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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：
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
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/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

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.

项目总结