How transcription disrupts genome 3D organization

职务名称： 转录如何破坏基因组3D组织 摘要： 核内染色质的三维包装在调节基因表达中起着重要作用。 虽然基因组如何在细胞核中折叠的原理越来越清楚，但我们知道， 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，通常 被发现与一个位点的区室关联相关。基因转录的进一步分析 揭示了粘附素损失与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本身参与了从染色质中置换粘着蛋白。研究这些 详细的现象，我们将全面表征表观遗传和转录的影响， 在去电子标记的细胞系中普遍通读作为转录诱导基因组的替代模型 3D结构的变化，并测试基因结构的贡献，以划定RNA聚合酶II 转录改变基因组的结构。在另一组实验中，我们将使用一个候选人， 方法来鉴定参与转录相关的粘附素卸载的蛋白质。这些研究将有助于 揭示转录如何影响染色质相互作用，并增加我们对机制的了解 动态重组基因组的三维结构。

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.