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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10 Jul 2014
5 citations
Dissertation•
28 Feb 2017
TL;DR: It is found that dietary and/or genetic folate metabolism disruption leads to alterations on short-term recognition memory, brain gene expression of APP-processing enzymes, neurotrophic factors, histone-acetylation and DNA methylation regulatory enzymes, and their role in orchestrating physical exercise and folate deficiency effects on brain health.
Abstract: [eng] Epigenetic changes are currently recognized as part of the aging process and have been implicated in many age-related chronic diseases such as Alzheimer’s disease (AD). The term epigenetics includes a variety of processes known to regulate gene expression in a stable and potentially reversible way, without altering the primary DNA sequence. The molecular mechanisms that mediate epigenetic regulation are principally DNA methylation, post-translational modifications of histones, and regulation by non-coding RNAs. Research on age-related disorders have recently focused in epigenetic mechanisms since they allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and a growing number of epigenetic alterations in AD have been described recently. Interestingly, it has been estimated that about one-third of AD dementia cases worldwide might be attributable to modifiable risk factors including depression, midlife hypertension, midlife obesity, diabetes, physical inactivity, smoking, and low education; whereas investigations like the FINGER study, a two-year landmark randomized controlled trial, show that a multicomponent approach targeting several vascular and lifestyle-related risk factors simultaneously in elderly people at risk of dementia can improve or maintain cognitive functioning. In fact, many nutrients or dietary compounds (including folate, vitamin B-12, curcumin, resveratrol, selenium, etc.) are described to exert a favorable or unfavorable effect regarding AD onset and progression through epigenetic mechanisms. Similarly, several studies have described a modulation of these mechanisms by physical exercise on different animal peripheral systems and central nervous system, highlighting beneficial epigenetic exercise-induced effects. Within this context, this thesis comprises three studies aiming to better understand the epigenetic contribution to pathological aging, the potential utility of epigenetic changes as early biomarkers of AD, and their role in orchestrating physical exercise and folate deficiency effects on brain health. In the first study we measured plasma miRNA levels in samples from AD patients, AD preclinical subjects (patients with intact cognitive abilities but ?-amyloid levels <500pg/mL in cerebrospinal fluid), and healthy elderly controls. We found that plasma miR-34a and miR-545-3p showed good diagnostic values in our first cohort and so they could constitute good early peripheral biomarkers for AD. However, contradictory results regarding a second cohort highlights possible sources of variability in miRNA analysis (e.g. age or environmental factors), which currently prevents their use as reliable clinical tools and warrants further research on the topic. In the second study, we found alterations on twenty-one microRNAs (previously reported to be involved in aging and neurodegeneration), histone-acetylation regulatory genes (histone deacetylases HDAC5, HDAC6, and SIRT1), and global histone H3 acetylation levels in the hippocampus of 10-month-old SAMP8 mice (a senescence-accelerated mouse model resembling features of AD), compared to SAMR1 control mice. We also observed that some of these parameters were modulated by 8 weeks of voluntary exercise; particularly, seven microRNAs (involved in the regulation of signaling pathways previously reported to be modulated in the brain by exercise), histone deacetylases HDAC3, HDAC5, and histone H3 acetylation levels. In fact, acetylation levels of histone H3, which have been described to positively correlate with cognitive function, were reduced in SAMP8 hippocampus, and the physical exercise intervention was able to restore its levels. Finally, in the last study we characterized epigenetic and transcriptional changes associated with folate metabolism disruption on 10-month old mice, and its potential impact on brain neurodegeneration and cognition. We found that dietary and/or genetic folate metabolism disruption leads to alterations on short-term recognition memory, brain gene expression of APP-processing enzymes, neurotrophic factors, histone-acetylation and DNA methylation regulatory enzymes. Particularly, dysregulation of both the neurotrophic factor Bdnf and the APP-processing enzyme Psen1, seems to be associated with changes on DNA methylation levels at their gene promoters. We concluded that this signature may be contributing to the higher neurodegeneration risk reported in dietary and genetic folate-deficiencies. [spa] Los cambios epigeneticos son reconocidos como parte del proceso de envejecimiento y estan implicados en muchas enfermedades relacionadas con la edad, como la enfermedad de Alzheimer (EA). Estos mecanismos regulan la expresion genica de una manera estable y potencialmente reversible, sin alterar la secuencia primaria del ADN. Incluyen principalmente la metilacion del ADN, modificaciones post-traduccionales de histonas, y ARNs no codificantes. Por otro lado, se ha estimado que alrededor de 1/3 de los casos de EA podria ser atribuible a factores de riesgo relacionados con el estilo de vida. De hecho, se ha reportado que muchos nutrientes ejercen un efecto favorable o desfavorable por lo que respecta al desarrollo o progresion de la EA a traves de mecanismos epigeneticos. Del mismo modo, tambien se ha descrito una modulacion de estos mecanismos por el ejercicio fisico en el sistema nervioso central, destacando sus beneficios. En este contexto, la siguiente tesis contiene tres estudios que tienen como objetivo mejorar la comprension de la contribucion de estos mecanismos al envejecimiento patologico y la EA, estudiar su papel en la orquestacion de los efectos inducidos por el ejercicio fisico y una deficiencia en folatos en la salud del cerebro, y su potencial como biomarcadores precoces de la EA. En el primer estudio se midieron los niveles plasmaticos de microARNs en muestras de pacientes con EA, sujetos preclinicos de la enfermedad (con capacidades cognitivas intactas, pero niveles alterados de beta-amiloide en liquido cefalorraquideo) y controles sanos de edad avanzada. Los microARNs miR-34a-5p y miR-545-3p destacaron como posibles biomarcadores tempranos de la EA. En el segundo estudio, se detectaron alteraciones en microARNs, genes reguladores de acetilacion de histonas y niveles globales de acetilacion de histona 3 en hipocampo de ratones SAMP8 de 10 meses de edad (un modelo de raton de senescencia acelerada con caracteristicas similares a la EA). Ademas, se observo que algunos de estos parametros fueron modulados, y en algunos casos restaurados, por una intervencion de 8 semanas de ejercicio voluntario. En el ultimo estudio se caracterizaron cambios de comportamiento, epigeneticos, y transcripcionales, asociados a una deficiencia en folatos en ratones de 10 meses. En consecuencia, se planteo su posible relacion con el mayor riesgo de neurodegeneracion observado en este tipo de deficiencias.
5 citations
TL;DR: Gene set enrichment analysis on a microarray dataset on Lewis rats confirmed enrichment of Drd2 in PFC in relation to PPI, contributing to the understanding of the genetic substrate behind alterations in sensorimotor gating, relevant for its linkage to neurodevelopmental disorders.
Abstract: Disruption of sensorimotor gating causes "flooding" of irrelevant sensory input and is considered a congenital trait in several neurodevelopmental disorders. Prepulse inhibition of acoustic startle response (PPI) is the operational measurement and has a high translational validity. Pharmacological studies in rodents have linked alterations in serotonin, dopamine and glutamate signalling to PPI disruption. How PPI response is associated with gene expression levels of these receptors is unknown. PPI response was assessed in 39 genetically heterogeneous National Institutes of Health-Heterogeneous Stock (NIH-HS) rats. Animals were classified as high, medium or low PPI. Expression levels of glutamate metabotropic receptor 2 (Grm2), dopamine receptor D2 (Drd2), dopamine receptor D1 (Drd1), serotonin receptor 1A (Htr1a), serotonin receptor 2A (Htr2a) and homer scaffolding protein 1 (Homer1) were investigated in prefrontal cortex (PFC) and striatum (STR). When comparing the two extreme phenotypes, only Drd2 in STR showed increased expression in the low PPI group. A multinomial model fitting all genes and all groups indicated that Grm2 in PFC, and Grm2 and Drd2 in the STR predicted PPI group. This was corroborated by a linear relationship of Grm2 with PPI in PFC, and Drd2 with PPI in STR. An interaction between levels of H3K27 trimethylation, associated with transcriptional repression, and PPI phenotype was observed for Drd2 in STR. Gene set enrichment analysis on a microarray dataset on Lewis rats confirmed enrichment of Drd2 in PFC in relation to PPI. These findings contribute to the understanding of the genetic substrate behind alterations in sensorimotor gating, relevant for its linkage to neurodevelopmental disorders.
5 citations
18 Apr 2012
TL;DR: The activation of ERK1/2 resulting in Elk-1 phosphorylation in striatal neurons supporting the hypothesis that prolonged exposure to substance abuse causes a dysregulation of MAPK pathway is shown.
Abstract: Drug addiction manifests clinically as compulsive drug seeking, and cravings that can persist and recur even after extended periods of abstinence.
The fundamental principle that unites addictive drugs is that each one enhances synaptic DA by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. Our attention has focused on the study of phenomena associated with the consumption of alcohol and heroin.
Alcohol has long been considered an unspecific pharmacological agent, recent molecular pharmacology studies have shown that acts on different primary targets.
Through gene expression studies conducted recently it has been shown that the classical opioid receptors are differently involved in the consumption of ethanol and, furthermore, the system nociceptin / NOP, included in the family of endogenous opioid system, and both appear able to play a key role in the initiation of alcohol use in rodents. What emerges is that manipulation of the opioid system, nociceptin, may be useful in the treatment of addictions and there are several evidences that support the use of this strategy.
The linkage between gene expression alterations and epigenetic modulation in PDYN and PNOC promoters following alcohol treatment confirm the possible chromatin remodeling mechanism already proposed for alcoholism.
In the second part of present study, we also investigated alterations in signaling molecules directly associated with MAPK pathway in a unique collection of postmortem brains from heroin abusers.
The interest was focused on understanding the effects that prolonged exposure of heroin can cause in an individual, over the entire MAPK cascade and consequently on the transcription factor ELK1, which is regulated by this pathway.
We have shown that the activation of ERK1/2 resulting in Elk-1 phosphorylation in striatal neurons supporting the hypothesis that prolonged exposure to substance abuse causes a dysregulation of MAPK pathway.
5 citations
Cites background from "Epigenetic codes in cognition and b..."
...In general, the more CpG islands located in the promoter of a gene, the more the trancription level is dependent on DNA methylation (Graff and Mansuy, 2008)....
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TL;DR: This work provides a concise overview of how the interaction between the environment and genetic as well as epigenetic mechanisms shapes complex neuronal processes such as learning, memory, and synaptic plasticity, and how this interaction contributes to the development of neurodegenerative and psychiatric disorders.
Abstract: Over the last two decades, the explosion of experimental, computational, and high-throughput technologies has led to critical insights into how the brain functions in health and disease. It has become increasingly clear that the vast majority of brain activities result from the complex entanglement of genetic factors, epigenetic changes, and environmental stimuli, which, when altered, can lead to neurodegenerative and neuropsychiatric disorders. Nevertheless, a complete understanding of the molecular mechanisms underlying neuronal activities and higher-order cognitive processes continues to elude neuroscientists. Here, we provide a concise overview of how the interaction between the environment and genetic as well as epigenetic mechanisms shapes complex neuronal processes such as learning, memory, and synaptic plasticity. We then consider how this interaction contributes to the development of neurodegenerative and psychiatric disorders, and how it can be modeled to predict phenotypic variability and disease risk. Finally, we outline new frontiers in neurogenetic and neuroepigenetic research and highlight the challenges these fields will face in their quest to decipher the molecular mechanisms governing brain functioning.
5 citations
Cites background from "Epigenetic codes in cognition and b..."
...Since such modifications of the DNA act in concert with histone modifications and do not occur independently of each other, it is paramount to extend the notion of a ‘‘histone code’’ to an ‘‘epigenetic code,’’ whereby specific patterns of epigenetic modifications regulate distinct gene expression networks within defined cell populations (Gräff and Mansuy, 2008)....
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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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