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：
8990016
负责人：
Dale L Dorsett
金额：
$ 29.63万
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/8990016
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 Genomic approach Genomics Goals Growth Growth and Development function Health 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 Sister Chromatid Syndrome Testing Transcription Initiation Site Work base biophysical techniques chromatin immunoprecipitation cohesin cohesion developmental disease genetic approach global run on sequencing human disease in vivo insight negative elongation factor novel outcome forecast premature prevent promoter research study tool tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：拟议工作的长期目标是确定姐妹染色单体凝聚蛋白如何控制基因转录。这将阐明某些人类遗传综合征和癌症基础的机制。粘蛋白拓扑环绕姐妹染色单体将它们固定在一起，直到细胞分裂为止。粘着素活性的中度降低不会破坏染色单体的内聚力，而是改变基因转录，导致生长和发育差。高粘着素活性与多种癌症的预后不良有关。粘着素如何控制转录的方式在很大程度上未知，但是当前的证据认为它直接参与了多种机制。最近的发现提出了一种新的范式，在这种范式中，粘蛋白与polycomb抑制性复合物1（PRC1）表观遗传沉默复合物全球控制着许多活性基因的基因沉默和转录。数据表明，粘着蛋白直接促进PRC1与活性基因的结合，在该基因中，PRC1阻止启动子处暂停的RNA聚合酶II（POL II）过早地伸长。他们还表明，在活性基因上的粘蛋白隔离PRC1，从而控制了多少可用于基因沉默，并且PRC1限制了在沉默和活性基因上粘着粘着蛋白的结合。该提案的目的是测试这种新范式，并确定粘蛋白和PRC1共同控制活性基因的基因沉默和转录的机制。提出的研究结合了生化，遗传，基因组和生物物理方法，以测试当前模型的关键预测。 AIM 1测试了与PRC1物理相互作用的思想，以直接促进PRC1与活性基因启动子的结合，并且PRC1通过与粘蛋白负荷或去除因子相互作用而限制了粘蛋白结合。 AIM 2测试了PRC1通过促进NELF和DSIF暂停因子或Pol II激酶活动来阻止PRC1过早进入延伸的想法。这些研究提供的粘蛋白和PRC1对照转录的机制的见解应提出纠正遗传综合征和癌症粘连蛋白PRC1失衡的新方法。