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 遗传和全基因组关联研究（GWAS）已经鉴定了许多基因和风险等位基因， 表明细胞自主机制和非细胞自主机制都有助于阿尔茨海默病 （AD）。除了神经元表达的基因外，一些风险等位基因，如TREM 2， 专门或主要在小胶质细胞中表达，导致人们越来越多地努力了解 AD病理学中的小胶质细胞。重要的是，GWAS识别的大多数风险变异存在于非编码基因中。 这意味着有些基因改变了基因的表达。我们最近对神经元 通过来自AD受试者和年龄匹配的对照的成纤维细胞的转分化衍生的细胞表达显著增加， AD神经元基因表达的变化。与此同时，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了在 与AD风险等位基因相关的免疫基因的表达。总的来说，这些发现表明， 可能导致AD易感性的基因表达的改变， β淀粉样蛋白增强子已经成为细胞内和细胞外信号整合的主要点 与发育、稳态和疾病相关，导致上下文特异性转录输出。 通过定义细胞的增强子景观，可以推断细胞所处的环境信号， 接收并解释其随之而来的基因表达程序。在本申请中，我们提出定义 “阿尔茨海默病的增强子代码”，以定性地推进我们对细胞自主和 非细胞自主因素，驱动致病程序的基因表达。具体目标1： 定义了从神经元和小胶质细胞分离的细胞核的转录组和增强子景观， 散发性和遗传性AD大脑以及来自年龄和性别匹配对照的大脑。这些研究将使 对完整老化和AD中神经元和小胶质细胞的调节景观进行了前所未有的分析， 个脑袋在具体目标2中，我们将通过直接验证和解释神经元的AD特异性增强子代码， 来自散发性和遗传性AD患者以及年龄/性别匹配的对照受试者的成纤维细胞的重编程。在 具体目标3，我们将定义通过以下方式获得的小胶质细胞的细胞自主AD特异性增强子代码： 来自对照和AD受试者的iPSC和单核细胞的重编程。这些研究将建立在我们最近的 表征人类小胶质细胞转录组和增强子景观，显示出惊人的水平 与AD风险相关的基因表达的个体差异。在具体目标4中，我们将定义 神经元-小胶质细胞相互作用对每种细胞类型的转录组和表观基因组的影响。通过 利用现有的资源和数据集，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，为定义AD的机制基础提供了概念证据。 遗传形式的AD，并提名其他途径进行进一步研究。