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• W2125006027 abstract "Review28 April 2014free access Mechanisms of epigenetic memory and addiction Luis M Tuesta Luis M Tuesta Howard Hughes Medical Institute, Boston, MA, USA Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA Department of Genetics, Harvard Medical School, Boston, MA, USA Search for more papers by this author Yi Zhang Corresponding Author Yi Zhang Howard Hughes Medical Institute, Boston, MA, USA Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA Department of Genetics, Harvard Medical School, Boston, MA, USA Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA Search for more papers by this author Luis M Tuesta Luis M Tuesta Howard Hughes Medical Institute, Boston, MA, USA Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA Department of Genetics, Harvard Medical School, Boston, MA, USA Search for more papers by this author Yi Zhang Corresponding Author Yi Zhang Howard Hughes Medical Institute, Boston, MA, USA Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA Department of Genetics, Harvard Medical School, Boston, MA, USA Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA Search for more papers by this author Author Information Luis M Tuesta1,2,3 and Yi Zhang 1,2,3,4 1Howard Hughes Medical Institute, Boston, MA, USA 2Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA 3Department of Genetics, Harvard Medical School, Boston, MA, USA 4Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA *Corresponding author. Tel: +1 617 713 8666; Fax: +1 617 713 8665; E-mail: [email protected] The EMBO Journal (2014)33:1091-1103https://doi.org/10.1002/embj.201488106 See the Glossary for abbreviations used in this article. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Epigenetic regulation of cellular identity and function is at least partly achieved through changes in covalent modifications on DNA and histones. Much progress has been made in recent years to understand how these covalent modifications affect cell identity and function. Despite the advances, whether and how epigenetic factors contribute to memory formation is still poorly understood. In this review, we discuss recent progress in elucidating epigenetic mechanisms of learning and memory, primarily at the DNA level, and look ahead to discuss their potential implications in reward memory and development of drug addiction. Glossary 5caC 5-carboxylcytosine 5fC 5-formylcytosine 5hmC 5-hydroxymethylcytosine 5mC 5-methylcytosine BDNF brain-derived neurotrophic factor BER base excision repair DA dopamine DNMT DNA methyltransferase GABA gamma-aminobutyric acid HAT histone acetyltransferase HDAC histone deacetylase HDM histone demethylase HMT histone methyltransferase LTP long-term potentiation NAc nucleus accumbens PFC prefrontal cortex SNpc substantia nigra pars compacta TDG thymine-DNA glycosylase TET ten-eleven translocation VTA ventral tegmental area Introduction The term ‘epigenetics’ refers to heritable changes in phenotype or gene expression that cannot be directly attributed to changes in DNA sequence (Jaenisch & Bird, 2003). In eukaryotes, DNA and histones are assembled into nucleosomes, the basic unit of chromatin. Nucleosomes are composed of 147 DNA base pairs wrapped around an octamer of four core histone proteins: H2A, H2B, H3, and H4 (Kornberg & Lorch, 1999). Histones contain extensive post-translational modifications that regulate their various functions (Kouzarides, 2007). Similarly, DNA methylation at CpG dinucleotides can also modulate transcriptional outcome (Jaenisch & Bird, 2003). Some of these modifications are heritable and are believed to be responsible for a number of phenomena such as genomic imprinting, paramutation, Polycomb silencing, and position effect variegation (Bird, 1986; Campos & Reinberg, 2009; Fedorova & Zink, 2008; Martin & Zhang, 2007). Epigenetic regulation has been mostly studied in the context of cellular differentiation and development, but accumulating evidence suggests that epigenetic mechanisms also play important roles throughout the lifespan of postmitotic cells. As such, epigenetic changes may also regulate mechanisms underlying learning and memory, including brain reward and the development of drug addiction. In this review, we will cover the various types of epigenetic modifications on DNA and histones. We will also address the role of epigenetic modifications in postmitotic neurons, in the context of brain learning and memory. Finally, we will review recent progress in understanding the epigenetic regulation of drug addiction that sets the stage for future research in this burgeoning field. DNA methylation DNA methylation is the best-characterized form of epigenetic modification. It takes place at the 5′ position of cytosine and usually occurs in the context of CpG dinucleotides. However, contiguous groups of CpG dinucleotides, called ‘CpG islands’, are generally unmethylated. Promoter methylation is generally associated with gene silencing either by preventing binding of transcription factors or by attracting methyl-CpG binding proteins that recruit co-repressors of transcription (Bird, 1986; Klose & Bird, 2006). DNA methylation plays important roles in several physiological phenomena (Jaenisch & Bird, 2003). For example, genomic imprinting, an allele-specific expression phenomenon, is controlled by allele-specific DNA methylation. Additionally, X-chromosome inactivation, a mechanism used to equalize X-linked gene expression in males and females, uses DNA methylation to silence one of the two female X chromosomes. DNA methylation also plays a crucial role in other cellular processes such as cell differentiation and tissue-specific gene expression. CpG island methylation is commonly detected in tissue-specific and germline-specific genes, X-linked genes, and imprinted genes (Jaenisch & Bird, 2003). DNA methylation is catalyzed by DNA methyltransferases (DNMTs), which are classified into de novo and maintenance DNMTs based on their substrate preference (Goll & Bestor, 2005). De novo DNMT3A and DNMT3B prefer unmethylated DNA substrates, while DNMT1 prefers hemimethylated DNA substrates and is mainly responsible for copying the DNA methylation pattern during DNA replication (Hermann et al, 2004; Inano et al, 2000; Moore et al, 2013). Interestingly, DNMT3A is abundantly expressed in the postnatal brain (Feng et al, 2005), which suggests that it may also play a regulatory role in postmitotic neurons. DNA methylation is relatively stable when compared to histone modifications, yet DNA demethylation has also been observed in various biological contexts by active and passive means. Active DNA demethylation involves enzymatic activity that selectively restores an unmodified cytosine base, while passive demethylation generally involves dilution of 5-methylcytosine (5mC) through progressive cell division where DNA methylation maintenance machinery is either absent or compromised (Moore et al, 2013; Ooi & Bestor, 2008). Until recently, a mechanism underlying active DNA demethylation has remained a topic of controversy. It has now been shown that ten-eleven translocation (TET) family proteins can catalyze oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and further to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (He et al, 2011b; Ito et al, 2010, 2011; Kriaucionis & Heintz, 2009; Tahiliani et al, 2009). Thymine DNA glycosylase (TDG), an enzyme previously known for its role in DNA repair, has been shown to excise 5fC and 5caC, creating abasic sites which can be repaired by the base excision repair (BER) pathway to generate an unmodified cytosine residue, thereby completing the demethylation process (He et al, 2011b; Shen et al, 2013; Zhang et al, 2012) (Fig 1). Interestingly, 5hmC, the major oxidation product of 5mC, positively correlates with transcription when it is located in the gene body, and is at its highest levels in neurons (Jin et al, 2011; Khare et al, 2012; Kriaucionis & Heintz, 2009; Szulwach et al, 2011). Figure 1. TET/TDG-mediated 5mC demethylationUnmodified cytosine residues (C), highlighted left, are methylated by DNMTs to produce 5mC. TET enzymes catalyze oxidation of 5mC to 5hmC (Ito et al, 2010; Tahiliani et al, 2009) and further to 5fC and 5caC (Ito et al, 2011). In this pathway, 5mC demethylation can occur through passive dilution (PD) of 5hmC, or through active excision of TET oxidation products 5fC and 5caC to generate abasic sites via TDG that are then restored to unmodified C by BER (He et al, 2011b; Shen et al, 2013; Zhang et al, 2012). Download figure Download PowerPoint Given the abundance of 5hmC in neurons, the discovery of this new cytosine modification is especially exciting as it suggests that neural systems may be under active TET regulation, independent of cell division and maturation, opening the possibility for epigenetic regulation of adaptive processes such as learning and memory. Histone modifications In addition to DNA methylation, covalent modifications on histones also play an important role in regulating gene expression. Major histone modifications include acetylation, methylation, ubiquitination, and phosphorylation (Bannister & Kouzarides, 2011). These modifications can either activate or repress transcription, depending on the modification and the specific substrate residues (Margueron et al, 2005; Martin & Zhang, 2005; Zhang, 2003), and can be deposited or removed by a large family of histone-modifying proteins. While DNA methylation is faithfully inherited through semi-conservative replication (Bestor, 1992; Holliday & Pugh, 1975; Leonhardt et al, 1992), the mechanisms by which epigenetic information is inherited through histone modifications still remain unresolved. Histone acetylation, which occurs at certain lysine (K) residues of histones H3 and H4, is one common form of histone modification associated with transcriptional activation. Upon acetylation, chromatin is generally decondensed due to the neutralization of the positively charged K residues in histone tails. Acetylation and deacetylation of K residues are mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively (Borrelli et al, 2008), yet the specificity of HDACs and HATs for specific K residues still remains poorly understood. Despite a general correlation between histone K acetylation and transcriptional activity, such general correlation seems to not hold true in brain at several promoters of genes involved in learning and memory, such as Bdnf, following chronic cocaine treatment, implying the involvement of alternate and complementary mechanisms of transcriptional regulation (Kumar et al, 2005; Renthal et al, 2009). Histone methylation has been associated with both transcriptional activation and repression depending on the specific K residue and valence of methylation (Martin & Zhang, 2005). However, unlike acetylation, histone methyltransferases (HMTs) and histone demethylases (HDMs) have greater residue specificity, with distinct HMTs or HDMs acting on specific residues, determining valence of methylation states (mono-, di-, or trimethylation). Transcriptional silencing is mainly associated with H3K27me3 and H3K9me, whereas transcriptional activation is associated with H3K4me3 and H3K36me3 marks. Additionally, methylation marks can act as recruiters for other effector proteins that assist in perpetuating transcriptional states. Furthermore, some methyltransferases have the ability to bind methylated DNA and certain transcriptional activators such as CREB-binding protein (CBP) (Volkel & Angrand, 2007). As mentioned above, HDMs possess greater functional specificity than HDACs and they belong to the LSD1 and the JmjC family of proteins (Klose et al, 2006). Histone demethylation appears to occur in a gene-specific manner, in part by conjunction with nuclear factor complexes (Metzger et al, 2005; Tsukada et al, 2006; Yamane et al, 2006). Despite this, similar to histone acetylation, methylation states at certain gene promoters also fail to faithfully predict transcriptional behavior in brain following drug treatment (Renthal et al, 2009). This indicates that the transcriptional effects can be modulated by other factors and consequently one cannot predict transcriptional activity solely based on histone modifications. Mechanisms of epigenetic inheritance Classical ‘epigenetic’ modifications require a component of heritability. In the context of this definition, DNA CpG methylation has the best understood mechanism. As depicted in Fig 2A, CpG methylation is copied in a semi-conservative fashion where DNMT1 is recruited by UHRF1 and PCNA to the replication fork and reestablishes methylation marks on newly synthesized DNA strands (Zhu & Reinberg, 2011). In a similar fashion, chromatin modifiers have been reported to localize to replication forks (Esteve et al, 2006; Milutinovic et al, 2002), raising the possibility that inheritance of histone modifications is an opportunistic phenomenon that utilizes DNA replication as an avenue to rapidly pass on epigenetic information. While histone modifications are a major source of heritable epigenetic information, the exact modifications, degree of fidelity, and mechanisms of inheritance still remain a subject of investigation. Figure 2. Models of epigenetic inheritance(A) Semi-conservative model of DNA CpG methylation: DNMT1 is recruited to the replication fork where it reestablishes methylation marks on the nascent DNA strand (Zhu & Reinberg, 2011). (B) Conservative model of histone segregation and templated inheritance of histone methylation: Intact H3-H4 tetramers are transferred to daughter DNA strands where methylation sensors such as PRC2 recognize existing histone methylation patterns which serve as a template to propagate the methylation signal onto newly deposited histones (Margueron et al, 2009). (C) Reinforcement model of histone methylation: DNTM1 recruits histone methyltransferase G9a to the replication fork where it restores methylation marks on newly deposited histones (Esteve et al, 2006). Download figure Download PowerPoint In the context of inheritance, K methylation has garnered special interest because of its relative stability (Huang et al, 2013). While histone lysine methylation marks possess a half-life ranging from hours to days (Zee et al, 2010), histone acetylation and phosphorylation marks are much more short-lived, with half-lives in the range of minutes (Chestier & Yaniv, 1979; Jackson et al, 1975). As such, histone K methylation has become a favored modification in the study of mechanisms of epigenetic inheritance. Based on the relationship to CpG methylation, several models for inheritance of histone modifications have been proposed (Xu et al, 2012; Zhu & Reinberg, 2011). Conservative model of chromatin assembly As mentioned previously, CpG methylation occurs in a semi-conservative fashion where DNMT1 is recruited to the replication fork, methylating CpGs on nascent DNA strands. This mechanism prompted the proposal of a semi-conservative model of chromatin assembly (Weintraub et al, 1976). This model purported replication-dependent dissociation of H3-H4 tetramers into two half nucleosomes that would be deposited into each daughter strand. This was later proven incorrect by sedimentation studies using heavy isotope-labeled histones showing that nucleosomes do not divide, supporting conservative segregation of histone octamers during replication (Leffak et al, 1977). However, speculation of a semi-conservative model was refueled when it was discovered that H3-H4 tetramers deposit onto chromatin, not as tetramers, but as dimers (Benson et al, 2006; English et al, 2005; Tagami et al, 2004), perhaps as a result of Asf1-mediated inhibition of H3-H4 tetramer formation (English et al, 2006). Regardless, more recent work suggests otherwise in that H3-H4 tetramers indeed do not divide and in fact, also suggests that inheritance of histone modifications occurs by copying modifications from neighboring pre-existing nucleosomes (Xu et al, 2010). This brings about an established conservative model of chromatin assembly in which H3-H4 tetramers are transferred intact to daughter strands and serve as methylation templates for cis nucleosomes (Martin & Zhang, 2007; Zhu & Reinberg, 2011) (Fig 2B). This raises the question of how modifications on ‘old’ histones are transferred to ‘new’ adjacent histones. The answer to this question remains under debate. Templated modification One mechanism used to spread histone modifications involves the coupling of a chromatin-modifying enzyme to an effector protein that recognizes specific epigenetic marks, thereby allowing propagation of a modification state (Zhu & Reinberg, 2011). For example, recognition of H3K27me3 by Polycomb repressive complex 2 (PRC2) promotes propagation of this repressive signal onto neighboring histones through allosteric activation of its catalytic domain (Margueron et al, 2009) (Fig 2B). This suggests that histone modifications may be copied from ‘template’ histones that use their existing modifications as molecular flags to attract chromatin-modifying enzymes and propagate epigenetic states. Modification reinforcement As mentioned earlier, chromatin-modifying enzymes, such as DNMT1, can be recruited to replication foci. This raises the possibility that replication-dependent DNA methylation can be coupled to histone modification. In fact, DNMT1 directly interacts with, and recruits G9a, an H3K9 methyltransferase, to replication foci and regulates G9a-dependent H3K9 methylation (Esteve et al, 2006). The fact that knockdown of DNMT1 impairs H3K9 methylation suggests that inheritance of histone modifications may involve an opportunistic mechanism where factors such as G9a ‘piggyback’ on DNA replication factors to rapidly restore histone modifications on nascent chromatin (Fig 2C). Histone maturation Some histone marks, such as H3K9 dimethylation reach similar levels in new histones as those in old histones shortly after S phase, suggesting a replication-dependent mechanism (Xu et al, 2012). However, other modifications such as H4K20, and H3K79 methylation, as well as H3K9 and H3K27 trimethylation, are gradually restored throughout the cell cycle, independent of replication (Pesavento et al, 2008; Sweet et al, 2010; Xu et al, 2012). This gradual ‘maturation’ of histone methylation suggests that epigenetic inheritance is not a rigid process, and its inexact fidelity provides a certain degree of epigenomic flexibility to adapt to changing conditions. Brain memory and long-term potentiation While the mechanisms outlined above largely rely on replication, it is unclear to what extent these mechanisms may play in postmitotic neurons, especially in the context of learning, memory, and addictive disorders. A fundamental tenet of brain learning and memory postulates that neuronal activity has the ability to either strengthen or weaken connections at the synapse, the anatomical interface where direct communication between neurons occurs. This adaptability is referred to as synaptic plasticity, and the underlying foundation of activity-dependent synaptic plasticity is measured by long-term potentiation (LTP). Experience-dependent LTP involves structural changes such as dendritic spine remodeling and receptor redistribution, resulting in long-term increases in efficacy of synaptic transmission between neurons (Bliss & Collingridge, 1993; Luscher & Malenka, 2012; Toni et al, 1999). As such, LTP represents an integral component of learning and memory. Fear conditioning is a widely used behavioral paradigm to measure associative learning in animals, where a neutral conditioned stimulus elicits a fear response (usually freezing behavior) following repeated pairing with a noxious, unconditioned stimulus such as a loud noise or a mild electrical foot shock (Kim & Jung, 2006). Indeed, fear conditioning via electrical foot shock has been shown to induce LTP in the amygdala of rats (Rogan et al, 1997). In addition to fear conditioning, reward learning in the form of active cocaine self-administration has also been shown to elicit LTP in brain regions implicated in drug reward (Chen et al, 2008). It is interesting to note that a memory can be perpetuated throughout the lifetime of an individual, yet conventional molecular players in LTP formation such as CaMKII do not appear to be involved in lifelong maintenance of a memory (Day & Sweatt, 2011), raising the possibility for alternative mechanisms such as epigenetic modifications in mediating memory maintenance. Epigenetic mechanisms underlying learning and memory Cellular differentiation and phenotypic manifestation is heavily influenced by epigenetic mechanisms. However, as discussed in the previous section, classical ‘epigenetic’ mechanisms involve some aspect of cell division. Stepping outside the realm of epigenetic inheritance in mitotic cells, the adult brain consists primarily of glia and postmitotic neurons, with very limited potential for proliferation (Emsley et al, 2005). If the cellular epigenetic toolbox is not utilized for the purpose of cell division or fate determination, another function must justify active regulation seen in these cells. Accumulating evidence suggests that epigenetic mechanisms play an important role in the formation and maintenance of memory in the brain. Histone acetylation in learning and memory Initial studies into the role of histone acetylation in learning and memory showed that MAP kinase (MAPK) activity regulates the formation of taste aversion in mice and that this in turn regulates histone acetylation in the insular cortex, a brain region associated with emotional processing and aversion memory (Swank & Sweatt, 2001). Further studies confirmed a role of histone acetylation in learning and memory. For instance, pharmacological inhibition of HDACs has proven to restore deficits in neuronal plasticity and fear memory in animals lacking the histone acetyltransferase CBP (Alarcon et al, 2004). Indeed, deficits in CBP expression are associated with impaired long-term fear memory and object recognition (Wood et al, 2006a,b). Furthermore, the HDAC inhibitor sodium butyrate (NaBut) significantly reduces the amount of training required for an animal to remember a novel object and prolongs the time the animal remembers the object following training (Stefanko et al, 2009). Another recent study also suggests that NaBut administration can improve retrieval of long-term inaccessible fear memories (Fischer et al, 2007). NaBut inhibits HDAC-mediated histone deacetylation, likely making DNA more accessible to transcriptional control, implying that histone acetylation plays a regulatory role in memory formation. In fact, aspects of memory formation and storage have shown to be mediated by several HDAC subtypes (Bahari-Javan et al, 2012; Guan et al, 2009; Kim et al, 2012; Sando et al, 2012). However, due to space limit, in the context of learning and memory, we focus our discussion on DNA methylation. DNA methylation in learning and memory DNA methylation has long been considered a relatively stable epigenetic mark. It is thus not surprising that efforts have been undertaken to explore the link between DNA methylation and learning and memory. Initial studies into the basic role of DNMTs in the brain suggest a role in DNA mismatch repair (Brooks et al, 1996), neuronal survival (Fan et al, 2001), and secondary neurodegeneration following ischemic insult (Endres et al, 2001, 2000). DNMT dysfunction has also been linked to cognitive and behavioral disorders such as schizophrenia (Veldic et al, 2004), fragile X syndrome (Sutcliffe et al, 1992), Rett syndrome (Amir et al, 1999), and aging-related cognitive decline (Oliveira et al, 2012). The question is whether DNA methylation has a role in the induction of synaptic plasticity. As discussed earlier, learning and memory depends heavily on plastic adaptations between neuronal connections, where LTP enhances synaptic transmission efficacy, thereby facilitating development of memory formation. Indeed, inhibition of DNMT activity disrupts LTP in adult hippocampal slices, and inhibition of DNMT alters DNA methylation within the promoter regions of reelin and BDNF, two genes previously implicated in synaptic plasticity within the adult hippocampus (Levenson et al, 2006). These experiments suggest a role for DNA methylation in memory formation by regulating LTP. In vivo studies using a fear-conditioning model have shown that inhibition of DNMT enzymes in the hippocampus disrupts conditioned shock-fear memory formation and does not affect maintenance of the fear memory trace (Miller & Sweatt, 2007). This suggests that while the hippocampus is a key mediator of memory formation, there are alternative brain structures that can maintain a long-term memory trace long after cessation of the initial stimulus (Miller et al, 2010). Furthermore, when DNA methylation is disrupted in the dorsomedial prefrontal cortex (dmPFC) in mice, severe deficits in long-term fear memory consolidation are observed although short-term fear memory remains unaffected (Miller et al, 2010). These studies further suggest that while memory formation depends on hippocampal activity, consolidation and long-term maintenance of the memory trace occurs in cortical regions and that these mechanisms rely heavily on temporally discrete DNA methylation patterns. It must be noted, however, that the studies outlined above (Miller et al, 2010; Miller & Sweatt, 2007) used 5-azacytidine (5-aza) and zebularine as pharmacological agents to inhibit DNA methylation in the brain and measure their effect on memory formation. Since 5-aza- and zebularine-mediated inhibition of DNA methylation requires their incorporation into DNA during replication (Szyf, 2009), it is mechanistically not clear how they could be incorporated into the postmitotic neurons to exert their effect on DNA methylation. Hypothetically, 5-aza may compete with cytosine for incorporation into neuronal DNA through a base excision repair (BER) mechanism if fear conditioning introduces DNA damage, but it is yet unclear how such a mechanism would contribute to the regulation of memory formation or whether the observed effects are due to a secondary effect of the small molecule. Regardless of how 5-aza and zebularine mediate the effects, the authors were able to confirm that DNMT inhibition indeed does disrupt long-term memory (Miller et al, 2010) using a non-nucleoside DNMT inhibitor, RG108, whose function in inhibiting DNA methylation does not require DNA replication (Brueckner et al, 2005). The majority of studies into the role of DNA methylation on cognition using in vivo approaches mainly employ pharmacological techniques (intracranial infusions) to inhibit DNMT enzymes in animals. Consequently, these studies cannot definitively link the observed effect to a specific DNMT isoform. Therefore, a major challenge in the field involves dissecting the functions of individual epigenetic modifying enzymes and how they contribute to learning and memory process. To begin to address this issue, studies using mice lacking Dnmt1, Dnmt3a, or both showed that learning deficits are only present in animals lacking both isoforms, but not in single KO animals (Feng et al, 2010), suggesting some level of functional redundancy between these two DNMT enzymes. Although we still do not know exactly how DNA methylation functions to promote and maintain memory, characterization of DNA methylation patterns in the brain following stimulation (Guo et al, 2011a; Ma et al, 2009) may shed light on this question. DNA demethylation in learning and memory Given that the DNA methylation level is controlled by the concerted action of DNMTs and the demethylation machineries, it is not surprising that learning and memory is also linked to loss of DNA methylation at certain genes. A recent study has shown that the offspring of mice conditioned to fear the odor of acetophenone (followed by electric foot shock) display greater behavioral sensitivity to the odorant, but not other odors (Dias & Ressler, 2014). Interestingly, fear conditioning results in hypomethylation of the Olfr151, a gene specific for the acetophenone odorant receptor, in fear-conditioned males as well as in their naïve progeny (Dias & Ressler, 2014). These results suggest that loss of DNA methylation caused by a traumatic experience can be inherited to subsequent generations. Although most of the studies on the role of DNA methylation in learning and memory have been focused on DNMTs, the recent identification of the DNA demethylation pathway has provided a new angle by which to study epigenetic changes involved in learning and memory (Kohli & Zhang, 2013; Wu & Zhang, 2011). As discussed earlier, DNA demethylation can be achieved through TET-mediated oxidation followed by TDG-mediated cleavage and BER (Fig 1). Interestingly, TET oxidation product 5hmC accumulates at the highest level in the mammalian brain when compared to other tissues (Kriaucionis & Heintz, 2009; Szulwach et al, 2011) and has been proposed to act as a mediator of passive demethylation by interfering with DNMT1 (Smith & Meissner, 2013) as well as to function as a key intermediate of active demethylation (Fig 1). Considering that all the three TET proteins (TET1-3) are abunda" @default.
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• W2125006027 title "Mechanisms of epigenetic memory and addiction" @default.
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