubinstein–Taybi, Coffin–Lowry

and Timothy syndromes, respectively. Figure 3 is modified with permission from [58�].

There are many examples of neural plasticity genes being

controlled by epigenetic mechanisms, but what about the

regulation of neural plasticity at the organism level, such

as individual differences in brain function and behavior?

Two provocative papers attempt to address this. Weaver

and colleagues (2004) showed that maternal care behavior

in rats can mediate changes in DNA methylation and

histone acetylation of the glucocorticoid receptor promo-

ter that allows transcription factor binding [59]. Muotri

and colleagues (2005) engineered a human LINE-1 (long

interspersed nuclear element-1, also called L1) indicator

cassette and found that there was retrotransposition of

their indicator (visualized by EGFP) in adult rat neural

progenitor cells [60��]. Interestingly, in clones where


retrotransposition occurred but EGFP expression was

negative (i.e. was either never expressed in the first place

or actively silenced from culture conditions), reactivation

of EGFP could only be detected during neuronal differ-

entiation and rarely during glial differentiation, reinfor-

cing the idea that chromatin remodeling is an active

process during neuronal induction. Moreover, many of

the L1 insertion sites analyzed were proximal to neuron-

ally expressed genes, and L1 insertion events could

modify the expression of these genes and mediate cell

fate changes. Together, these data suggest that alterations

of chromatin structure are a general mechanism under-

pinning the long-term effects of environment on neuronal

differentiation, plasticity and diversification.



ConclusionsOne of the biggest mysteries regarding brain function is

how specific instructions for cellular and tissue patterning

are laid out without preventing a large degree of plasticity

being retained in order for the brain to respond to the

changing environment. The brain must be able to relay

environmental information down to the cellular and

molecular level where it can effect changes in gene

expression. Epigenetic and chromatin modifications of

target genes in response to variations in environmental

conditions might serve as a major source of variation in

gene expression and function, and ultimately as a

mechanism mediating neuronal plasticity and individual

differences in behavior. We propose that chromatin remo-

deling conveys dynamic environmental experiences to a

static genome, resulting in heritable and reversible

changes in the CNS during development and throughout

adulthood.

AcknowledgementsWe thank ML Gage for editorial assistance and J Simon for graphics.

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� of special interest

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chromatin remodeling in neural development and plasticity

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