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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.

摘要