How transcription disrupts genome 3D organization

转录如何破坏基因组 3D 组织

• 批准号: 10390097
• 负责人: SVEN W HEINZ
• 金额: $ 3.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10390097
• 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; ENG gene; 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; Process; Proteins; RNA Polymerase II; Research; Role; Shapes; Stimulus; Structure; System; Testing; Transcription Elongation; Transcription Initiation; Viral; Work; cell type; cohesin; epigenome; epigenomics; experimental study; genetic information; genome-wide; in vivo; insight; loss of function; parent grant; programs; protein complex; protein degradation; termination factor; three dimensional structure; transcription termination; transcriptomics

Title: How transcription disrupts genome 3D organization Abstract (From parent grant, R01 GM129532): 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.

职务名称： 转录如何破坏基因组3D组织 摘要（来自母基金，R01 GM129532）： 核内染色质的三维包装在调节基因表达中起着重要作用。而 我们知道，基因组在细胞核中如何折叠的原理越来越被理解， 关于驱动基因组3D结构动态变化的机制， 分化我们最近发现，甲型流感感染抑制转录终止，导致 通读转录通常使数百个内切酶延伸超过基因的3 ′末端。转录 这些区域破坏局部粘着蛋白介导的染色质相互作用，导致染色质解压缩， 频繁地诱导先前无活性的基因组区域向活性区室的转换。这些 隔室变化发生在几个小时内，并且在没有表观遗传变化的情况下，表观遗传变化通常是 发现与一个位点的隔室关联相关。基因转录的进一步分析显示， 粘附素损失与RNA聚合酶II到达粘附素结合位点在时间上密切相关，这表明 RNA聚合酶II本身参与从染色质置换粘着蛋白。为了详细研究这些现象， 我们将全面描述普遍通读的表观遗传和转录效应， degron标记的细胞系作为转录诱导的基因组3D结构变化的替代模型，以及 测试基因结构对界定RNA聚合酶II转录改变基因组的贡献 organization.在一组单独的实验中，我们将使用候选方法来鉴定参与蛋白质， 转录相关粘附素卸载。这些研究将有助于揭示转录如何影响 染色质相互作用，增加我们对动态重组基因组3D的机制的了解 organization.