Enhancer RNAs in brain gene regulation and Alzheimer's disease

大脑基因调控和阿尔茨海默病中的增强子 RNA

• 批准号: 10667052
• 负责人: Wenbo Li
• 金额: $ 78.38万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667052
• 关键词: 3-Dimensional; Aberrant DNA Methylation; Address; Affect; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Apolipoprotein E; Architecture; Area; Binding; Biological; Biology; Brain; Cause of Death; Cell Nucleus; Cell model; Cells; ChIP-seq; Chemicals; Chromatin; Chromatin Conformation Capture and Sequencing; Coenzyme A; Cognitive; Complex; Country; DNA; DNA Binding; Dementia; Deterioration; Development; Disease; Economic Burden; Elderly; Enhancers; Epigenetic Process; Fishes; Fluorescent in Situ Hybridization; Gene Expression; Gene Expression Regulation; Gene Mutation; Genes; Genetic; Genetic Risk; Genetic Transcription; Genome; Health; Hi-C; Histone Acetylation; Human; Individual; Induced pluripotent stem cell derived neurons; Interferons; Intervention; Knowledge; Lead; Mediating; Medical Economics; Methods; Methylation; Microglia; Modeling; Modification; Molecular; Neurons; Nuclear; Nuclear RNA; Oncogene Deregulation; Organoids; Pathogenesis; Pathologic; Patients; Play; Population; Proteins; RNA; RNA-Binding Proteins; Reader; Regulation; Research Personnel; Ribonucleoproteins; Risk; Role; Sampling; Signal Induction; Signal Transduction; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Intervention; United States; Untranslated RNA; Variant; Work; apolipoprotein E-4; brain cell; cell type; chromatin modification; chromosome conformation capture; epigenomics; genetic variant; genome wide association study; improved; induced pluripotent stem cell; insight; methylome; new therapeutic target; novel; prevent; programs; reduce symptoms; response; risk variant; socioeconomics; tau Proteins; tau mutation; therapeutic target; therapeutically effective; therapy development; transcription factor; transcriptome

ABSTRACT Alzheimer's disease (AD) is the most common form of dementia in elderly population, and is the seventh leading cause of death in the US. Despite decades of efforts in understanding AD biology and in developing therapies, effective strategies to cure AD or to alleviate AD symptoms remain limited. AD poses a significant medical and socioeconomical burden to the world that requires urgent solutions to understand the basis of its pathogenesis and to develop effective means to prevent cognitive deterioration, or to improve patient lives. GWAS studies identified many risk genetic variants in the noncoding genome regions, particularly in enhancers, suggesting key roles of enhancer malfunction and gene deregulation in AD pathogenesis. Epigenetic studies of human AD brains also revealed significant changes such as histone acetylation at enhancers. Better knowledge of gene deregulation and enhancer malfunction is critical to better understand AD pathology and to identify new therapeutic targets. The recent findings that active enhancers often generate noncoding enhancer RNAs (eRNAs) have provided a new perspective to interpret enhancer malfunction in AD. This proposal aims to explore a unique direction by characterizing the molecular mechanisms underlying eRNA functions in brain and AD. Our overall hypothesis is that enhancers were aberrantly active in AD, resulting in deregulated eRNAs to assemble ribonucleoprotein complexes (RNPs) to organize a nuclear RNA compartment that can impact gene expression networks in brain cells. We have assembled a strong investigator team to test this hypothesis with three specific aims. First, we plan to identify deregulated eRNAs from both human samples and iPSC derived neuron and microglia cells, and identify functions of specific eRNAs in AD associated gene regulation. Second, we will study mechanisms of eRNAs' functions in depth, by using a robust RNA capture method that we have developed to systematically identify neuronal and microglia eRNA:protein interactomes. We will examine the mechanisms of eRNA-binding proteins (eRBPs) in regulating AD associated enhancer and gene transcription, and in impacting the three-dimensional genome architecture. Third, based on our recent findings of a critical role of RNA m6A methylation on eRNAs in enhancer activation and signal induced gene transcription, we will examine eRNA methylome in human brain samples and iPSC derived neuron/microglia in response to AD-associated signaling. This aim will uncover new knowledge to understand how chemical modifications of chromatin associated RNAs may mechanistically impact gene transcription to contribute to AD. Together, the expected results from this proposal will not only provide mechanistic insights into brain gene regulation and noncoding RNA functions in AD, but also can offer new therapeutic targets and strategies to intervene this devastating disease.

摘要 阿尔茨海默病(AD)是老年人群中最常见的痴呆形式，位居第七 在美国居死因首位。尽管几十年来在理解AD生物学和开发 治疗阿尔茨海默病或缓解阿尔茨海默病症状的有效策略仍然有限。广告构成了一个重要的 给世界带来医疗和社会经济负担，需要紧急解决方案来了解其基础 并开发有效的手段来防止认知退化，或改善患者的生活。 Gwas的研究在非编码基因组区域发现了许多危险的遗传变异，特别是在 增强子，提示增强子功能障碍和基因失控在AD发病机制中的关键作用。 人类AD脑的表观遗传学研究也显示了显著的变化，如组蛋白乙酰化 增强剂。更好地了解基因解除调控和增强子故障对于更好地理解 AD病理，并寻找新的治疗靶点。活性促进剂经常产生的最新发现 非编码增强子RNA(ERNAs)为解释AD增强子功能障碍提供了新的视角。 这一提议旨在通过表征Erna的分子机制来探索一个独特的方向 大脑和AD的功能。我们的总体假设是，增强剂在AD中异常活跃，导致 解除管制的eRNAs组装核糖核蛋白复合体(RNPs)以组织核RNA间隔室 这会影响脑细胞中的基因表达网络。我们已经组建了一支强大的调查团队来测试 这一假设有三个具体目的。首先，我们计划从人类和人类中识别放松管制的eRNAs 样本和IPSC来源的神经元和小胶质细胞，并鉴定特定eRNAs在AD中的功能 相关基因调控。其次，我们将深入研究eRNAs的功能机制，通过使用Robust 我们开发的用于系统鉴定神经元和小胶质细胞Erna：蛋白质的RNA捕获方法 互动。我们将研究Erna结合蛋白(ERBPs)调节AD相关的机制 增强子和基因转录，以及影响三维基因组结构。第三，基于 我们最近发现RNA m6A甲基化在eRNAs的增强子激活和信号转导中起关键作用 诱导基因转录，我们将检测人脑样本和IPSC来源的Erna甲基组 神经元/小胶质细胞对AD相关信号的反应。这一目标将发现新的知识来理解 染色质相关RNA的化学修饰如何机械地影响基因转录 对AD做出贡献。综上所述，这项提案的预期结果不仅将提供机械性的见解 研究AD的脑基因调控和非编码RNA功能，也可以提供新的治疗靶点和 干预这种毁灭性疾病的策略。