Mechanisms Underlying Enhancer Rnp Mediated Gene Regulation And Genome Organization

增强子 Rnp 介导的基因调控和基因组组织的潜在机制

基本信息

批准号：
10260610
负责人：
Wenbo Li
金额：
$ 35.77万
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：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10260610
关键词：
3-Dimensional Address Architecture Binding Binding Proteins Biochemical Biological Markers Biological Process Biological Response Modifier Therapy Biophysics Bromodomain Categories Cell Nucleus Cells ChIP-seq Chemicals Complement Complex DNA Data Development Disease Drug Targeting Elements Enhancers Estrogen Receptor alpha Etiology Exhibits Gene Activation Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Genomics Goals Health Hi-C Human Immune System Diseases Inflammation Malignant Neoplasms Mammalian Cell Mediating Methods Methylation Modification Molecular Mutation Nerve Degeneration Nuclear Pathologic Phase Physiological Play Proteins RNA RNA Binding RNA Sequences RNA-Binding Proteins RNA-Protein Interaction Regulation Research Ribonucleoproteins Role SS DNA BP Specificity Structure Testing Transcript Transcription Coactivator Transcriptional Regulation Untranslated RNA Work base cell type human disease improved in vivo insight new therapeutic target novel novel strategies novel therapeutic intervention programs protein complex protein degradation recruit risk variant success targeted treatment

项目摘要

PROJECT ABSTRACT Enhancers play critical roles in determining lineage-specific gene expression and cellular identities, and are enriched in noncoding disease mutations and risk loci. There is an urgent need to elucidate the complete mechanisms of enhancer functions and malfunctions to better understand disease etiology and to develop new, enhancer-targeting therapies. The recent finding that active enhancers often generate noncoding enhancer RNAs (eRNAs) has provided a new perspective to interpret enhancer activity in the context of RNA-mediated regulation. This proposal aims to establish a unique research direction by developing new approaches to address the molecular mechanisms underlying eRNA functions in gene/genome regulation. Our overall hypothesis is that eRNAs assemble specific ribonucleoprotein complexes (RNPs) to organize high-order enhancer structures in the three-dimensional nucleus to control gene transcription. We have three specific aims in this proposal. We plan to use a robust RNA capture method that we have developed to systematically identify eRNA:protein interactomes in human cells. For the first aim, we plan to focus on two novel eRNA- binding proteins (eRBPs) to characterize their functions in gene transcription and 3D genome interaction in mammalian cells. Subsequently, we have two aims to study the mechanisms of each of the two eRBPs to fully characterize the biochemical basis permitting eRNA:protein interaction and their possible involvement in mediating the formation of transcriptionally-associated sub-nuclear condensates. The expected results from this proposal will provide novel mechanistic insights into gene transcriptional regulation and RNA functions in mammalian cells. As enhancers become important drivers in disease development, these mechanistic insights may offer new therapeutic strategies to treat enhancer-driven diseases.

项目摘要增强子在确定谱系特异性基因表达和细胞身份方面发挥着关键作用，并且富含非编码疾病突变和风险位点。迫切需要阐明完整的增强子功能和功能障碍的机制，以更好地了解疾病病因并开发新的、增强子靶向治疗。最近发现活性增强子经常产生非编码增强子 RNA (eRNA) 为解释 RNA 介导的增强子活性提供了新的视角规定。该提案旨在通过开发新方法来建立独特的研究方向解决基因/基因组调控中 eRNA 功能的分子机制。我们的整体假设是 eRNA 组装特定的核糖核蛋白复合物 (RNP) 来组织高阶三维核中的增强子结构控制基因转录。我们有三个具体的本提案的目标。我们计划使用我们开发的强大的 RNA 捕获方法来系统地识别人类细胞中的 eRNA：蛋白质相互作用组。对于第一个目标，我们计划重点关注两种新型 eRNA—— 结合蛋白 (eRBP) 来表征其在基因转录和 3D 基因组相互作用中的功能哺乳动物细胞。随后，我们有两个目标来研究这两种 eRBP 的机制，以充分描述允许 eRNA:蛋白质相互作用的生化基础及其可能参与介导转录相关亚核凝聚物的形成。预期结果来自该提案将为基因转录调控和 RNA 功能提供新的机制见解哺乳动物细胞。随着增强子成为疾病发展的重要驱动因素，这些机制见解可能为治疗增强子驱动的疾病提供新的治疗策略。