Genome-wide mapping and integrative analysis of DNA 6mA methylome in human AD brain

人类 AD 大脑 DNA 6mA 甲基化组的全基因组作图和综合分析

• 批准号: 10172823
• 负责人: DAVID ALAN BENNETT
• 金额: $ 73.29万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172823
• 关键词: 3-Dimensional; Adenine; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Attention; Autopsy; Bioinformatics; Biological; Biological Process; Brain; Brain Mapping; Candidate Disease Gene; Chemicals; Clinical; Communities; Cytosine; DNA; DNA Methylation; DNA Modification Process; DNA analysis; Data; Data Set; Dementia; Development; Dimensions; Disease; Epigenetic Process; Etiology; Exons; Freezing; Gene Expression; Genes; Genetic; Genetic Variation; Genomics; Goals; Histone Acetylation; Human; Intercistronic Region; Introns; Joints; Lead; Link; Maps; Measures; Memory; Mental Depression; Meta-Analysis; Methylation; MicroRNAs; Modification; Molecular; Molecular Target; Mus; Neurofibrillary Tangles; Organoids; Participant; Pathogenesis; Pathway interactions; Pattern; Phenotype; Play; Population; Positioning Attribute; Prefrontal Cortex; Prosencephalon; Quantitative Trait Loci; Research; Role; Sampling; Senile Plaques; Site; Stress; System; Testing; Tissue Sample; Tissues; Validation; Variant; Work; aging brain; base; brain tissue; cell type; cohort; design; effective therapy; epigenetic marker; epigenetic regulation; frontier; genetic epidemiology; genome wide association study; genome-wide; genomic locus; induced pluripotent stem cell; innovation; insight; knock-down; mammalian genome; methylation pattern; methylome; multidisciplinary; multiple omics; neuropathology; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; overexpression; population based; promoter; religious order study; tool; transcriptome; transcriptome sequencing

Project Summary Alzheimer’s disease (AD) is the most common form of dementia among older people with no cure or effective treatment. A thorough understanding of its molecular mechanisms is required for discovering novel diagnostic and therapeutic strategies against AD. Chemical modifications of DNA such as methylation play critical roles in regulating gene expression and many other key biological processes, and altered DNA methylation pattern has been implicated in brain aging and AD. While much attention has focused on DNA methylation at the fifth position on cytosine (5mC), recent research identified a new form of DNA modification at the sixth position on adenine (6mA) in mammalian brains. However, little is known about its presence, genomic distribution, and possible functions in human brain and relevance to AD. Our preliminary data in mouse and human brain indicated that 6mA is dynamically responsive to environmental stress and accumulates in human AD brain. Our central hypothesis is that altered signature of 6mA modification is causally associated with AD neuropathology. The objectives of this project are to generate the first detailed map of brain 6mA methylome and identify causative genes harboring aberrant 6mA alterations associated with quantitative neuropathological measures for early features of AD pathology (e.g., amyloid plaques, neurofibrillary tangles). To achieve this, we propose three specific aims: (1) Genome-wide mapping of brain DNA 6mA methylome to identify differentially methylated genes/regions harboring altered 6mA sites (D6AMRs) associated with AD pathology in 1,200 postmortem brain tissue samples collected by two large, community-based population cohorts of aging and dementia. (2) Integrated multiomics analysis to elucidate the potential mechanistic role of 6mA alteration in AD pathology; and (3) Functionally validation of top-ranked candidate genes in 3D brain organoids derived from human iPSCs. This innovative project leverages the wealth of deep clinical and neuropathological phenotypes along with rich omics data including genetic (GWAS, WGS), epigenetic (5mC, 5hmC, 6mA, H3K9Ac), and transcriptome (RNA-seq) profiled on the same prefrontal cortex, and will provide unprecedented opportunities to uncover novel molecular mechanisms implicated in AD pathology. Our proposal brings together an exceptionally strong and unique multidisciplinary team with complementary expertise in genetic epidemiology, statistical genetics, bioinformatics, molecular and neuroepigenetics, and Alzheimer’s research. The work proposed represents the frontier in the interface between AD and omics research. Findings of this study will provide novel mechanistic insight into AD pathogenesis, and are likely to discover new molecular targets with important clinical and translational implications.

项目摘要 阿尔茨海默氏病（AD）是老年人中最常见的痴呆形式，没有治愈或有效 治疗。发现新型诊断需要彻底了解其分子机制 和针对AD的治疗策略。 DNA的化学修饰（例如甲基化）在 调节基因表达和许多其他关键的生物学过程，而DNA甲基化模式的改变具有 在大脑衰老和AD中隐含。虽然很多关注集中在第五次的DNA甲基化上 在胞嘧啶（5MC）上的位置，最近的研究确定了在第六位的DNA修饰形式 哺乳动物大脑中的腺嘌呤（6mA）。但是，关于其存在，基因组分布和 人脑的可能功能与与AD相关。我们在鼠标和人脑中的初步数据 表明6MA对环境压力有动态响应，并在人类AD大脑中积累。 我们的中心假设是，6MA修饰的签名有时与AD有关 神经病理学。该项目的目的是生成第一个详细的脑6MA甲基组图 并确定具有与定量神经病理相关的异常6MA改变的属 AD病理学早期特征的度量（例如淀粉样蛋白斑，神经纤维缠结）。为此， 我们提出了三个特定目的：（1）脑DNA 6MA甲基甲基的全基因组映射以鉴定 与AD病理相关的6MA位点（D6AMR）的差异甲基化基因/区域 1200个由两个大型社区人群衰老收集的死后脑组织样品 和痴呆症。 （2）综合多图解分析，以阐明6MA改变在中的潜在机械作用 广告病理； （3）在衍生的3D脑器官中对顶级候选基因的功能验证 来自人类IPSC。这个创新的项目利用了深层临床和神经病理的财富 表型以及丰富的OMIC数据包括遗传（GWAS，WGS），表观遗传学（5MC，5HMC，6MA，6MA， H3K9AC）和转录组（RNA-Seq）在同一前额叶皮层上进行了介绍，并将提供前所未有的 发现在AD病理学中实施的新型分子机制的机会。我们的建议带来了 共同拥有一个非常强大且独特的多学科团队，具有通用专业知识 流行病学，统计遗传学，生物信息学，分子和神经毛皮物质以及阿尔茨海默氏症的研究。 提出的工作代表了AD和OMICS研究之间界面的前沿。这一点 研究将为AD发病机理提供新的机械洞察力，并可能发现新的分子 具有重要临床和翻译意义的目标。