How transcription disrupts genome 3D organization

标题： 转录如何扰乱基因组3D组织 摘要(摘自家长赠款，R01 GM129532)： 染色质在细胞核内的3D包装在调控基因表达方面起着重要作用。而当 我们知道，基因组如何在细胞核内折叠的原理越来越清楚 关于驱动基因组3D结构动态变化的机制，例如在 差异化。我们最近发现，甲型流感感染抑制转录终止，导致 通读转录通常延伸数百个千碱基，超过基因的3‘端。抄写： 这些区域扰乱了局部粘附素介导的染色质相互作用，导致染色质分解和 频繁地诱导先前不活跃的基因组区域切换到活跃的隔室。这些 隔室变化在几个小时内发生，并且在没有表观遗传变化的情况下发生，这通常是 发现与一个基因座的隔室关联相关。进一步的基因转录分析显示， 粘附素丢失与RNA聚合酶II到达粘附素结合部位在时间上密切相关，这表明 RNA聚合酶II本身参与了从染色质中取代粘附素的过程。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。 变性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 检测基因结构对确定RNA聚合酶II转录改变基因组的作用 组织。在另一组实验中，我们将使用一种候选方法来识别与 转录相关的粘附素卸载。这些研究将有助于揭示转录如何影响 染色质相互作用和增加我们对动态重组基因组3D的机制的了解 组织。

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.