Epigenetic roles of DNA adenine methylation in Alzheimer's Disease

DNA 腺嘌呤甲基化在阿尔茨海默病中的表观遗传学作用

• 批准号: 10618183
• 负责人: Bing Yao
• 金额: $ 38.97万
• 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: 2019-08-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618183
• 关键词: APP-PS1; Ablation; Adenine; Adenosine; Age; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease risk; Area; Bacteria; Behavioral; Binding; Binding Proteins; Biological Assay; Brain; Brain Diseases; Brain region; Catalytic Domain; Cell Nucleus; Chemicals; Chronic stress; Clinical; Cognition; Coupled; Cytosine; DNA; DNA Methylation; DNA Modification Methylases; DNA Modification Process; Data; Defect; Dementia; Development; Disease; Drosophila genome; Drosophila genus; Elderly; Embryonic Development; Epigenetic Process; Equilibrium; Etiology; Gene Expression; Genes; Genetic; Genome; Glutamates; Hippocampus; Homologous Gene; Human; Hypoxia; In Vitro; Knowledge; Language; Lentivirus; Light; Link; Mammals; Maps; Mass Spectrum Analysis; Mediating; Memory; Mental Depression; Methods; Methylation; Methyltransferase; Modification; Molecular; Molecular Target; Mus; Neurodegenerative Disorders; Neurons; Onset of illness; Pathogenesis; Play; Polycomb; Process; Proteins; Reader; Regulation; Research; Role; Stress; Testing; Wild Type Mouse; age related; cell type; clinically relevant; effective therapy; epigenetic marker; epigenetic regulation; excitatory neuron; fly; genome-wide; human embryoid body; in vitro activity; in vivo; inhibitory neuron; insight; knock-down; mammalian genome; mouse model; neural circuit; neurodevelopment; novel; overexpression; postnatal; preference; recruit; transcriptome; transcriptome sequencing; transcriptomic profiling

Alzheimer's disease (AD) is an irreversible, progressive brain disorder featuring gradual decline in memory, language and other areas of cognition. AD is the most common cause of dementia among the elderly worldwide, but no effective treatments are available. Aging has been demonstrated to be the primary risk factor for AD onset. Mounting evidence at the molecular level suggests epigenetic regulation, such as chemical modifications on DNA molecules that modulate special and temporal gene expression, plays fundamental roles in aging progression and AD pathogenesis. Methylation on the DNA adenine, N6-methyladenine (6mA) that enriched in the bacteria genome, was recently found in higher eukaryotic genomes, including mammals. 6mA is dynamically regulated during embryonic development and could play epigenetic roles in regulating gene and transposon expression. However, the molecular functions of 6mA, particularly in the brains, remain largely unexplored. Our preliminary study highlights that 6mA, and its molecular machinery, is required for proper neurodevelopment in Drosophila brains. Consistently, we found 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. Importantly, we found global alterations of 6mA and its putative molecular machinery in the brains of human AD patient and an AD mouse model. Our data strongly support 6mA serve as a causal mechanism to contribute to AD pathogenesis. However, there is little research precisely examining the brain region-specific and neuronal cell type-specific 6mA dynamics during aging progression and AD-associated alterations. Furthermore, the lack of knowledge regarding the 6mA methyltransferases (“writers”) and its binding proteins (“readers”) in the mammalian genome limits our understanding of 6mA-dependent epigenetic regulation in normal and diseased brains. Furthermore, the epigenetic roles of 6mA in excitation/inhibition balance of neural circuitries whose perturbation linked to AD pathogenesis remain completely unexplored. Based on these data, we hypothesize that 6mA and its molecular machinery play crucial roles in aging and their dysregulation contribute to AD pathogenesis. We will first delineate 6mA profiling in various brain regions and excitatory/inhibitory neuronal subtypes associated with aging and their dysregulation in AD (Aim 1). We will then define the functions of N6amt1 as a 6mA methyltransferase and determine their roles in aging and AD 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 roles of Hif1 and mammalian Polycomb proteins in aging and AD at the neuronal levels as well (Aim 3). Findings of this study will provide a novel mechanistic insight into disease etiology and are likely to discover new molecular targets with important clinical and translational implications.

阿尔茨海默病（AD）是一种不可逆转的进行性脑部疾病，其特征是记忆力逐渐下降，