Epigenetic codes in cognition and behaviour.
TL;DR: Recent findings on the role and mechanisms of epigenetic codes in the brain are described, and their implication in synaptic plasticity, cognitive functions and psychiatric disorders are discussed.
About: This article is published in Behavioural Brain Research.The article was published on 2008-09-01. It has received 260 citations till now. The article focuses on the topics: Epigenetic code & Epigenetics.
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TL;DR: These studies indicate that SES is an important predictor of neurocognitive performance, particularly of language and executive function, and that S ES differences are found in neural processing even when performance levels are equal.
1,258 citations
TL;DR: An epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect is highlighted.
1,176 citations
TL;DR: The results of this work suggest that patterns of transcription regulation represent the molecular signatures of long-term synaptic changes and memory formation.
Abstract: Transcription is a molecular requisite for long-term synaptic plasticity and long-term memory formation. Thus, in the last several years, one main interest of molecular neuroscience has been the identification of families of transcription factors that are involved in both of these processes. Transcription is a highly regulated process that involves the combined interaction and function of chromatin and many other proteins, some of which are essential for the basal process of transcription, while others control the selective activation or repression of specific genes. These regulated interactions ultimately allow a sophisticated response to multiple environmental conditions, as well as control of spatial and temporal differences in gene expression. Evidence based on correlative changes in expression, genetic mutations, and targeted molecular inhibition of gene expression have shed light on the function of transcription in both synaptic plasticity and memory formation. This review provides a brief overview ...
902 citations
Cites background from "Epigenetic codes in cognition and b..."
...[From Gräff and Mansuy (82), with permission from Elsevier....
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...[From Gräff and Mansuy (82), with permission from Elsevier.]...
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TL;DR: As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.
Abstract: Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms. Of the epigenetic modifications identified in cognitive processes, histone acetylation has spurred considerable interest. Whereas increments in histone acetylation have consistently been shown to favour learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and ageing. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.
506 citations
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TL;DR: This Review develops four defining criteria that enable us to critically assess the recent progress that has been made towards finding the engram, and proposes that findings from 'capture' studies represent considerable progress in allowing us to observe, erase and express the engrams.
Abstract: Many attempts have been made to localize the physical trace of a memory, or engram, in the brain However, until recently, engrams have remained largely elusive In this Review, we develop four defining criteria that enable us to critically assess the recent progress that has been made towards finding the engram Recent 'capture' studies use novel approaches to tag populations of neurons that are active during memory encoding, thereby allowing these engram-associated neurons to be manipulated at later times We propose that findings from these capture studies represent considerable progress in allowing us to observe, erase and express the engram
464 citations
References
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TL;DR: It is found that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide.
Abstract: Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate–dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.
1,369 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...Note that the existence of DMs is still hypothetical (but see [149]), and that the implication o vo....
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...[149] Gerken T, Girard CA, Loraine Tung Y-C, Webby CJ, Saudek V, Hewitson KS, et al....
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TL;DR: It is demonstrated here that this maternal epigenetic effect is not the result of a maternally contributed environment, and results from incomplete erasure of an epigenetic modification when a silenced Avy allele is passed through the female germ line, with consequent inheritance of the epigenetic modified.
Abstract: Epigenetic modifications have effects on phenotype, but they are generally considered to be cleared on passage through the germ line in mammals, so that only genetic traits are inherited. Here we describe the inheritance of an epigenetic modification at the agouti locus in mice. In viable yellow ( Avy/a) mice, transcription originating in an intra-cisternal A particle (IAP) retrotransposon inserted upstream of the agouti gene ( A) causes ectopic expression of agouti protein, resulting in yellow fur, obesity, diabetes and increased susceptibility to tumours1. The pleiotropic effects of ectopic agouti expression are presumably due to effects of the paracrine signal on other tissues. Avy mice display variable expressivity because they are epigenetic mosaics for activity of the retrotransposon: isogenic Avy mice have coats that vary in a continuous spectrum from full yellow, through variegated yellow/agouti, to full agouti (pseudoagouti). The distribution of phenotypes among offspring is related to the phenotype of the dam; when an Avy dam has the agouti phenotype, her offspring are more likely to be agouti2,3. We demonstrate here that this maternal epigenetic effect is not the result of a maternally contributed environment. Rather, our data show that it results from incomplete erasure of an epigenetic modification when a silenced Avy allele is passed through the female germ line, with consequent inheritance of the epigenetic modification. Because retrotransposons are abundant in mammalian genomes, this type of inheritance may be common.
1,351 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...[119] Morgan HD, Sutherland HG, Martin DI, Whitelaw E....
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...Strikingly, such induced epigenetic modfication can be passed to subsequent generations through both aternal [119] and paternal [123] germline, suggesting a DNA ethylation-dependent transgenerational epigenetic inheritance nduced by nutrition....
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...Differential methylation of the LTR results n different coat colour ranging from yellow when the LTR s demethylated, to black or pseudoagouti when the LTR is ypermethylated [119]....
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TL;DR: This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.
Abstract: Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.
1,303 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...[88] Tsankova N, Renthal W, Kumar A, Nestler EJ....
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...In addition to cognitive disorders, epigenetic mechanisms ave been implicated in the etiology of psychiatric diseases uch as schizophrenia, addiction, depression, and stress-related isorders (reviewed in [88]) (Table 2)....
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...Interestngly, HDAC inhibitors such as sodium butyrate might represent otent candidates [103], since virus-mediated HDAC5 overexression reverses the imipramine-induced H3 hyperacetylation nd BdnfIII and BdnfIV transcription [88]....
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...rogramming [88], with acetylated H3 being a preferential mark or chronic administration....
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TL;DR: It is shown that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF).
Abstract: Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt) Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF) In cell-free assays, Httex1p also inhibits the acetyltransferase activity of at least three enzymes: p300, P/CAF and CBP Expression of Httex1p in cultured cells reduces the level of the acetylated histones H3 and H4, and this reduction can be reversed by administering inhibitors of histone deacetylase (HDAC) In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease These findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington's disease and other polyglutamine-repeat diseases, even after the onset of symptoms
1,247 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...[84] Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL,...
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...his extension directly binds and inhibits the HAT domain of BP and p300/CBP-associated factor (P/CAF) [84], which ultiately leads to transcriptional dysregulation....
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...In cultured cells f Drosophila, overexpression of the polyglutamine-containing omain reduces the overall level of H3 and H4 acetylation, n effect that can be reversed by the application of SAHA or odium butyrate [84]....
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TL;DR: It is found that MeCP2 binds selectively to BDNF promoter III and functions to repress expression of the BDNF gene and suggests that the deregulation of this process may underlie the pathology of RT T.
Abstract: Mutations in MeCP2, which encodes a protein that has been proposed to function as a global transcriptional repressor, are the cause of Rett syndrome (RT T), an X-linked progressive neurological disorder Although the selective inactivation of MeCP2 in neurons is sufficient to confer a Rett-like phenotype in mice, the specific functions of MeCP2 in postmitotic neurons are not known We find that MeCP2 binds selectively to BDNF promoter III and functions to repress expression of the BDNF gene Membrane depolarization triggers the calcium-dependent phosphorylation and release of MeCP2 from BDNF promoter III, thereby facilitating transcription These studies indicate that MeCP2 plays a key role in the control of neuronal activity-dependent gene regulation and suggest that the deregulation of this process may underlie the pathology of RT T
1,241 citations
"Epigenetic codes in cognition and b..." refers background or result in this paper
...his has been further corroborated by two studies showing hat neuronal activity in particular, membrane depolarization, nduces calcium-dependent MeCP2 phosphorylation, which in urn leads to its dissociation from the BDNF promoter region, nd ultimately increases BDNF transcription [67,68]....
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...[68] Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, et al....
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