Epigenomic hotspots linking environmental adversity & stress to psychopathology

描述（由申请人提供）：众所周知，环境因素，如早期生活逆境和成人慢性压力，对行为有长期影响，并有助于精神疾病的发展。虽然环境诱导的DNA甲基化和染色质结构在一些候选疾病基因的表观遗传学变化已牵连在疾病表型的发展，它仍然是未知的表观遗传学改变是全球性的还是局部的，如果他们是一个原因或表型的后果。我们最近对海马神经元同质群体的全基因组表观遗传分析表明，广泛的环境损伤改变了离散域的表观基因组。这些表观基因组“热点”的特征在于将它们与基因组的其余部分区分开的特定特征。表观基因组热点通常是基因内的，优先位于外显子中，并且发现于参与突触可塑性和基因调控过程的基因的内含子中。我们假设这些表观基因组结构域的存在在进化上是有益的，因为它允许神经可塑性基因响应环境输入的快速甲基化变化，最终导致基因表达和行为的适应性变化。然而，持续的不利环境输入可以将这些环境敏感的表观基因组结构域锁定为不可逆状态，导致可塑性丧失和适应不良行为。这些独特的表观基因组结构域的发现具有基础和翻译的意义，因为它们可以机械地将环境因素与所得的行为表型联系起来。此外，它们可以用作生物标志物，以评估先前的压力暴露，并作为药理学靶点，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，我们建议调查的监管（目的1），神经生物学（目的2），和潜在的诊断/临床的重要性（目的3）的鉴定表观基因组域。

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.