Epigenomic hotspots linking environmental adversity & stress to psychopathology

表观基因组热点与环境逆境相关

基本信息

批准号：
8743291
负责人：
Miklos Toth
金额：
$ 33.48万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-26 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8743291
关键词：
Ablation Address Adult Basic Science Behavior Behavioral Biological Assay Biological Markers Blood Cells Brain Candidate Disease Gene Chromatin Chromatin Structure Chronic Chronic stress Clinical DNA Methylation DNA Modification Process DNMT3a Detection Development Diagnostic Enhancers Environment Environmental Risk Factor Epigenetic Process Exons Fetus Frequencies Fright Future Gene Expression Genes Genome Genomics Hippocampus (Brain)Hypermethylation Immune system Inflammatory Introns Learning Life Link Maintenance Mental disorders Methylation Modeling Molecular Neurobiology Neuronal Plasticity Neurons Pattern Pharmaceutical Preparations Phenotype Population Process Protein Isoforms Psychopathology RNA Splicing Regulation Regulator Genes Rest Role Signal Transduction Stress Synaptic plasticity Techniques Testing Tissues Translational Research Translations Work biological adaptation to stress disease phenotype disorder risk environmental enrichment for laboratory animals epigenome epigenomics genome-wide inhibitor/antagonist interest postnatal prevent promoter public health relevance response therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): It is well established that environmental factors, such as early life adversity and adult chronic stress, have long-lasting effects on behavior and contribute to the development of psychiatric diseases. Although environmentally-induced epigenetic changes in DNA methylation and chromatin structure at some candidate disease genes have been implicated in the development of disease phenotypes, it is still unknown whether the epigenetic alterations are global or local and if they are a cause or a consequence of the phenotype. Our recent work with genome-wide epigenetic profiling of homogenous populations of hippocampal neurons showed that a wide range of environmental insults alter the epigenome at discrete domains. These epigenomic "hotspots" are characterized by specific features that distinguish them from the rest of the genome. The epigenomic hotspots are typically intragenic, located preferentially in exons, and found in introns of genes involved in synaptic plasticity and gene regulatory processes. We hypothesize that the presence of these epigenomic domains is evolutionarily beneficial because it allows rapid methylation changes at neuroplasticity genes in response to environmental inputs, which ultimately leads to adaptive changes in gene expression and behavior. However, sustained adverse environmental inputs can lock these environmentally-sensitive epigenomic domains into an irreversible state, resulting in loss of plasticity and maladaptive behavior. The discovery of these unique epigenomic domains has both basic and translation implications because they can mechanistically link environmental factors to the resultant behavioral phenotypes. Furthermore, they may be used as biomarkers, to assess prior stress exposure, and as pharmacological targets, to prevent and reverse adversity/stress induced psychopathology. To address these possibilities we propose to investigate the regulatory (Aim 1), neurobiological (Aim 2), and the potential diagnostic/clinical importance (Aim 3) of the identified epigenomic domains.

描述（由申请人提供）：众所周知，环境因素（例如早期生命逆境和成人慢性压力）对行为产生了长期影响，并有助于精神病的发展。尽管某些候选疾病基因的DNA甲基化和染色质结构的表观遗传变化与疾病表型的发展有关，但表观遗传学改变是全球还是局部，以及它们是否是表型的原因或结果。我们最近与海马神经元同质种群的全基因组表观遗传分析的工作表明，广泛的环境损伤会改变离散域的表观遗传组。这些表观基因组的“热点”的特征是将它们与基因组的其余部分区分开来的特定特征。表观基因组热点通常是内部的，优先位于外显子中，并在参与突触可塑性和基因调节过程的基因内含子中发现。我们假设这些表观基因组域的存在在进化上是有益的，因为它允许响应环境输入的神经可塑性基因的快速甲基化变化，这最终导致基因表达和行为的适应性变化。但是，持续的不利环境输入可以将这些对环境敏感的表观基因组域锁定到不可逆的状态，从而导致可塑性和适应不良的行为丧失。这些独特的表观基因组域的发现既具有基本和翻译的意义，因为它们可以将环境因素与最终的行为表型联系起来。此外，它们可以用作生物标志物，评估先前的压力暴露以及作为药理目标，以预防和逆转逆境/压力诱导的精神病理学。为了解决这些可能性，我们建议调查调节性（AIM 1），神经生物学（AIM 2）以及所鉴定的表观基因组域的潜在诊断/临床重要性（AIM 3）。