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大脑疾病，其特征是记忆力逐渐下降。 语言和其他认知领域。AD是全球老年人痴呆症最常见的原因， 但目前还没有有效的治疗方法。老龄化已被证明是AD的主要危险因素 开始了。分子水平上越来越多的证据表明，表观遗传调控，如化学修饰 在调节特殊和时间基因表达的DNA分子上，在衰老中起着基础性作用 进展与AD发病机制。DNA腺嘌呤N6-甲基腺嘌呤(6 MA)的甲基化 细菌基因组，最近在包括哺乳动物在内的高等真核生物基因组中被发现。6 mA是动态的 在胚胎发育过程中被调节，并可能在调节基因和转座子方面发挥表观遗传作用 表情。然而，6 mA的分子功能，特别是在大脑中的功能，在很大程度上仍然没有被探索。我们的 初步研究强调，6 mA及其分子机制是脑内正常神经发育所必需的 果蝇的大脑。我们一致地发现，6 mA在出生后的小鼠脑和人的脑中都有动态的调节 类胚体发育。环境慢性应激诱导小鼠脑内6 mA的动态变化， 该基因座与抑郁症高度相关。重要的是，我们发现了6 mA的全球变化及其推定的 人类阿尔茨海默病患者和阿尔茨海默病小鼠模型脑中的分子机制。我们的数据有力地支持6 mA 在AD的发病机制中起着致病作用。然而，几乎没有准确的研究。 检测衰老过程中脑区特定的和神经细胞类型特定的6 mA动力学 与广告相关的更改。此外，缺乏关于6 mA甲基转移酶(“作者”)的知识 而它在哺乳动物基因组中的结合蛋白(阅读器)限制了我们对6 mA依赖的理解 正常和疾病大脑中的表观遗传调节。此外，6 mA在表观遗传学中的作用 其扰动与AD发病相关的神经回路的兴奋/抑制平衡仍然存在 完全没有被开发过。基于这些数据，我们假设6 mA及其分子机制起着至关重要的作用 阿尔茨海默病的发病机制与其在衰老中的作用有关。我们将首先描述6 mA的配置文件 不同脑区和兴奋性/抑制性神经元亚型与衰老及其失调的关系 在AD(目标1)。然后我们将N6amt1的功能定义为6 mA甲基转移酶，并确定它们的作用 在衰老和AD中，兴奋性和抑制性神经元(目标2)。我们的数据表明，6 mA可能会与 或分别招募低氧诱导因子-1(HIF1)和果蝇多糖(Pc)。根据这些结果， 我们将在神经元水平上确定HIF1和哺乳动物多梳蛋白在衰老和AD中的作用 好的(目标3)。这项研究的发现将为疾病病因学提供一种新的机制洞察，并可能 发现具有重要临床和翻译意义的新分子靶点。