The Enhancer Code of AD-A Genetic Approach

AD-A遗传方法的增强子代码

• 批准号: 9905343
• 负责人: Christopher K Glass
• 金额: $ 106.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905343
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Appearance; Atlases; Brain; Cell Nucleus; Cells; Clinical; Code; Data Set; Deposition; Development; Disease; Disease Progression; Enhancers; Environment; Epigenetic Process; Exhibits; Fibroblasts; Freezing; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Genomics; Homeostasis; Human; Immune; Impaired cognition; Individual; Inherited; Intervention; Investigation; Link; Methods; Microglia; Mutation; Neurofibrillary Tangles; Neurons; Output; Pathogenicity; Pathologic Processes; Pathway interactions; Predisposition; Resources; Role; Signal Transduction; Symptoms; TREM2 gene; Technology; Testing; Untranslated RNA; brain tissue; cell type; differential expression; disorder risk; epigenome; extracellular; genetic approach; genetic variant; genome wide association study; improved; individual variation; induced pluripotent stem cell; intercellular communication; monocyte; neuron loss; programs; promoter; risk variant; sex; transcription factor; transcriptome; transdifferentiation

Project Summary Genetic and genome wide association studies (GWAS) have identified numerous genes and risk alleles that indicate both cell autonomous and non-cell autonomous mechanisms contributing to Alzheimer's Disease (AD). In addition to genes expressed by neurons, the observation that several risk alleles, such as TREM2, are exclusively or mainly expressed in microglia, has led to increased efforts to understand the roles of microglia in AD pathology. Importantly, the majority of risk variants identified by GWAS reside in non-coding regions of the genome, implying that some act to alter gene expression. Our recent comparisons of neurons derived by trans-differentiation of fibroblasts from AD subjects and age matched controls demonstrate marked changes in gene expression in AD neurons. In parallel, our recent ability to globally analyze the transcriptomes and enhancer atlases of human microglia demonstrated marked individual variation in expression of immune genes associated with AD risk alleles. Collectively, these findings suggest widespread alterations in the expression of genes that may contribute to susceptibility of AD independent of the generation of βamyloid. Enhancers have emerged as major points of integration of intra and extra-cellular signals associated with development, homeostasis and disease, resulting in context-specific transcriptional outputs. By defining a cell's enhancer landscape, it is possible to both infer the environmental signals the cell is receiving and explain its consequent program of gene expression. In this application, we propose to define the `Enhancer codes of Alzheimer's Disease' to qualitatively advance our understanding of cell autonomous and non-cell autonomous factors that drive pathogenic programs of gene expression. In Specific Aim 1, we will define transcriptomes and enhancer landscapes of nuclei isolated from neurons and microglia derived from sporadic and genetic AD brains and brains from age and sex-matched controls. These studies will enable an unprecedented analysis of the regulatory landscapes of neurons and microglia in the intact aging and AD brain. In Specific Aim 2, we will validate and explain AD-specific enhancer codes of neurons by direct reprogramming of fibroblasts from sporadic and genetic AD patients and age/sex-matched control subjects. In Specific aim 3, we will define cell autonomous AD-specific enhancer codes of microglia obtained by reprograming of iPSCs and monocytes from control and AD subjects. These studies will build upon our recent characterization of human microglia transcriptomes and enhancer landscapes that demonstrate striking levels of individual variation in the expression of genes linked to risk of AD. In Specific Aim 4, we will define consequences of neuron-microglia interactions on the transcriptomes and epigenomes of each cell type. By leveraging existing resources and data sets, these studies will define transcriptional networks that are dysregulated in neurons and microglia in AD, provide proof of concept for defining the mechanistic basis of inherited forms of AD, and nominate additional pathways for further investigation.

项目摘要 遗传和基因组广泛关联研究（GWAS）已经确定了许多基因和风险等位基因 指示促成阿尔茨海默氏病的细胞自主和非细胞自主机制 （广告）。除了神经元表达的基因外，几个风险等位基因（例如TREM2）的观察 仅在小胶质细胞中或主要表达 AD病理学中的小胶质细胞。重要的是，GWAS确定的大多数风险变体都存在于非编码 基因组的区域，这意味着有些是改变基因表达的作用。我们最近对神经元的比较 通过从AD受试者和年龄匹配的对照组的成纤维细胞的跨差异来得出 AD神经元基因表达的变化。同时，我们最近的全球分析能力 人类小胶质细胞的转录组和增强子图谱显示出明显的个人变化 与AD风险等位基因相关的免疫基因的表达。这些发现共同表明了宽度 基因表达的改变可能导致AD易感性独立于产生的敏感性 βAMYOID。增强剂已成为内部和细胞外信号整合的主要点 与发育，稳态和疾病有关，导致特定于上下文的转录输出。 通过定义细胞的增强剂景观，可以推断出细胞为环境信号 接受并解释其随之而来的基因表达程序。在此应用程序中，我们建议定义 “阿尔茨海默氏病的增强剂法规”，以促进我们对细胞自主的理解和 驱动基因表达病原体程序的非细胞自主因素。在特定目标1中，我们将 定义从源自神经元和源自的小胶质细胞的核的转录组和增强子景观 来自年龄和性别匹配的对照组的零星和遗传大脑和大脑。这些研究将使 完整衰老和AD中神经元和小胶质细胞的调节景观的前所未有的分析 脑。在特定目标2中，我们将通过直接验证和解释神经元的广告特异性增强剂代码 从零星和遗传AD患者以及年龄/性别匹配的对照组的成纤维细胞重编程。在 特定的目标3，我们将定义由通过 从对照和AD受试者中重新编程IPSC和单核细胞。这些研究将以我们的最新为基础 人类小胶质细胞转录组和增强剂景观的表征，证明了罢工水平 与AD风险相关的基因表达的个体变异。在特定目标4中，我们将定义 神经元 - 神经元相互作用对每种细胞类型的转录组和表观观察员的后果。经过 利用现有资源和数据集，这些研究将定义转录网络 AD中神经元和小胶质细胞的失调，提供了定义机械基础的概念证明 遗传的AD形式，并提名其他途径进行进一步研究。