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Molecular Mechanisms of Promoter-Terminator Gene Looping

启动子-终止子基因循环的分子机制

基本信息

批准号：
8865248
负责人：
Xin Liu
金额：
$ 30.53万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-02 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8865248
关键词：
Address Binding Biochemical Biochemistry Biological Assay Biological Phenomena Biology C-terminal Cell physiology Chemicals Chromatin Chromatin Loop Chromatin Structure Complex Coupled Crystallography DNA DNA Polymerase I DNA Polymerase III DNA-Directed RNA Polymerase Development Elements Enhancers Environment Essential Genes Eukaryota Eukaryotic Cell Event Gene Expression Regulation Genes Genetic Genetic Transcription Genome Genomics Goals HIV In Vitro Intercistronic Region Interphase Link Macromolecular Complexes Maintenance Maps Mediating Memory Messenger RNA Mitochondrial RNA Molecular Molecular Conformation Nuclear Nuclear Pore Complex Pathway interactions Phosphoric Monoester Hydrolases Physiological Plant Genes Play Polyadenylation Polymerase Process Promoter Regions Proviruses RNA RNA Binding RNA Polymerase II Recycling Regulation Research Role Series Signal Transduction Site Structure Surface Synthetic Genes System Terminator Regions Testing Titrations Transcript Transcription Factor TFIIB Transcription Initiation Transcriptional Regulation Untranslated RNA Yeasts base biochemical tools cancer cell cohesin condensin crosslink gene function gene terminator global run on sequencing human GTF2B protein human disease in vivo insight mutant new therapeutic target promoter public health relevance research study structural biology tool transcription factor transcription factor TFIIIC tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Accumulating evidence has indicated that high-order genome structures influence transcription and mediate critical co-transcriptional crosstalk among distinct DNA elements. The functional significance of a variety of types of chromatin loops (e.g. promoter-terminator, enhancer-promoter, and interchromosomal) in gene regulation during development and in cancer cells has been demonstrated recently. Essential factors from the transcription initiation and mRNA 3'-end cleavage and polyadenylation (poly(A)) machineries have been shown to form complexes to confer promoter-terminator gene looping. The general transcription factor TFIIB mediates a critical interaction network involving Ssu72 (a pol II C-terminal domain phosphatase) and Rna15 (the poly(A) RNA-binding subunit of the cleavage factor IA complex). Gene looping is a widespread phenomenon in yeast and has also been identified for mammalian genes, plant genes, and human immunodeficiency virus provirus. In addition, gene looping has been connected to a number of fundamental cellular processes, which include transcription reinitiation, maintenance of transcriptional memory, and control of transcriptional directionality. In the proposed research, we will address the following key questions: (1) how do TFIIB and TFIIB- centered gene looping complexes regulate transcription (Aim 1), (2) what is the structural and biochemical basis for the pol II transcription-coupled gene loop establishment and maintenance (Aim 2), and (3) what are the mechanisms and physiological consequences of gene looping-dependent pol II reinitiation (Aim 3)? Our broad hypothesis is that unique macromolecular complexes formed by nuclear factors and non-coding RNAs mediate gene looping and create unique local chromatin environments to control pol II transcription. Specifically, we will test this hypothesis by (1) biochemically and structurally mapping binding interfaces of the TFIIB-centered gene looping complexes and connect them to the gene looping process directly in vivo, (2) revealing the pathways of TFIIB-dependent gene loop formation during the course of transcription and identifying additional nuclear factors (e.g. cohesin, condensin, nuclear pore complexes, and TFIIIC) required for gene looping, and (3) determining pol II and transcription factor dynamics on chromatin governed by gene loops with tools including the competition ChIP, the nuclear anchor-away system, and the chemically induced artificial gene looping system. Collectively, built upon our preliminary results these studies will provide the molecular mechanisms of gene looping and its mediated co-transcriptional crosstalk. In addition, we will link gene looping to other cellular pathways by identifying additional nuclear factors critical for this process. Finally, our studies may offer insights into the common principles of all types of transcription-dependent chromatin loops implicated in development and human disease and hence suggest novel targets for therapeutics.