epigenetic regulation of genes in learning and...

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© The Authors Journal compilation © 2010 Biochemical SocietyEssays Biochem. (2010) 48, 263–274; doi:10.1042/BSE0480263 16

Epigenetic regulation of genes in learning and memory

Tania L. Roth1, Eric D. Roth1 and J. David Sweatt2

Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A.

Abstract

Rapid advances in the field of epigenetics are revealing a new way to understand how we can form and store strong memories of signifi cant events in our lives. Epigenetic modifi cations of chromatin, namely the post-translational modifi cations of nuclear proteins and covalent modifi cation of DNA that regulate gene activity in the CNS (central nervous system), continue to be recognized for their pivotal role in synaptic plasticity and memory formation. At the same time, studies are correlating aberrant epigenetic regulation of gene activity with cognitive dysfunction prevalent in CNS disorders and disease. Epigenetic research, then, offers not only a novel approach to understanding the molecular transcriptional mechanisms underlying experience-induced changes in neural function and behaviour, but potential therapeutic treatments aimed at alleviating cognitive dysfunction. In this chapter, we discuss data regarding epigenetic marking of genes in adult learning and memory formation and impairment thereof, as well as data showcasing the promise for manipulating the epigenome in restoring memory capacity.

1Present address: Department of Psychology, University of Delaware, Newark,

DE 19716, U.S.A.2To whom correspondence should be addressed (email [email protected]).

0048-0016 Sweatt.indd 2630048-0016 Sweatt.indd 263 8/15/10 9:05:46 AM8/15/10 9:05:46 AM

© The Authors Journal compilation © 2010 Biochemical Society

264 Essays in Biochemistry volume 48 2010

Introduction

The brain possesses an amazing capacity for signal integration and information storage. It is appreciated that neurons receive an enormous number of synaptic inputs, and in response to stimuli, whether internal or extrinsic, the physiology of neuronal synapses can be modified for days, months or potentially a lifetime. However, the molecular mechanisms in place in neurons to drive and sustain these changes are poorly defi ned. One molecular substrate that is responsive to environmental infl uences and can remain stable for the lifetime of a neuron is chromatin, or the DNA–histone protein complex in the nucleus that compacts and contains the entire genome.

We and others have hypothesized that chromatin serves as an ideal sub-strate for both the dynamic signal integration necessary for learning and the stable storage of information underlying long-term memory (for other recent reviews, see [1–3]). One fact making chromatin an ideal substrate for learning and memory is that the human genome contains well over 20000 protein-coding genes, with each gene possessing numerous sites for transcrip-tional regulation that might subserve signal integration. Secondly, chromatin is not continually degraded and resynthesized, which renders it a stable molecu-lar substrate that might subserve long-term information storage.

Recent studies highlight that the DNA and histone proteins that com-prise the core chromatin particle are an integral component of learning and memory processes, and that DNA methylation, DNA demethylation and histone modifications appear to help encode the salience of intrinsic and extrinsic signals. Overall, this is a new way to understand how intrinsic and extrinsic signals evoke not only transcriptional changes, but also structural and functional changes in the physiology of the CNS (central nervous system). For our purposes, in this chapter, we defi ne epigenetics as the covalent modifi cation of chromatin that infl uences activity-dependent changes in gene transcription that drive cognitive processes. In the following sections, we briefl y review these mechanisms, and then discuss evidence for their role in synaptic plasticity, learning and memory, and cognitive dysfunction. We also discuss the promise of drug targets of epigenetic machinery to enhance and even restore memory.

DNA methylation and demethylation

One way the genome can be epigenetically regulated is through DNA methylation (Figure 1). Catalysed by a class of enzymes known as DNMTs (DNA methyltransferases), DNA methylation is the direct chemical modifi cation of a cytosine side chain by the covalent addition of a methyl (-CH3) group. DNMTs transfer methyl groups to cytosine residues at the 5-position of the pyrimidine ring [4], and only cytosines that are immediately followed by a guanine are targets for such methylation. These CpG sequences (the ‘p’ simply indicates that a phosphodiester bond connects the cytosine and guanine nucleotides) are highly under-represented in the



T.L. Roth, E.D. Roth and J.D. Sweatt 265

genome, and often occur in small clusters commonly referred to in the literature as CpG islands [4].

To date, DNA methylation has been in most cases associated with the negative regulation of gene transcription. As it is currently best understood, methylation of CpG dinucleotides triggers the recruitment of transcriptional suppressors, such as methyl-DNA-binding proteins [such as MeCP2 (methyl CpG-binding protein 2)] and HDACs (histone deacetylases). This then results in a higher-affi nity interaction between DNA and the histone core through localized regulation of the three-dimensional structure of DNA and its asso-ciated histone proteins [4]. As depicted in Figure 1, this cascade ultimately suppresses gene transcription. However, whereas DNA methylation is pre-dominately associated with suppression of gene activity, recent studies provide evidence that DNA methylation status alone is not an accurate measure of whether a gene is suppressed, as it appears that, in some cases, MeCP2 can also be associated with transcriptional activators and active gene transcription [5,6].

DNA demethylation has been historically viewed as a passive and largely irreversible process in differentiated cells, whereby several rounds of cell division without DNMT-mediated remethylation are necessary to erase epigenetic marks. Whether there is active DNA demethylation in post-mi-totic cells, including neurons, is still under debate. Several active DNA demethylation pathways have been proposed, including the direct removal of methyl groups via MBD2 (methyl-CpG-binding domain protein 2) [7] or a Gadd45 (growth-arrest and DNA-damage-inducible protein 45)-coupled DNA repair-like process [8,9].

Figure 1. DNMTs transfer methyl groups to cytosine-guanine dinucleotidesMeCP2 binds methylated DNA and recruits chromatin-remodelling co-repressor complexes, including HDACs. This condenses chromatin, which then limits accessibility of the transcriptional machinery to gene promoters, and thus suppresses gene transcription.




Histone modifi cations

Another way the genome can be epigenetically regulated is through post-translational histone modifi cations (Figure 2). In the nucleus, DNA is wrapped around a core of eight histone proteins (histones 2A, 2B, 3 and 4, with two copies of each molecule). The N-terminal tails of histones protrude beyond the DNA and can be post-translationally modifi ed [10]. At present, we understand these modifi cations to include acetylation, phosphorylation, methylation, ubiquitination and SUMOylation. Whereas acetylation is typically linked with gene activation, SUMOylation is associated with gene repression. However, some histone modifi cations, particularly methylation, are more complex and can be associated with either gene activation or repression depending on the nature of the modifi cations [10].

Of the histone modifi cations, histone acetylation has been the most stud-ied with regard to learning and memory. Acetylation of histones occurs at lysine residues, via enzymes called HATs (histone acetyltransferases), effec-tively decreasing the affi nity between the protein tail and DNA, and relax-ing the chromatin structure, which allows the recruitment of transcriptional machinery [10]. As Figure 2 illustrates, histone acetylation is a reversible proc-ess, and the enzymes that catalyse the reversal of histone acetylation are the HDACs.

Figure 2. Acetylation of lysine residues by HATs decreases the affi nity between histones and DNA, thereby relaxing chromatin and making DNA accessible for transcriptionThe opposite reaction is carried out by HDACs.




Epigenetic mechanisms in synaptic plasticity

Biologists have known for decades that epigenetic mechanisms, particularly DNA methylation, are involved in cellular differentiation, helping to encode, for example, a pattern of gene expression that enables one cell to be a skin cell, and then a distinct pattern that enables another cell to be a liver cell. Biologists have also recognized that heritable patterns of DNA methylation enable a cell to retain its identity through subsequent cell divisions. Thus DNA methylation has historically been viewed as static process in modifying the genome.

Perhaps some of the best evidence that DNA methylation is actively regu-lated in post-mitotic cells and that the genome remains responsive to stimuli from the environment came by way of work from Michael Meaney’s group in 2004 [11]. Using rodents that displayed various levels of maternal care, they demonstrated that the quality of maternal care received during the fi rst postnatal week (high levels of care compared with low levels of care) directly infl uenced DNA methylation patterns of the glucocorticoid receptor gene in offspring, and this in turn programmed the expression of this gene throughout the animal’s lifespan. These data, along with those regarding the substantial expression of DNMTs (specifi cally, DNMT3a and DNMT1) in non-diving neuronal cells [12–14] were among the fi rst to suggest that the DNA methyla-tion machinery remains active and responsive in the CNS. Such observations provided the impetus for several laboratories, including our own, to begin to investigate the capacity of changes in DNA methylation to regulate synaptic plasticity and memory in adult animals.

Changes in DNA methylation and LTP (long-termpotentiation)

Synaptic plasticity refers to the process in which synapses undergo activity-dependent changes in their strength. Synaptic plasticity is a long-standing and candidate cellular mechanism for information storage in the CNS, and has been implicated in a wide range of cognitive functions. As such, several laboratories have examined whether DNA methylation (or demethylation) has a role in synaptic plasticity. LTP is a form of synaptic plasticity whereby synaptic strength is enhanced in response to high-frequency synaptic activity. Work from our laboratory provided the fi rst demonstration that the acute application of the demethylating agents zebularine or 5-aza-2-deoxycytidine to hippocampal slices from the adult brain not only alters the methylation status of DNA [of the Bdnf (brain-derived neurotrophic factor) and reelin genes], but also disrupts the induction of LTP [15,16]. The ability of these same drugs, or the direct disruption of the DNA methylation machinery itself via a DNMT-knockout animal, to block induction of LTP have been independently confi rmed and extended by others [17–19]. Because both zebularine and 5-aza-2-deoxycytidine are nucleoside analogues that need to be incorporated into DNA to trap DNMT and block




DNA methylation, the mechanism of how these drugs are able to alter methylation in hippocampal slices and affect LTP is not clear, but most likely involves a replication-independent event (i.e. a DNA repair-like process). As an aside, zebularine and 5-aza-2-deoxycytidine are undergoing clinical evaluation for their promise as anticancer treatments.

Histone modifi cations and LTP

Some of the earliest evidence for the role of histone modifi cations in synaptic plasticity came from studies in the laboratories of Eric Kandel, Mark Mayford and Ted Abel in which they investigated the role of a particular HAT, CBP {CREB [CRE (cAMP-response element)-binding protein]-binding protein}. CBP acetylates histones associated with CREs. In two examples of these types of studies, using genetically altered mice with impaired CBP function (but void of any effects of CBP on development), the Kandel and Abel laboratories found that CBP/HAT-defi cient mice exhibited pronounced defi cits in LTP [20,21]. In a complementary series of studies, we hypothesized that blocking HDACs and thus augmenting histone acetylation would enhance plasticity. Thus we found that acute application of either sodium butyrate or trichostatin A indeed enhanced hippocampal LTP [22].

Epigenetic mechanisms in learning and memory

DNA methylation and demethylation in learned fear

In our laboratory, we have recently begun examining whether associative learning and memory consolidation elicit any changes in methylation of CpG dinucleotides in the adult hippocampus. Contextual-fear conditioning is a paradigm we have commonly used to assess hippocampal-dependent learning and memory function. In this paradigm, animals learn to associate a novel context (the conditioned stimulus) with a mildly aversive unconditioned stimulus (typically, this is a brief foot-shock) that naturally elicits a freezing response (the unconditioned response). In our first study, we found that, whereas associative learning and fear memory formation elicits rapid methylation and transcriptional silencing of the memory-suppressor gene PP1 (protein phosphatase 1), this also elicits rapid demethylation and transcriptional activation of the synaptic plasticity gene reelin [23]. Additional work from our laboratory demonstrated that the associative learning and memory formation induced by contextual-fear conditioning also evokes rapid methylation and demethylation of various regulatory regions of the Bdnf gene [24]. Thus both active methylation and demethylation appear to serve as important layers, much like transcription factors, in controlling activity-dependent gene regulation necessary for memory.

We have also used various pharmacological approaches (zebularine, 5-aza-2-deoxycytidine or RG-108) to demonstrate that disrupting DNA methylation and DNMT activity before training blocks hippocampus-dependent memory




formation in the contextual-fear conditioning paradigm [23,24]. In related work, Lisa Monteggia’s laboratory has shown that disruption of the function of MeCP2 impairs an animal’s ability to form long-term memory in the cued-fear condition-ing paradigm [25]. Cued-fear conditioning evokes an amygdala-dependent learning process similar to that described for contextual-fear conditioning, but, in this case, an animal forms a conditioned fear response to a cue instead of a context.

Changes in DNA methylation and long-term gene regulation

The stable nature of DNA methylation renders it an ideal substrate for the long-term cellular changes necessary for the maintenance and persistence of memory. To date, behavioural studies have examined whether there are changes in DNA methylation at what are deemed relatively short time periods following an experience. For example, the 1–2 h time frame we have examined post-learning would, at best, include the early stages of memory consolidation. The question of whether these epigenetic changes have contributed to the maintenance and persistence of a learned-fear memory has yet to be addressed. We do know that the hippocampal changes in methylation are rather short-lived, in that within 24 h of the contextual-fear conditioning, they are no longer present [23,24]. This would therefore suggest that these DNA methylation and demethylation changes brought about by contextual-fear conditioning are supporting memory formation rather than long-term storage of the fear memory in the hippocampus. This then begs for future investigations to address whether these experiences have evoked similar modifi cations in other regions of the brain that are more linked to the stable and long-term storage of the recently acquired information, such as the prefrontal cortex.

If we look at the developmental literature, we fi nd some of the best evi-dence that experiences produce stable and long-term epigenetic changes in regulation of genes. Some of our work has demonstrated that maltreatment of an infant rat by a caregiver induces signifi cant methylation of Bdnf DNA in the prefrontal cortex, an effect that persists throughout development and well into adulthood [26]. This hypermethylation is associated with lasting reduc-tion in the expression of the Bdnf gene [26]. Stable changes in expression of the AVP (arginine vasopressin) gene in the paraventricular nucleus caused by maternal separation stress have also been recently linked to lasting changes in DNA demethylation of the gene [27]. If epigenetic mechanisms can contribute to the memory of early-life experiences on the cellular level, then it is cer-tainly plausible that they can contribute to the long-term memory induced by contextual-fear conditioning.

Histone modifi cations in learning and memory

Some of the earliest evidence for the role of histone modifi cations in memory came from the same studies that investigated the role of CBP in synaptic plasticity. As alluded to above, investigators demonstrated that CBP/




HAT-defi cient mice had pronounced defi cits in memory capacity, including long-term memory defi cits for passive avoidance, novel object recognition and cued-fear conditioning [20,21,28]. Some of our initial work in this realm revealed that in mice that had learned a contextual-fear association, there were signifi cant increases in both acetylation and phosphorylation of histone H3 that were regulated by the ERK (extracellular-signal-regulated kinase)/MAPK (mitogen-activated protein kinase) pathway [22,29]. Furthermore, we showed that the same HDAC inhibitors that enhanced hippocampal LTP also enhanced memory in these animals [22]. Together, these observations were among the fi rst to indicate that epigenetic marking of histone tails occurs in long-term memory formation and that, surprisingly, manipulation of these processes is a viable way to alter memory capacity.

In 2007, Li-Huei Tsai’s group published a seminal study in which they demonstrated that the use of sodium butyrate is suffi cient to restore learning and memory in cognitively impaired mice [30]. This benefi cial effect of various HDAC inhibitors in improving learning and memory in non-diseased rodents and in other models of neurodegeneration and brain injury has continued to be replicated. For example it has now been shown by Marcelo Wood’s labora-tory that HDAC inhibition (via sodium butyrate) can facilitate extinction of a cocaine-induced conditioned place preference [31]. Finally, in one of our lat-est series of studies, we found the systemic delivery of one of various HDAC inhibitors (valproic acid, sodium butyrate or suberoylanilide hydroxamic acid) was suffi cient to rescue the cognitive defi cits present in a mouse model of Alzheimer’s disease [32]. As such, there is much excitement in the fi eld sur-rounding the potential clinical utility of HDAC inhibitors in treating neurode-generative and neuropsychiatric diseases.

A handful of studies have examined the involvement of histone modifi ca-tions at specifi c gene loci that control gene transcription in long-term memory. For example, we have shown that the memory of a contextual-fear association involves increased acetylation of histone H3 at promoter IV of Bdnf, which parallels the experience-induced changes in the expression of this specifi c tran-script [24]. The extinction of conditioned fear in mice has been shown to evoke histone H4 acetylation around Bdnf exon IV in the prefrontal cortex [33]. Finally, Isabelle Mansuy’s group has just shown that the selective inhibition of PP1 in forebrain neurons (via a transgenic mouse) not only enhances various forms of long-term memory, but that it does so through specifi c histone modi-fi cations occurring at the promoter of the memory-linked CREB and NF-κB (nuclear factor κB) genes [34].

Investigators continue to show that stressors and memories of stress-ful events in adulthood evoke complex patterns of histone modifications. For example, chronic social defeat stress in adult mice produces a lasting down-regulation of hippocampal Bdnf transcripts III and IV that is associ-ated with increased histone H3 lysine methylation at their promoters [35]. A psychological challenge, such as forced swimming, has been shown to evoke




histone H3 Ser10 phosphorylation and Lys14 acetylation in the dentate gyrus, through the ERK/MAPK pathway [36]. Additionally, Bruce McEwen’s group has just shown that acute or chronic restraint stress evokes patterns of hippocampal histone H3 trimethylation that vary by hippocampal subregion [37]. Discovering the complexity of such histone modifi cations not only offers an exciting new way to understand how intrinsic and extrinsic signals are inte-grated by the hippocampus, but also will probably help us to understand how stress can produce such long-term damage on the hippocampus and whether this damage is reversible.

Epigenetic mechanisms in cognitive dysfunction

It is becoming increasingly clear that epigenetic mechanisms help to regulate both the dynamic and stable capacity of the CNS. Thus an epigenetic contribution to cognitive dysfunction associated with psychiatric and brain disorder in aging continues to gain traction, and evidence gathered to date supports this hypothesis. For example, a growing body of literature suggests that aberrant DNA methylation of reelin and Gad1 (glutamic acid decarboxylase 1) may underlie dysfunction of GABAergic neurons in schizophrenia, and altered GABA (γ-aminobutyric acid) activity appears to be responsible for at least some of the clinical features of schizophrenia (for a recent review, see [38]). Several studies have reported aberrant DNA methylation and histone acetylation in Alzheimer’s disease patients (for a review, see [39]). Of course, the question remains unanswered whether these epigenetic alterations are causally related to the pathogenesis of such disorders and diseases. However, data gathered from post-mortem studies will undoubtedly provide us with some very important clues in understanding the complex gene–environmental interactions that probably confer susceptibility and lead cognition awry.

Conclusions

A central tenet in the fi eld of epigenetics has been that the epigenome is static following cellular development and differentiation. Although this may be the case for many cells, the data reviewed in this chapter indicate that this is not always the case for neurons. There is increasing evidence that neurons and specifi c genes within neurons retain their sensitivity to epigenetic factors beyond development, and that epigenetic regulation of gene transcription is a necessary component in CNS plasticity and memory (Figure 3). The involvement of epigenetic factors in memory is motivating the interest of an increasing number of investigators, which will undoubtedly revolutionize our understanding of how the CNS works and how we form both transient and enduring memories. Furthermore, the continued study of epigenetic mechanisms in cognition promises a future where epigenetic therapy may help to combat or alleviate memory dysfunction prominent in CNS disorders and disease.




Summary

• Studies continue to highlight the emerging role of the epigenome in

CNS function and memory in the adult.

• Following contextual-fear conditioning, there is both rapid DNA

methylation and demethylation of memory-linked genes in the hippoc-

ampus of adult rats. There is also involvement of histone modifi cations

at specifi c gene loci during fear-memory formation.

• Interfering with DNA methylation or histone acetylation disrupts both

LTP and memory formation. Drugs that promote histone acetylation

enhance memory capacity in cognitively impaired animals.

• An understanding of epigenetic mechanisms in learning and memory

is relevant not only to helping us better understand the processes

underlying cognition, but will also be important and relevant for future

therapeutics.

This work was funded by grants from the National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression, Civitan International, the Rotary Clubs CART fund, and the Evelyn F. McKnight Brain Research Foundation.

Figure 3. Epigenetic mechanisms provide a substrate for long-term neural and behavioural modifi cationsLearning and remembering the salience of extrinsic stimuli, such as that occurring with contextual-fear conditioning, modulates the activity of chromatin-modifying enzymes, such as HATs, HDACs and DNMTs. This evokes activity-dependent changes in DNA methylation and histone tail modifi cations, and ultimately the gene transcription that is necessary for the synaptic plasticity and behavioural modifi cations underlying long-term fear memory.




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