Epigenetic roles of DNA adenine methylation in stress response

DNA 腺嘌呤甲基化在应激反应中的表观遗传作用

基本信息

批准号：
10084319
负责人：
Bing Yao
金额：
$ 39.25万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084319
关键词：
Ablation Adenine Adenosine Affect Age Bacteria Behavioral Binding Binding Proteins Biological Assay Brain Brain Diseases Brain region Catalytic Domain Cell Nucleus Chronic stress Clinical Complex Coupled Cytosine DNA DNA Methylation DNA Modification Methylases DNA Modification Process Data Defect Development Drosophila genome Drosophila genus Embryonic Development Epigenetic Process Equilibrium Future Gene Expression Genes Genetic Genome Glutamates Hypoxia In Vitro Knowledge Lentivirus Light Link Mammals Maps Mass Spectrum Analysis Mediating Mental Depression Mental Health Mental disorders Methods Methylation Methyltransferase Modification Molecular Molecular Target Mus Neurons Play Polycomb Prefrontal Cortex Process Proteins Reader Regulation Research Role Stress Testing Wild Type Mouse Work base biological adaptation to stress cell type epigenetic marker epigenetic regulation excitatory neuron fly genome-wide human embryoid body in vitro activity in vivo inhibitory neuron insight knock-down link protein mammalian genome neural circuit neurodevelopment novel overexpression postnatal postnatal development preference recruit therapy development tool transcriptome transcriptome sequencing

项目摘要

Project Summary Methylation on the DNA adenine, N6-methyladenine (6mA) that enriched in the bacteria genome, was recently found in the Drosophila and mammalian genomes. 6mA is dynamically regulated during embryonic development and could play epigenetic roles in regulating gene and transposon expression. However, the roles of 6mA in mammalian brains remain largely unknown. Our preliminary study highlights that 6mA, and its molecular machinery, is required for proper neurodevelopment in Drosophila brains. Preliminary data consistently demonstrated a dynamic regulation of 6mA during postnatal mouse brain and human embryoid body development. Environmental chronic stress induces dynamic alteration of 6mA in mouse brains, in the loci highly correlated with depression. The complex changes in postnatal brain development due to the epigenetic alteration could account for the altered stress response and many mental illnesses, the molecular mechanisms connecting these processes remain unclear. The involvement of 6mA and its putative machinery in brain development and stress response makes them an attractive causal mechanism in these connected processes. However, there is little research precisely examining the brain region-specific and neuronal cell type-specific 6mA dynamics and their epigenetic roles during brain development. Furthermore, the lack of knowledge regarding the 6mA methyltransferases (“writers”) and its binding proteins (“readers”) in the mammalian genome hinders our further understanding of their precise epigenetic roles in brain development and stress response. Based on this work, we hypothesize that 6mA and its molecular machinery play crucial roles in mammalian brain development, and their dysregulation contributes to altered stress response in the brain. We will first use established genome-wide 6mA mapping tools to identify brain region-specific and cell type-specific differentially 6mA methylated regions (D6AMRs) during mouse postnatal development and correlate these data with global transcriptome analysis to pinpoint the detailed and precise epigenetic roles of 6mA in these processes (Aim 1). We will then define 6mA putative methyltransferases “writers” in the mammalian genome and modulate their expression in vivo to test their roles in development-related stress response through 6mA regulation in excitatory and inhibitory neurons (Aim 2). Our data suggest 6mA could potentially antagonize or recruit hypoxia-induced factor-1 (Hif1) and Drosophila Polycomb (Pc), respectively. Based on these results, we will determine the interplay of Hif1 and mammalian Polycomb proteins with 6mA and their roles in development-related stress response at the neuronal levels as well (Aim 3). Findings of this study will provide novel mechanistic insights of 6mA in brain development and its related stress response and are likely to discover new molecular targets with important clinical and translational implications in mental illnesses.

项目概要最近，细菌基因组中富集的 DNA 腺嘌呤 N6-甲基腺嘌呤 (6mA) 发生甲基化果蝇和哺乳动物基因组中发现 6mA 在胚胎发育过程中受到动态调节。并可能在调节基因和转座子表达中发挥表观遗传作用，但 6mA 的作用在其中。我们的初步研究强调了 6mA 及其分子水平仍然未知。初步数据一致，是果蝇大脑正常神经发育所必需的。在出生后的小鼠大脑和人类胚胎体中证实了 6mA 的动态调节环境慢性应激会导致小鼠大脑中高度位点的 6mA 动态变化。由于表观遗传改变，出生后大脑发育的复杂变化与抑郁症相关。可以解释压力反应和许多精神疾病，连接的分子机制这些过程仍不清楚 6mA 及其推定机制在大脑发育和发育中的作用。压力反应使它们成为这些相互关联的过程中有吸引力的因果机制。很少有研究精确检查大脑区域特异性和神经细胞类型特异性 6mA 动力学和此外，缺乏有关 6mA 的知识。哺乳动物基因组中的甲基转移酶（“作家”）及其结合蛋白（“读者”）阻碍了我们的进一步研究基于这项工作，了解它们在大脑发育和应激反应中的精确表观遗传作用。我们认为 6mA 及其分子机制在哺乳动物大脑发育中发挥着至关重要的作用，并且它们的失调会导致大脑应激反应的改变，我们将首先使用已建立的全基因组。 6mA 绘图工具可识别大脑区域特异性和细胞类型特异性差异 6mA 甲基化区域（D6AMR）在小鼠产后发育过程中并将这些数据与全局转录组分析相关联查明 6mA 在这些过程中的详细而精确的表观遗传作用（目标 1）然后我们将定义 6mA。哺乳动物基因组中假定的甲基转移酶“作家”并调节其体内表达以测试它们通过兴奋性和抑制性神经元的 6mA 调节在发育相关应激反应中的作用（目标 2）我们的数据表明 6mA 可能会拮抗或招募缺氧诱导因子 1 (Hif1) 和果蝇 Polycomb (Pc) 分别根据这些结果，我们将确定 Hif1 和 Hif1 的相互作用。具有 6mA 的哺乳动物 Polycomb 蛋白及其在神经元发育相关应激反应中的作用水平（目标 3）将提供 6mA 在大脑发育中的新机制见解。及其相关的应激反应，并有可能发现具有重要临床和意义的新分子靶点精神疾病的转化意义。