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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：
10461048
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/10461048
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