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WIREs Syst Biol Med
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Experience‐sensitive epigenetic mechanisms, developmental plasticity, and the biological embedding of chronic disease risk

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A wide range of developmental, nutritional, environmental, and social factors affect the biological activities of epigenetic mechanisms. These factors change spatiotemporal patterns of gene expression in a variety of different ways and bring significant impacts to bear on development, physiology, and disease risk throughout the life course. Abundant evidence demonstrates that behavioral stressors and adverse nutritional conditions are particularly potent inducers of epigenetic changes and enhancers of chronic disease risks. Recent insights from both human clinical studies and research with model organisms further indicate that such experience‐dependent changes to the epigenome can be transmitted through the germline across multiple generations, with important consequences for the heritability of both adaptive and maladaptive phenotypes. Epigenetics research thus offers many possibilities for developing informative biomarkers of acquired chronic disease risk and determining the effectiveness of preventive and therapeutic interventions. Moreover, the experience‐sensitive nature of these disease risks raises important questions about societal and individual responsibilities for the prevention of ill‐health and the promotion of well‐being during development, across the life course and between generations. Better understanding of how epigenetic mechanisms regulate developmental plasticity and mediate the biological embedding of chronic disease risks is therefore likely to shed important new light on the nature of the pathophysiological mechanisms linking social and health inequalities, and will help to inform public policy initiatives in this area. WIREs Syst Biol Med 2015, 7:53–71. doi: 10.1002/wsbm.1291 This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease Physiology > Physiology of Model Organisms Biological Mechanisms > Regulatory Biology
Diverse molecular mechanisms mediate epigenetic regulation of gene expression at transcriptional and post‐transcriptional levels. A wide variety of covalent histone modifications and DNA methylation marks signify distinct transcriptional states of associated genes, and chromatin remodeling factors regulate accessibility of histone‐modifying enzymes and transcription factors to their targets. Long noncoding RNAs interact with chromatin components and short noncoding RNAs modulate stability of cognate mRNAs.
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Transgenerational inheritance of dietary‐ and stress‐induced metabolic and behavioral phenotypes in mice is accompanied by altered expression of microRNAs in sperm, suggesting a potential regulatory role for these molecules in epigenetic programming.
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Maternal and paternal undernourishment induce cardiometabolic disorders in offspring, which are accompanied by epigenetic and transcriptional changes.
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Parallels between the effects of early‐life stress on (a) hypothalamo‐pituitary‐adrenal (HPA) axis function, epigenetic modifications, gene transcription, and adult behavior in rodents, and (b) its impacts on the human epigenome and psychiatric disorders in adulthood, potentially via HPA axis dysregulation.
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(a) The hypothalamo‐pituitary‐adrenal (HPA) axis. Cortisol production stimulates a glucocorticoid receptor (GR)‐mediated negative feedback loop that limits further cortisol production. (b) Chronic persistent activation of the HPA axis causes fearfulness, aggression, and anxiety, which over prolonged periods can cause post‐traumatic stress disorder, memory loss, and eventually the negative feedback elicited by elevated cortisol leads to stably attenuated responsiveness of the HPA axis to stressful stimuli.
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Neural activity‐dependent signaling to chromatin in neurones. Induction of immediate early gene transcription in neurones by excitatory neurotransmission at synapses. Activation of glutamate receptor by glutamate causes an increase in intracellular calcium, activating CaMKII, protein kinase A, and ERK, which then phosphorylate and activate DNA‐binding transcription factors such as CREB/ELK1 and nuclear kinases such as MSK1/RSK1. MSK1/RSK activation leads to histone H3 S10 phosphorylation and recruitment of chromatin remodeler Brg1. Variant histone H3.3 is enriched at loci poised for transcription. CREB and ELK1 phosphorylation allosterically activates CBP and p300, leading to increased local histone acetylation and onset of transcription.
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Endocrine signaling to chromatin via the glucocorticoid receptor (GR). Repression of pomc transcription in hypothalamic‐pituitary cells by stress hormone‐activated GR. Cortisol‐bound GR binds to target sites in the pomc promoter accompanied by the histone deacetylase HDAC2. Reduced local histone acetylation is accompanied by attenuation of pomc transcription while liganded GR and HDAC2 remain bound to the promoter.
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Developmentally regulated intercellular signaling to chromatin. Induction of immediate early gene transcription by intercellular signaling proteins, such as epidermal growth factor, fibroblast growth factor, and brain‐derived neurotrophic factor. Receptor activation by ligand leads to ERK phosphorylation. Phospho‐ERK then phosphorylates nuclear kinases MSK1/RSK1 and transcription factor ELK1. MSK1/RSK activation leads to histone H3 S10 phosphorylation and recruitment of chromatin remodeler Brg1. Variant histone H3.3 is enriched at loci poised for transcription. ELK1 phosphorylation allosterically activates p300, leading to increased local histone acetylation and onset of transcription.
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The epigenetic machinery is a molecular interface for interpreting the developmental, nutritional, environmental, and social signals underlying adaptive and maladaptive phenotypic plasticity.
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Developmental Biology > Developmental Processes in Health and Disease
Physiology > Physiology of Model Organisms
Biological Mechanisms > Regulatory Biology

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