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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

抽象的阿尔茨海默氏病（AD）是老年人中最常见的痴呆症，位居第七位。是美国的首要死因。尽管几十年来人们努力了解 AD 生物学并开发治疗方法、治愈 AD 或缓解 AD 症状的有效策略仍然有限。 AD 具有重要意义世界面临的医疗和社会经济负担，需要紧急解决方案来了解其基础发病机制并开发有效的方法来预防认知恶化或改善患者的生活。 GWAS 研究发现了非编码基因组区域中的许多风险遗传变异，特别是增强子，提示增强子功能障碍和基因失调在 AD 发病机制中的关键作用。人类 AD 大脑的表观遗传学研究也揭示了显着的变化，例如组蛋白乙酰化增强剂。更好地了解基因失调和增强子故障对于更好地理解至关重要 AD 病理学并确定新的治疗靶点。最近发现活性增强剂经常产生非编码增强子 RNA (eRNA) 为解释 AD 中的增强子功能障碍提供了新的视角。该提案旨在通过表征eRNA背后的分子机制来探索独特的方向大脑和 AD 中的功能。我们的总体假设是增强子在 AD 中异常活跃，导致解除管制的 eRNA 组装核糖核蛋白复合物 (RNP) 来组织核 RNA 区室可以影响脑细胞中的基因表达网络。我们组建了强大的调查团队进行测试这一假设具有三个具体目标。首先，我们计划从人类和人类中鉴定出解除管制的 eRNA。样本和 iPSC 衍生的神经元和小胶质细胞，并识别 AD 中特定 eRNA 的功能相关基因调控。其次，我们将通过使用稳健的方法深入研究 eRNA 的功能机制。我们开发的 RNA 捕获方法可系统地识别神经元和小胶质细胞 eRNA：蛋白质相互作用组。我们将研究 eRNA 结合蛋白 (eRBP) 调节 AD 相关的机制增强子和基因转录，并影响三维基因组结构。三、基于我们最近发现 RNA m6A 甲基化对 eRNA 在增强子激活和信号中的关键作用诱导基因转录，我们将检查人脑样本和 iPSC 衍生的 eRNA 甲基化组神经元/小胶质细胞响应 AD 相关信号传导。这个目标将发现新的知识来理解染色质相关 RNA 的化学修饰如何从机制上影响基因转录为 AD 做出贡献。总之，该提案的预期结果不仅将提供机械见解研究 AD 中的脑基因调控和非编码 RNA 功能，而且还可以提供新的治疗靶点和干预这种毁灭性疾病的策略。