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: 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
• 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

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，富含细菌基因组的DNA腺嘌呤N6-甲基趋化（6MA）上的甲基化是 在果蝇和哺乳动物基因组中发现。 6MA在胚胎发育过程中受动态调节 并且可以在调节基因和转座子表达中发挥表观遗传作用。但是，6mA在 哺乳动物的大脑在很大程度上尚不清楚。我们的初步研究强调了6MA及其分子 机械是果蝇大脑中正确神经发育所必需的。初步数据一致 在产后小鼠脑和人类胚胎体内对6MA的动态调节 发展。环境慢性应激会诱导小鼠大脑中6ma的动态改变，高度高度 与抑郁症相关。由于表观遗传改变而导致产后大脑发育的复杂变化 可以解释压力反应改变和许多精神疾病，分子机制连接 这些过程尚不清楚。 6MA及其推定的机械参与大脑发育和 压力反应使它们成为这些连接过程中有吸引力的因果机制。但是，有 精确研究大脑区域特异性和神经元细胞类型特异性6MA动力学的研究很少 它们在大脑发育过程中的表观遗传作用。此外，缺乏有关6MA的知识 哺乳动物基因组中的甲基转移酶（“作者”）及其结合蛋白（“读者”）进一步阻碍了我们 了解它们在大脑发育和压力反应中的精确表观遗传作用。基于这项工作， 我们假设6MA及其分子机械在哺乳动物脑发育中起着至关重要的作用，并且 它们的失调会导致大脑的压力反应改变。我们将首先使用已建立的全基因组 6MA映射工具以识别大脑区域特异性和细胞类型特异性的6MA甲基化区域 （D6AMR）在小鼠产后开发过程中，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（AIM 1）。然后，我们将定义6MA 哺乳动物基因组中的假定甲基转移酶“作者”，并调节其体内表达 它们通过6MA调节在兴奋性和抑制性神经元中通过6MA调节在与发育相关的应力反应中的作用 （目标2）。我们的数据表明6MA可能会拮抗或募集缺氧诱导的因子1（HIF1）和 果蝇多康布（PC）。基于这些结果，我们将确定HIF1和 具有6MA的哺乳动物聚酮蛋白及其在神经元的发育相关应力反应中的作用 水平也（目标3）。这项研究的结果将提供6MA的新机械见解 及其相关的压力反应，可能会发现具有重要临床和重要临床和的新分子靶标 精神疾病的翻译意义。