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How transcription disrupts genome 3D organization

转录如何破坏基因组 3D 组织

基本信息

批准号：
10538566
负责人：
SVEN W HEINZ
金额：
$ 31.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10538566
关键词：
3-Dimensional Acute Address Aging Architecture Binding Binding Sites Cell Line Cell Nucleus Cells Characteristics Chromatin Chromatin Structure Chromosomes Collaborations Communicable Diseases Complex Data Development Disease Epigenetic Process Gene Expression Gene Expression Regulation Gene Structure Genes Genetic Transcription Genome Genomic Segment Hour Infection Influenza A virus Interphase Kinetics Knowledge Laboratories Link Malignant Neoplasms Mediating Methods Modeling Molecular Molecular Conformation Mutation Organizational Change Play Polymerase Protein Degradation Induction Proteins RNA Polymerase II Research Role Shapes Stimulus System Testing Transcription Elongation Transcription Initiation Transcription Process Viral Work cell type cohesin epigenome epigenomics experimental study genetic information genome-wide in vivo insight loss of function programs protein complex termination factor three dimensional structure transcription termination transcriptomics

项目摘要

Title: How transcription disrupts genome 3D organization Abstract: The 3D packaging of chromatin within the nucleus plays an important role in regulating gene expression. While the principles of how the genome is folded in the nucleus are increasingly well understood, we know remarkably little about the mechanisms that drive dynamic changes in genome 3D structure, e.g. during differentiation. We recently discovered that influenza A infection inhibits transcription termination, resulting in read-through transcription often extends hundreds of kilobases past the 3’ ends of genes. Transcription of these regions disrupts local cohesin-mediated chromatin interactions, leads to chromatin decompaction and frequently induces switching of previously inactive genome regions to the active compartment. These compartment changes occur in a matter of hours, and in the absence of epigenetic changes, which usually are found to correlate with compartment association of a locus. Further analysis of genic transcription revealed that cohesin loss is closely temporally linked to RNA polymerase II arrival at cohesin binding sites, suggesting that RNA polymerase II itself is involved in displacing cohesin from chromatin. To study these phenomena in detail, we will comprehensively characterize the epigenetic and transcriptional effects of pervasive read-through in degron-tagged cell lines as an alternative model for transcription-induced genome 3D structure changes, and test the contribution of gene structure to delimiting where RNA polymerase II transcription changes genome organization. In a separate set of experiments, we will use a candidate approach to identify proteins involved in transcription-associated cohesin unloading. These studies will help reveal how transcription influences chromatin interaction and increase our knowledge of the mechanisms that dynamically reorganize genome 3D organization.

标题：转录如何破坏基因组 3D 组织抽象的：细胞核内染色质的 3D 包装在调节基因表达中发挥着重要作用。虽然基因组如何在细胞核中折叠的原理越来越被人们所理解，但我们知道关于驱动基因组 3D 结构动态变化的机制知之甚少，例如期间差异化。我们最近发现甲型流感病毒感染会抑制转录终止，从而导致通读转录通常会延伸超过基因 3' 端数百个碱基。转录这些区域破坏了局部粘连蛋白介导的染色质相互作用，导致染色质解压缩并经常诱导先前不活跃的基因组区域切换到活跃的区室。这些区室变化在几个小时内发生，并且没有表观遗传变化，而表观遗传变化通常是发现与基因座的区室关联相关。基因转录的进一步分析表明粘连蛋白损失与 RNA 聚合酶 II 到达粘连蛋白结合位点在时间上密切相关，表明 RNA 聚合酶 II 本身参与从染色质中取代粘连蛋白。要研究这些详细现象，我们将全面表征表观遗传和转录效应降解决定子标记细胞系中的普遍通读作为转录诱导基因组的替代模型 3D 结构变化，并测试基因结构对界定 RNA 聚合酶 II 位置的贡献转录改变基因组组织。在一组单独的实验中，我们将使用候选者识别参与转录相关粘连蛋白卸载的蛋白质的方法。这些研究将有助于揭示转录如何影响染色质相互作用并增加我们对其机制的了解动态重组基因组 3D 组织。