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Cohesin Polycomb Interactions in Gene Regulation

基因调控中的粘连蛋白多梳相互作用

基本信息

批准号：
8611280
负责人：
Dale L Dorsett
金额：
$ 29.03万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8611280
关键词：
Affinity Chromatography Amino Acids Binding Biochemical Biochemical Genetics Bruck-de Lange syndrome Cancer Prognosis Cell division Cells Chromatids Chromosome Segregation Chromosomes Complex Data Defect Development Diagnosis Drosophila genus Ensure Epigenetic Process Equilibrium Excision Fluorescence Recovery After Photobleaching Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Genetic Transcription Genomics Goals Growth Growth and Development function Histones Human Genetics Individual Knowledge Link Malignant Neoplasms Maps Messenger RNA Methods Modeling Molecular Mutation Organism PRC1 Protein Patients Phosphotransferases Polycomb Polymerase Positive Transcriptional Elongation Factor B Properdin Proteins Prothrombin Proto-Oncogenes RNA Polymerase II Recruitment Activity Role Running Sister Chromatid Syndrome Testing Transcription Initiation Site Work base biophysical techniques chromatin immunoprecipitation cohesin cohesion developmental disease human disease in vivo insight negative elongation factor novel outcome forecast premature prevent promoter public health relevance research study tool tumor tumor growth

项目摘要

The long-term goal of the proposed work is to determine how sister chromatid cohesion proteins control gene transcription. This will illuminate mechanisms that underlie certain human genetic syndromes and cancers. Cohesin topologically encircles sister chromatids to hold them together until a cell divides. Moderate reductions in cohesin activity don't disrupt chromatid cohesion, but alter gene transcription, leading to poor growth and development. High cohesin activity is linked to poor prognosis in multiple cancers. How cohesin controls transcription is largely unknown, but current evidence argues that it participates directly in multiple mechanisms. Recent discoveries argue for a new paradigm in which a balance between cohesin and the Polycomb Repressive Complex 1 (PRC1) epigenetic silencing complex globally controls both gene silencing and transcription of many active genes. The data argue that cohesin directly facilitates binding of PRC1 to active genes, where PRC1 prevents paused RNA polymerase II (Pol II) at the promoter from prematurely entering into elongation. They also suggest that cohesin at active genes sequesters PRC1, thereby controlling how much is available for gene silencing, and that PRC1 limits cohesin binding at silenced and active genes. The goal of this proposal is to test this new paradigm, and determine the mechanisms by which cohesin and PRC1 together control both gene silencing and transcription of active genes. The proposed studies combine biochemical, genetic, genomic, and biophysical approaches to test key predictions of the current model. Aim 1 tests the ideas that cohesin physically interacts with PRC1 to directly facilitate PRC1 binding to active gene promoters, and that PRC1 limits cohesin binding through interactions with cohesin loading or removal factors. Aim 2 tests the idea that PRC1 prevents premature entry of paused Pol II into elongation by facilitating NELF and DSIF pausing factor or Pol II kinase activities. The insights into the mechanisms by which cohesin and PRC1 control transcription provided by these studies should suggest new methods for correcting cohesin-PRC1 imbalances in genetic syndromes and cancer.

这项工作的长期目标是确定姐妹染色单体凝聚蛋白是如何控制基因转录这将阐明某些人类遗传综合征的机制，癌的在细胞分裂之前，粘着蛋白拓扑地环绕姐妹染色单体将它们保持在一起。中度粘着蛋白活性的降低不会破坏染色单体的粘着，但会改变基因转录，导致细胞内蛋白质的缺乏。促进经济增长和发展。高粘附素活性与多种癌症的预后不良有关。粘着蛋白如何控制转录在很大程度上是未知的，但目前的证据表明，它参与直接在多个机制中。最近的发现提出了一种新的范式，黏连蛋白和多梳抑制复合物1（PRC 1）表观遗传沉默复合物全面控制这两种基因，基因沉默和许多活性基因的转录。数据表明，粘着蛋白直接促进结合的PRC 1到活性基因，其中PRC 1阻止暂停RNA聚合酶II（Pol II）在启动子，过早进入伸长状态。他们还表明，活性基因上的粘着蛋白隔离了PRC 1，从而控制有多少可用于基因沉默，PRC 1限制沉默时的粘着蛋白结合，活跃的基因。本提案的目标是测试这种新的范例，并通过以下方式确定机制：其粘附素和PRC 1一起控制基因沉默和活性基因的转录。拟议的研究结合了联合收割机生物化学，遗传学，基因组学和生物物理学方法来测试关键的当前模型的预测。目的1测试了粘附素与PRC 1物理相互作用，促进PRC 1与活性基因启动子的结合，PRC 1通过相互作用限制粘着蛋白结合具有粘附素加载或去除因子。目标2测试PRC 1防止过早进入暂停的想法 Pol II通过促进NELF和DSIF暂停因子或Pol II激酶活性而进入伸长。深入了解这些研究提供的粘附素和PRC 1控制转录的机制应该表明，用于纠正遗传综合征和癌症中的粘附素-PRC 1失衡的新方法。