The finger of an angel: memory return with epigenetic manipulation

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ISSN 1750-191110.2217/EPI.12.19 © 2012 Future Medicine Ltd Epigenomics (2012) 4(3), 295–302

The finger of an angel: memory return with epigenetic manipulation

A Jewish legend suggests that each baby arrives knowing everything, but an angel places a finger above its mouth to ‘shush’ the baby from express-ing all this memory, forming the philtrum on the upper lip [1]. From legend to science, recent research studies indicate epigenetic modifica-tions, much like the finger of an angel, touch the DNA to alter its structure and expression, thus regulating the process of memory.

This article is an overview of current research on epigenetic regulation of long-term memory. Introductions to basic concepts in genetics, epi-genetics and psychological memory will be given previous to the overview. Clinical relevance and suggestions for future research will be discussed at the end of the overview.

Genetics: DNA, chromatin & the Central DogmaIt is well known that the basic genetic mate-rial found in eukaryotes, prokaryotes and most viruses is DNA. This molecule has two chains, each made of nucleotides composed of deoxy-ribose sugar, a phosphate group and a hetero-cyclic base containing nitrogen, forming the structure of a double helix. DNA coils around histone proteins to form nucleosomes that are packaged to chromatin fiber and condensed metaphase chromosomes [2]. Crick described the irreversible transfer of information from the transcription of DNA to RNA and then translation to protein as the Central Dogma [3]. His description of the ‘dogma’ simply meant a bold hypothesis with no experimental support [4,5]. Indeed, with time, the Central Dogma

has gained both support and challenges [6–11]. Recently, evidence from epi genetic research has also emerged to challenge the ‘irreversible’ claim in the Central Dogma, stating that ‘the information’ can flow from RNAs and pro-teins back to DNA in order to regulate gene expression [12–44].

Epigenetics: definition & mechanismsIn 1942, Waddington originally defined epi-genetics as “the study of how genotypes give rise to phenotypes through programmed changes during development,” describing the cell-to-cell phenotypic alterations during the development of a multicellular organism [45]. With the evolv-ing knowledge that all the cells in an organism share almost identical DNA sequences, but may differ remarkably in their phenotypic expres-sions, epigenetics was later defined as “nuclear inheritance that is not based on differences in DNA sequence” [46]. Subsequently, several other definitions were developed, but without substantive changes [47–49]. In 2009, Berger and colleagues defined epigenetics as “the study of heritable changes in gene expression that do not involve coding sequence modifications” [50]. This definition is parsimonious and compre-hensive to include other modifications besides chromatin patterning in the nucleus, such as RNA inter ference, leading scientists to a world of epigenetic possibilities [13–15]. However, since epigenetic marks can be transient and are not necessarily heritable, especially for the post-mitotic neurons targeted in this article, a less

Scientists have been trying to crack the memory code for hundreds of years; however, centuries later, even the simplest elements of memory formation are still not fully understood. Recent studies in epigenetics indicate neuronal activity can induce transient reprogramming of epigenetic codes required for long-term memory consolidation. This suggests epigenetics as a basic mechanism in the regulation of long-term memory; and highlights the possibility that epigenetic modifications, as well as environmental factors, can change certain gene expression of brain neurons to restore the ability to remember, even with an aging brain or innate mental deficits. This article is an overview of basic knowledge and current research on epigenetic regulation of long-term memory, and prospects for future research.

KEYWORDS: DNA methylation n epigenetics n histone acetylation n long-term memory n mental deficits

Ran He & Julia A Eggert*Healthcare Genetics Program, College of Health, Education & Human Development, Clemson University, Clemson, SC 29634, USA *Author for correspondence: Tel.: +1 864 656 7938 Fax: +1 864 656 5488 [email protected]

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comprehensive, but more appropriate definition of epigenetics by Bird will be used here: “the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states” [51].

Epigenetic mechanisms primarily include DNA methylation, histone modifications and RNA interference, all of which are inter-related [52]. Since most research targets the regulation of long-term memory by DNA methylation and histone acetylation, this overview primarily focuses on the regulation of long-term memory by these two mechanisms.

In eukaryotic cells, DNA methylation occurs at the cytosine of CG dinucleotides with S-adenosyl-methionine as the methyl donor and DNA methyltransferases as the catalysts [53] (Figure 1). These methylated cytosines (methyl-cytosines) occur on approximately 70–80% of CG dinucleotides throughout the genome [54]. When DNA methylation occupies the space where transcriptional factors usually bind, the downstream gene is silenced because of lack-ing transcriptional factors [2]. Furthermore, methylated DNA also recruits methylcytosin-binding proteins and chromatin-remodeling proteins to contribute to the formation of

condensed chromatin (heterochromatin). Heterochromatin may cause the neighborhood of genes to be silenced, because the transcrip-tional factors may lose access to a segment of DNA once the chromatin has condensed [53].

As shown in Figure 2, heterochromatin can be relaxed by some of the histone modifica-tions, including the most investigated, histone acetylation. Histone acetylation involves the binding of acetyl groups to lysines in the tails of histones, which is catalyzed by histone acetyl-transferases (HATs) and reversed by histone deacetylases (HDACs) [55]. Histone acetylation usually balances the positive charge on histone tails, reduces the interaction between positively charged histones and negatively charged DNA backbone, and relaxes the chromatin structure so the genes are more accessible to transcrip-tional factors for transcription [2,56,57]. In addi-tion, combinations of histone acetylation and other histone modifications including histone phospho rylation, methylation, ubiquitination and ADP-ribosylation, serve as a unique his-tone language that is read by other proteins, such as bromo-domain-containing proteins, to bring about downstream events and regulate transcription [58–61].

SAH

SAMUnknownmechanism

DNMTs

Gene on

Gene off

Transcriptionfactors

Methyl group

Cytosine

Guanine

Adenine

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Figure 1. Illustration of DNA methylation. DNA methylation occurs at the cytosine of CG dinucleotides with SAM as the methyl donor and DNMTs as the catalysts. Methyl groups take up the space where transcriptional factors usually bind in order to turn off the downstream gene. DNMT: DNA methyltransferase; SAH: S-adenosyl-homocysteine; SAM: S-adenosyl-methionine.

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The finger of an angel: memory return with epigenetic manipulation Review

Memory: definition & classification Memory is an abstract term that is not adequately or systematically defined, and is still subject to corrections and updates. In addition to denoting a field of study, memory can designate a number of other different concepts. Among these, the most frequently used meanings of memory include: neurocognitive capacity to encode, store and retrieve information; hypothetical store in which information is held; inform ation in that store; property of that inform ation; componential pro-cess of retrieval of that information; and an indi-vidual’s phenomenal awareness of remembering something [62]. As illustrated in Figure 3, the key elements of the human memory system include sensory memory, short-term memory and long-term memory [63]. The dynamic processes that transfer information throughout these three key memory systems are acquisition, consolidation and storage [64].

People experience stimulations from the environ ment by sensory systems and then regis-ter, interpret, and retain it into sensory memory located in the brain cortex for a very brief period of time, normally seconds [64]. The information in sensory memory is constantly overwritten by new information coming into the sensory channel, while the brain continues processing [62]. Information in sensory memory is passed to short-term memory by attention that filters stimuli by interest. This process of transforming external events into temporary neural represen-tations is acquisition [62]. Current research shows that at cellular and molecular levels, this process involves activation of synaptic receptors and sig-naling pathways, release of BDNF, activation

of TrkB, and covalent modifications of proteins (Figure 3) [65–67].

Short-term memory involves retention of small amounts of information in the cerebral cortex for a very short interval, while long-term memory works as a system to store inform ation over long periods of time [63,68]. Long-term memory can be classified as explicit or declarative memory, and implicit or nondeclarative memory. Explicit mem-ory includes semantic memory related to facts and episodic memory related to events (Figure 3) [69].

The transfer of information from the short-term memory system to the long-term memory system requires the efforts of consolidation. The mechanisms for memory consolidation are not well understood, but it is different from the mech-anisms for memory acquisition because it involves DNA modifications [70,71]. General research con-sensus is that consolidation is hippo campal depen-dent, the process is time-limited and the infor-mation yielded is eventually transferred to other locations in the brain for storage (Figure 3) [69,72]. As described below, recent research indicates epi-genetic modifications, such as DNA methyl ation and histone acetylation/deacetylation, may be critical for the changes that underlie memory con-solidation and storage, thus impacting long-term memory formation [16–44].

Epigenetic regulation of long-term memory formationLevenson et al. were the first to hypothesize that DNA methyltransferase activity is responsible for regulating synaptic plasticity – the ability to change the strength of synaptic connec-tions – in the CNS; therefore, methylation was a

Transcriptionfactors

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HATs

HDACs

Histones

Acetylatedhistones

dsDNA

Epigenomics © Future Medicine (2012)

Figure 2. Illustration of histone acetylation. Histone acetylation relaxes the chromatin structure so that the genes are more accessible to transcriptional factors for transcription. The reaction is catalyzed by HATs and reversed by HDACs. HAT: Histone acetyltransferase; HDAC: Histone deacetylase.


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potential epigenetic mechanism associated with long-term memory formation [16]. To test the hypothesis, methylation inhibitors, zebularine and 5-aza-2-deoxycytidine, were used to inhibit DNA methyltransferase activity in the hippocam-pal slices of sacrificed mice. After inhibition, the promoter regions of the memory promoting genes, Reelin and Bdnf, had rapid and dramatic decreases in DNA methylation. It was projected this process may have contributed to the failure of long-term potentiation induction (a type of synaptic plastic-ity important in long-term memory formation) at the hippocampal region of these sacrificed mice.

After the first in vitro evidence, Miller and Sweatt implemented an in vivo study to better illustrate that DNA methylation is not only asso-ciated with, but crucial and necessary in long-term memory formation [17]. For this experiment, researchers first induced a group of adult male Sprague–Dawley rats with a contextual fear con-ditioning (CFC) test. After sacrificing, the DNA methylation pattern of several genes in the hippo-campus was analyzed. Rapid methylation (tran-scriptional silencing) of the memory suppressor gene, Pp1, and demethylation (activation) of the memory promoting gene, Reelin, were found after CFC, but not prior to it. Second, these research-ers randomly assigned another set of adult male Srague–Dawley rats into two groups. In group one, the experimental rats received the training for the CFC test, then a combined injection of DNA methyltransferase inhibitors, zebularine and 5-aza-2-deoxycytidine. In group two, the con-trol rats also received training for the CFC test, then an injection of placebo. The performance

in subsequent CFC tests was compared in both groups. The researchers found that after block-ing the DNA methyltransferase activity, the rats ‘froze’ less in the CFC test compared with their placebo counterparts, indicating a decrease in l ong-term memory.

Using a similar methodology with the CFC and the same type of rats, these researchers found changes in methylation affected differential regulation of the Bdnf gene expression, together with alterations in chromatin structure, again indicating the critical role of DNA methylation in the formation of long-term memory [18].

In 2010, a study by Feng et al. also illustrated that DNA methylation is required for long-term memory [19]. These researchers engineered DNMT1 and DNMT3a double conditional knockout mice to determine if complete loss of gene expression of these two proteins in forebrain neurons would lead to abnormal memory func-tion. Results indicated a number of genes in fore-brain neurons of these double conditional knock-out mice had an abnormal methylation pattern and deregulated expression, causing deficits in the ability to learn and memorize. A neuronal loss was not identified, but the neurons did appear smaller than those seen in the wild-type mice.

The association of DNA methylation and intellectual disability can be illustrated by frag-ile X syndrome. As the most common inherited intellectual disability with approximately one in 4000 males affected, fragile X syndrome can be caused by hypermethylation of CGG repeats in the 5́ -UTR region of the FMR1 gene, causing the absence of its product, FMRP [20,21]. Other

AcquisitionConsolidation (hippocampus)

Storage

Long-term memory (cortex)

Retention of environmentalstimulus for seconds

Retention of information for a short interval

Storage of information for a long periodExplicit memory includes episodic and semantic memoryImplicit memory includes procedural, priming and classical conditioning

Human memory system

Protein modifications DNA modifications

Sensory memory (cortex)

Short-term memory (cortex)

Figure 3. Memory basics. The key elements of the human memory system include sensory memory, short-term memory and long-term memory. The dynamic processes that transfer information throughout these different memory systems are acquisition, consolidation and storage. Adapted from [69,71].



research indicates treatment of the fragile X cell line by methylation inhibitor 5-aza-2-deoxy-cytidine can cause passive demethylation of the FMR1 gene promoter and reactivate the gene expression [22].

Compared with DNA methylation, there is more evidence indicating the importance of his-tone acetylation and deacetylation in long-term memory formation. Levenson et al. were the first to directly test the in vivo regulation of memory and learning by histone acetylation [23]. These researchers used HDAC inhibitors, tricho-statin A or sodium butyrate to elevate the level of histone acetylation, and found it enhanced long-term potentiation at Schaffer-collateral syn-apses in vitro. The injection of HDAC inhibitors prior to CFC enhanced formation of long-term memory in vivo. However, there is evidence suggesting that nonspecific HDAC inhibitors, including sodium valproate, sodium butyrate and vorinostat, only blocked the activity of class I HDACs [24]. The inhibition of class I HDACs using these nonspecific inhibitors restored con-textual memory in an early-stage Alzheimer’s disease mouse model [24]. This indicates that some HDACs are more crucial in the regula-tion of long-term memory than others. Indeed, Guan et al. revealed that forebrain overexpres-sion of HDAC2, but not HDAC1, negatively regulates memory formation [25], and McQuown et al. illustrated that HDAC3 is also a critical negative regulator of long-term memory [26].

In 2007, Fischer et al. engineered a bitrans-genic mouse model with learning and memory deficits by inducing postnatal expression of protein p25 [27]. p25 is an abnormal truncated form of protein p35 that interacts with a protein kinase Cdk5 to regulate normal development of the mammalian CNS [28]. However, the interac-tion of p25 with Cdk5 can cause neuronal cell death and lead to learning and memory deficits [29–31]. In addition to HDAC inhibitors, Fischer et al. found that two other variables, an enriched environment with a variety of frequently changed toys, as well as exercise (two wheels for voluntary running), have the ability to increase histone acetylation in brain neurons of mice [27,32]. Together, these factors have the ability to reverse learning deficit in bitransgenic mice, and re-establish access to long-term memory.

The chromatin remodeling HAT activity of cAMP-responsive element binding protein (CREB) binding protein (CBP/CREBBP) has also been linked to formation of long-term memory and mental deficits [33–38]. Korzus et al. generated transgenic mice with eliminated HAT

function of CBP. They found the consolidation of short-term memory to long-term memory in these mice was impaired, and suppression of transgene expression or administration of the HDAC inhibitor trichostatin A restored long-term memory formation [36]. Similarly, several other studies demonstrated that CBP is not only involved in, but also plays a necessary and critical role in long-term memory formation [33,37,38].

A Rubinstein–Taybi syndrome mouse model, with less than normal expression of CBP, was used by Alarcon et al. to examine the effect of HDAC inhibitors on mental retardation [34]. These researchers found that inhibitors of HDAC could reverse the mental retardation typical for mice with Rubinstein–Taybi syndrome, offering evidence that symptoms associated with this syn-drome may result from the abnormal epigenetic histone acetylation function of CBP [34]. Similarly, Giralt et al. demonstrated reduced hippocampal expression of CBP and a lower level of histone H3 acetylation for hetero zygous Huntington’s disease knockin mutant mice (Hdh Q7/Q111) com-pared with wild-type mice [35]. Administration of HDAC inhibitor trichostatin A helped to rescue memory deficits in these Hdh Q7/Q111 mice [35]. These studies were significant because they impli-cated the promising role of epigenetic regulation in the treatment of innate mental diseases.

It is important to note that DNA methyl ation and histone acetylation may work in concert to regulate long-term memory formation and syn-aptic plasticity. Miller et al. found that DNA methyltransferase inhibition blocks memory and memory-associated acetylation, while increasing histone acetylation before administering a DNA methyltransferase inhibitor can prevent memory deficits [39]. A methyl-CpG-binding protein, MeCP2, has been reported to function as the media that connects DNA methylation and histone acetylation [40–42]. MeCP2 encodes a 486-amino acid protein with three recognizable domains: the methyl-CpG-binding domain that mediates methyl-CpG-binding; a C-terminal domain; and the transcriptional repression domain that recruits coprepressor complexes Sin3A, c-Ski and N-CoR [43]. These complexes contain HDAC components that function in chromatin remodeling [44]. Mutations in MeCP2 cause Rett syndrome, a postnatal pro-gressive neuro developmental disorder character-ized by gradual loss of speech, motor skills and mental impairments [43]. Evidence suggests that mutations in MeCP2 lead to abnormal histone acetylation, both of which play a role in Rett syndrome [44].


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Conclusion & future perspectiveTaken together, although still in early stages, these pioneering studies suggest the possibility of using epigenetic modification, as well as an enriched environment to modify certain gene expression of brain neurons to restore the ability to remember, even with an aging brain or innate mental deficits.

Numerous fundamental questions still need to be addressed in future research. First, the distinc-tion between long-term memory consolidation and storage has been vague in epigenetic studies. Most experiments have focused on the hippo-campus of the brain, thought to be the location of memory consolidation, but not storage. However, some papers have described it as ‘memory storage’ or more general ‘memory formation’ [17,23,39,55,73]. It is difficult to tell which description is more concise, because it is difficult to separate the physiological parameters of these concepts using experimental methodology currently available in the laboratory [74–76].

Based on the articles reviewed in this paper, epigenetic mechanisms are definitely not the only indispensable mediator in the encoding of long-term memory, but one of the indispens-able mediators in the regulation of memory formation, since the reviewed mental deficits were mostly caused by genetic mutations that lead to abnormal epigenetic modifications [19–22,24,27,34,35,44]. Therefore, a second question ponders whether epigenetic manipulation can be the ‘all-in-one’ solution for all mental diseases. It is surprising to see that histone acetyl ation can

reverse the memory changes caused by genetic mani pulations, so research focusing on improv-ing cognitive function by increasing histone acetylation might yield valuable results [77,78]. Ultimately, generations of researchers have been unable to decode where and how memory is stored. Is the memorized information stored in genetic code, the folding of chromatin within the cell’s nucleus or somewhere else within the neuron? If epigenetic encryptions are responsible for coding memory, then how the memorized information is translated to epigenetic codes and influences gene expression and behavioral phe-notypes, are key pieces of knowledge that need to be revealed.

For centuries, scientists have been trying to unveil the secret of memory in the human brain. Undoubtedly, the research into the epigenetic aspects of memory has brought hope that some of those secrets are being uncovered. However, there are no definitive answers and there is still much that needs to be deciphered before understanding the many levels of memory.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Genetics: DNA, chromatin & the Central Dogma � Epigenetic mechanisms have posed new challenges to the Central Dogma.

Epigenetics: definition & mechanisms � Epigenetics is defined as “the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states”.

� DNA methylation and histone acetylation are the two main epigenetic mechanisms studied in long-term memory formation.

Memory: definition & classification � Memory is a vague term that is hard to adequately define.

� Long-term memory is one of the key elements of the human memory system.

� As an essential step to form long-term memory, consolidation requires modification of DNA and de novo protein synthesis.

Epigenetic regulation of long-term memory formation � Both DNA methylation and histone acetylation have been implicated as crucial in long-term memory formation in vitro and in vivo.

� DNA methylation and histone acetylation work in concert to regulate long-term memory formation.

Conclusion & future perspective � Epigenetic modifications, as well as environmental enrichments, are promising solutions in clinical practice to fight memory loss and/or innate mental deficits.

� The extent to which epigenetic modifications are involved in long-term memory encoding is a key question to answer.

� Memory code remains a mystery and more research is needed to explore its mechanisms.



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The finger of an angel: memory return with epigenetic manipulation

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