Novel Coregulators of Estrogen Receptor in Enhancer-regulated Transcription

增强子调节转录中雌激素受体的新型共调节因子

基本信息

批准号：
10549772
负责人：
Zhijie Jason Liu
金额：
$ 6.2万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2020-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549772
关键词：
Address Antiestrogen Therapy Applications Grants Binding Biological Biotin Breast Cancer cell line Cell Fate Control Cell Line Cells ChIP-seq Chromatin DNA DNA Binding Data Defect Development Disease Disease Resistance Distal EP300 gene Enhancers Epigenetic Process Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Foundations Functional disorder Future Gene Expression Gene Expression Profile Genetic Transcription Genomics Grant Hormones Image Individual Knock-out Knowledge Mammary gland Mediating Mediator Methodology Molecular Names Nuclear Nuclear Receptors Organ Pathway interactions Phenotype Play Proteins Proteomics Regulation Regulatory Element Reporting Resistance Role Running Signal Transduction Tamoxifen Technology Testing Untranslated RNA Work Xenograft procedure cell growth cofactor combinatorial conditional knockout global run on sequencing hormone resistance improved in vivo insight knock-down mouse model novel overexpression programs receptor function recruit targeted treatment transcription factor

项目摘要

Novel Coregulators of Estrogen Receptor in Enhancer-regulated Transcription Estrogen (E2 or 17b-estradiol) and its nuclear receptor ERα are critical for the normal development and disease conditions of multiple organs, including mammary glands. E2 and ERα regulate transcriptional programs in these biological contexts through binding primarily at distal enhancers. Increasing evidence indicates that functional dysregulation of ERα-bound enhancers profoundly alters normal transcriptional programs, leading to developmental defects, diseases, and hormone resistance. However, the molecular mechanisms underlying the enhancer function/dysfunction are largely unknown. My lab has been focusing on studying two key questions on ERα-bound enhancers: 1) how are estrogen-regulated enhancers assembled under different conditions? 2) how do the enhancer components encode the context-specific function of each individual enhancer in vivo? Using a powerful proximity proteomics approach, we recently identified additional ERα-interacting coregulators including YAP/TEAD, two key components of Hippo pathway to mediate nuclear effects. Our preliminary data suggest YAP/TEAD function in a non-canonical manner to interact with ERα on ERα-bound enhancers and play a key role in ERα-mediated transcriptional programs under normal signaling condition or during the development of hormone resistance . In this grant proposal, we are proposing two specific aims to test the hypothesis that YAP/TEAD are important novel coregulators required for the activation of ERα-bound enhancers, and the cooperative interactions between YAP/TEAD and ERα control the context-specific function of ERα-bound enhancers in vivo through enhancer reprogramming. The proposed work will provide a mechanistic interpretation on how YAP/TEAD and ERα signaling crosstalk at the chromatin level and converge on enhancers to control downstream gene expression under different conditions, and lay the foundation for future development of improved ER-targeted therapy.

雌激素受体在增强子定期（E2或17b-雌二醇）中的新型核心测量剂是核受体评论家Al，用于多个器官的正常发育和疾病条件，E2和ERα在生物学上通过远端增强剂的结合在生物学上调节了超静脉表明ERα结合的增强子的功能深刻地改变了MAL转录程序，导致发育缺陷和激素耐药性。增强剂组装的s不同？与ERα结合增强子相互作用并在ERα介导的转录程序中起关键作用。通过增强子重新编程，ERα结合增强子在体内激活ERα结合的增强子的新型核心测量器所需未来改进的EER靶向疗法的发展。