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Nuclear Architecture, NcRNAs and Epigenetics in Transcriptional Regulation by ER

ER 转录调控中的核结构、NcRNA 和表观遗传学

基本信息

批准号：
8708062
负责人：
Chunru Lin
金额：
$ 24.9万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-29 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708062
关键词：
Address Affect Antibodies Architecture Award Binding Biological Assay Breast Cancer Cell Cell Line ChIP-seq Chromatin Complex Cytoplasmic Granules Data Databases Development Disease Environment Epigenetic Process Epithelial Cells Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Event Excision Female Functional RNA Gene Activation Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Transcription Goals Growth Histone Code Histones Homeostasis In Vitro Ligands Location Mammary gland Mediating Metabolic Metabolism Methylation Modification Molecular Nuclear Peptides Play Polycomb Positioning Attribute Process Proteins Reader Reading Regulation Repression Research Personnel Role Signal Transduction Small Interfering RNA Small RNA Structure Tail Testing Therapeutic Time Transcript Transcriptional Regulation base blood glucose regulation cofactor demethylation digital drug development genome-wide glucose metabolism in vivo innovation insight malignant breast neoplasm mammary gland development novel novel strategies preference programs promoter protein function reproductive function response transcription factor transcriptome sequencing

项目摘要

Project Summary Estradiol, which acts through the Estrogen Receptor alpha (ER¿), is essential for the development and homeostasis of female reproductive function, exerting critical control of many transcriptional programs, including these regulatory proliferation, and metabolism. The molecular mechanism used by ER¿ to mediate coactivator/corepressor exchanges in gene activation has been reasonably well elucidated. ER¿, chromatin modifiers and dynamic positioning of particular loci are all essential for establishing precise transcriptional regulation and achieving the correct patterns of gene expression. However, it is not clear how these factors are spatially regulated in distinct subnuclear structures and how this regulation may contribute to gene regulation. Our recent findings demonstrated a signal-induced relocation of the transcription units from a transcriptional repressive compartment to a permissive environment. I hypothesize that non-coding RNAs (ncRNAs) TUG1 and NEAT2 control ER¿ target genes to relocate from the transcriptional repressive Polycomb bodies (PcGs) to the gene activation milieu of the interchromatin granules, by selectively interacting with methylated and unmethylated Polycomb 2 protein (Pc2) present on ER¿ target gene promoters. To address this long-term goal, I propose to investigate the hypothesis from three specific aims: 1) to define non- histone methylation/demethylation events and ncRNAs as a novel molecular strategy responsible for genome- wide ER¿ transcriptional programs; 2) to determine the potential role of two ncRNAs, TUG1 and NEAT2, located in PcGs and interchromatin granules, respectively, in controlling relocation of ER¿ target genes between these two subnuclear structures, depending on the status of Pc2 methylation in response to estrogen; 3) to investigate the potential allosteric role of ncRNA in modulating the ability of "readers" of the histone code, such as Pc2, to recognize histone tail modifications. To achieve these aims, I propose to define the genome-wide location of methylated vs. unmethylated Pc2 by ChIP-Seq analysis using specific antibodies and the functional roles of Pc2 or other active "readers" and ncRNAs in controlling the ER¿ transcriptome by a combination of GRO-Seq, RNA-Seq analysis and siRNA knockdown strategies. I will also investigate the potential relocalization of ER¿-regulated genes from PcG bodies to interchromatin granules upon E2 stimulation and the underlying mechanisms, by which the binding of TUG1 or NEAT2 ncRNAs directs the preference of Pc2 recognition of histone tail modification. Taken together, the proposed study evaluates a new concept that ER¿ target gene loci relocate between functionally distinct nuclear architectural structures and the roles of several novel modulators that play a critical role in ER¿ target gene regulation. These findings will provide innovative targets for drugs development for a number of intriguing therapeutic implications. Based on the extensive preliminary data, I am confident of accomplishing these aims in the period of the award and emerging as an Independent Investigator.

项目总结