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: An overview of schizophrenia is presented and the role of nature versus nurture in its pathology is discussed, where 'nature' is considered to be inherited or genetic vulnerability to schizophrenia, and 'nurture' is proposed to exert its effects through epigenetic mechanisms.
163 citations
TL;DR: This review outlines major cognitive disorders known to be associated with epigenetic dysregulation, and discusses the potential of ‘epigenetic medicine’ as a promising cure.
Abstract: Epigenetic mechanisms are not only essential for biological functions requiring stable molecular changes such as the establishment of cell identity and tissue formation, they also constitute dynamic intracellular processes for translating environmental stimuli into modifications in gene expression. Over the past decade it has become increasingly clear that both aspects of epigenetic mechanisms play a pivotal role in complex brain functions. Evidence from patients with neurodegenerative and neurodevelopmental disorders such as Alzheimer's disease and Rett syndrome indicated that epigenetic mechanisms and chromatin remodeling need to be tightly controlled for proper cognitive functions, and their dysregulation can have devastating consequences. However, because they are dynamic, epigenetic mechanisms are also potentially reversible and may provide powerful means for pharmacological intervention. This review outlines major cognitive disorders known to be associated with epigenetic dysregulation, and discusses the potential of 'epigenetic medicine' as a promising cure.
162 citations
Cites background from "Epigenetic codes in cognition and b..."
...Epigenetic mechanisms were further shown to be dynamically regulated and can be modulated by learning and memory (for recent reviews see Levenson & Sweatt, 2005, 2006; Gräff & Mansuy, 2008)....
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TL;DR: A novel proteomic approach is described that allows the isolation and identification of PTMs on synaptic and nuclear proteins, in particular on histones, and reveals potentially important regulatory sites on proteins involved in synaptic plasticity and brain functions.
Abstract: Post-translational modifications (PTMs) of proteins in the adult brain are known to mark activity-dependent processes for complex brain functions such as learning and memory. Multiple PTMs occur in nerve cells, and are able to modulate proteins in different subcellular compartments. In synaptic terminals, protein phosphorylation is the primary PTM that contributes to the control of the activity and localization of synaptic proteins. In the nucleus, it can modulate histones and proteins involved with the transcriptional machinery and, in combination with other PTMs such as acetylation, methylation and ubiquitination, acts to regulate chromatin remodelling and gene expression. The combination of histone PTMs is highly complex and is known to be unique to each gene. The ensemble of PTMs in the adult brain, however, remains unknown. Here, we describe a novel proteomic approach that allows the isolation and identification of PTMs on synaptic and nuclear proteins, in particular on histones. Using subcellular fractionation, we identified 2082 unique phosphopeptides from 1062 phosphoproteins, and 196 unique PTM sites on histones H1, H2A, H2B, H3 and H4. A comparison of phosphorylation sites in synaptic and nuclear compartments, and on histones, suggests that different kinases and kinase motifs are involved. Overall, our data demonstrates the complexity of PTMs in the brain and the prevalence of histone PTMs, and reveals potentially important regulatory sites on proteins involved in synaptic plasticity and brain functions.
145 citations
TL;DR: Overall, the present data newly identify a specific histone code in the mouse brain and reveal its level of complexity, suggesting its potential relevance for higher-order brain functions.
Abstract: Post-translational modifications (PTMs) of proteins are biochemical processes required for cellular functions and signalling that occur in every sub-cellular compartment. Multiple protein PTMs exist, and are established by specific enzymes that can act in basal conditions and upon cellular activity. In the nucleus, histone proteins are subjected to numerous PTMs that together form a histone code that contributes to regulate transcriptional activity and gene expression. Despite their importance however, histone PTMs have remained poorly characterised in most tissues, in particular the brain where they are thought to be required for complex functions such as learning and memory formation. Here, we report the comprehensive identification of histone PTMs, of their combinatorial patterns, and of the rules that govern these patterns in the adult mouse brain. Based on liquid chromatography, electron transfer, and collision-induced dissociation mass spectrometry, we generated a dataset containing a total of 10,646 peptides from H1, H2A, H2B, H3, H4, and variants in the adult brain. 1475 of these peptides carried one or more PTMs, including 141 unique sites and a total of 58 novel sites not described before. We observed that these PTMs are not only classical modifications such as serine/threonine (Ser/Thr) phosphorylation, lysine (Lys) acetylation, and Lys/arginine (Arg) methylation, but also include several atypical modifications such as Ser/Thr acetylation, and Lys butyrylation, crotonylation, and propionylation. Using synthetic peptides, we validated the presence of these atypical novel PTMs in the mouse brain. The application of data-mining algorithms further revealed that histone PTMs occur in specific combinations with different ratios. Overall, the present data newly identify a specific histone code in the mouse brain and reveal its level of complexity, suggesting its potential relevance for higher-order brain functions.
137 citations
Cites background from "Epigenetic codes in cognition and b..."
...These learning-induced codes are reminiscent of developmental processes such as the differentiation of stem cells, in that they are associated with the ability of cells to respond and adapt to their environment while at the same time, keeping a cellular memory of their previous activity [53]....
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TL;DR: Evidence that changes in DNA methylation contribute to memory formation and maintenance is presented, howDNA methylation affects readout of memory-related genes is considered, and how these changes may be important in the large-scale context of memory circuits are discussed.
135 citations
References
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TL;DR: The best understood form of long-term potentiation is induced by the activation of the N-methyl-d-aspartate receptor complex, which allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and post Synaptic mechanisms to generate a persistent increase in synaptic strength.
Abstract: Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.
11,123 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...These forms f plasticity reflect respectively, an increase and a decrease in he efficiency of synaptic transmission, and have been extenively studied in the hippocampus, a brain area required for earning and memory (for a review see [30])....
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TL;DR: The surface of nucleosomes is studded with a multiplicity of modifications that can dictate the higher-order chromatin structure in which DNA is packaged and can orchestrate the ordered recruitment of enzyme complexes to manipulate DNA.
10,046 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...Chronic xposure to an aggressor results in pronounced social avoidnce, prolonged downregulation of two splice variants of Bdnf, dnfIII and BdnfIV in the hippocampus and increased promoter imethylation of H3K27 [102], a mark of transcriptional represion [20]....
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TL;DR: It is proposed that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
Abstract: Chromatin, the physiological template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a “histone code” that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
9,309 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...These nzymes operate both independently and in synergy to establish “histone code”, a highly dynamic and flexible chromatin markng that, in combination with chromatin-associated proteins, etermines the pattern of gene expression in response to given xternal stimuli [24,25]....
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TL;DR: The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development.
Abstract: The character of a cell is defined by its constituent proteins, which are the result of specific patterns of gene expression. Crucial determinants of gene expression patterns are DNA-binding transcription factors that choose genes for transcriptional activation or repression by recognizing the sequence of DNA bases in their promoter regions. Interaction of these factors with their cognate sequences triggers a chain of events, often involving changes in the structure of chromatin, that leads to the assembly of an active transcription complex (e.g., Cosma et al. 1999). But the types of transcription factors present in a cell are not alone sufficient to define its spectrum of gene activity, as the transcriptional potential of a genome can become restricted in a stable manner during development. The constraints imposed by developmental history probably account for the very low efficiency of cloning animals from the nuclei of differentiated cells (Rideout et al. 2001; Wakayama and Yanagimachi 2001). A “transcription factors only” model would predict that the gene expression pattern of a differentiated nucleus would be completely reversible upon exposure to a new spectrum of factors. Although many aspects of expression can be reprogrammed in this way (Gurdon 1999), some marks of differentiation are evidently so stable that immersion in an alien cytoplasm cannot erase the memory. The genomic sequence of a differentiated cell is thought to be identical in most cases to that of the zygote from which it is descended (mammalian B and T cells being an obvious exception). This means that the marks of developmental history are unlikely to be caused by widespread somatic mutation. Processes less irrevocable than mutation fall under the umbrella term “epigenetic” mechanisms. A current definition of epigenetics is: “The study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence” (Russo et al. 1996). There are two epigenetic systems that affect animal development and fulfill the criterion of heritability: DNA methylation and the Polycomb-trithorax group (Pc-G/trx) protein complexes. (Histone modification has some attributes of an epigenetic process, but the issue of heritability has yet to be resolved.) This review concerns DNA methylation, focusing on the generation, inheritance, and biological significance of genomic methylation patterns in the development of mammals. Data will be discussed favoring the notion that DNA methylation may only affect genes that are already silenced by other mechanisms in the embryo. Embryonic transcription, on the other hand, may cause the exclusion of the DNA methylation machinery. The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development. Indeed, the possibility will be discussed that DNA methylation and Pc-G/trx may represent alternative systems of epigenetic memory that have been interchanged over evolutionary time. Animal DNA methylation has been the subject of several recent reviews (Bird and Wolffe 1999; Bestor 2000; Hsieh 2000; Costello and Plass 2001; Jones and Takai 2001). For recent reviews of plant and fungal DNA methylation, see Finnegan et al. (2000), Martienssen and Colot (2001), and Matzke et al. (2001).
6,691 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...ecause of the covalent nature of the binding of methyl groups o the C5 carbon in cytosine, DNA methylation is thought to be he most stable epigenetic mark [9]....
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...DNA methylation is commonly associated with ranscriptional silencing because it can directly inhibit the bindng of transcription factors or regulators, or indirectly recruit ethyl-CpG binding proteins (MBPs), which have repressive hromatin-remodeling functions [9,10]....
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...Most cases of RS are caused by mutaions in the gene coding for methyl-CpG binding protein 2 MeCP2) [62], a member of the MBP family involved in ong-term gene silencing (for a review see [9])....
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TL;DR: Advances in the understanding of the mechanism and role of DNA methylation in biological processes are reviewed, showing that epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression.
Abstract: Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.
5,760 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...ot be explained by changes in the DNA sequence itself [3] reviewed in [4,5])....
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