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

• 批准号: 10323656
• 负责人: Bing Yao
• 金额: $ 39.03万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/10323656
• 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

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.

项目摘要 最近，富含在细菌基因组中的DNA腺嘌呤N6-甲基腺嘌呤(6 MA)发生了甲基化 发现于果蝇和哺乳动物的基因组中。6 mA在胚胎发育过程中动态调节 并在基因和转座子的表达调控中发挥表观遗传作用。然而，6 mA在其中的作用 哺乳动物的大脑在很大程度上仍不为人所知。我们的初步研究强调了6 mA及其分子 机械，是果蝇大脑正常神经发育所必需的。初步数据一致 证实了6 mA在出生后小鼠脑和人类类胚体中的动态调节 发展。环境慢性应激诱导小鼠脑内6 mA的动态变化 与抑郁症相关。表观遗传学改变对出生后脑发育的复杂影响 可以解释压力反应的改变和许多精神疾病，分子机制连接 这些过程仍不清楚。6 mA及其可能的机制参与脑发育和 在这些相互关联的过程中，应激反应使它们成为一种有吸引力的因果机制。然而，还有 很少有研究精确地检查特定于大脑区域和特定于神经细胞类型的6 mA动力学和 它们在大脑发育过程中的表观遗传作用。此外，对6MAA缺乏了解 哺乳动物基因组中的甲基转移酶(编写者)及其结合蛋白(读取器)阻碍了我们进一步 了解它们在大脑发育和应激反应中的精确表观遗传作用。基于这项工作， 我们假设6 mA及其分子机制在哺乳动物脑发育中起着关键作用，并且 它们的失调导致了大脑中压力反应的改变。我们将首先使用已建立的全基因组 6 mA映射工具用于识别特定于大脑区域和特定于细胞类型的不同6 mA甲基化区域 (D6AMRs)，并将这些数据与全球转录组分析相关联，以 明确6 mA在这些过程中的详细和精确的表观遗传作用(目标1)。然后我们将定义6 mA 哺乳动物基因组中假定的甲基转移酶“编写者”并在体内调节其表达以测试 它们通过6 mA调节兴奋性和抑制性神经元在发育相关应激反应中的作用 (目标2)。我们的数据表明，6 mA可能拮抗或招募缺氧诱导因子-1(HIF1)和 分别为果蝇Pc.基于这些结果，我们将确定HIF1和HIF1的相互作用 哺乳动物6 mA多梳蛋白及其在神经元发育相关应激反应中的作用 水平也是如此(目标3)。这项研究的发现将为6 mA在脑发育中的作用提供新的机制见解 及其相关的应激反应，并有可能发现新的分子靶点，具有重要的临床和 精神疾病中的翻译含义。