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细胞类型特异性转录选择性依赖中介体
2020-06-02 20:47

奥地利科学院Georg E. Winter、德国马普所Patrick Cramer等研究人员合作发现,细胞类型特异性转录选择性依赖中介体。2020年6月1日,《自然—遗传学》在线发表了这一成果。

研究人员通过耦合快速亚基降解与正交实验读数来量化了中介体调控的RNA聚合酶II(Pol II)动力学。与相分离驱动的转录起始模型相一致,在中介体降解后,大量低磷酸化的Pol II簇迅速分解。这伴随着细胞类型特异性转录回路的选择性显著破坏。
 
值得注意的是,大多数其他基因的转录输出在很大程度上不受急性中介体敲低的影响。这些基因转录活性的维持与依赖CDK9的补偿性反馈回路有关,进而提高了基因组中Pol II暂停释放的速率。
 
总的来说,这些工作将人类中介体定位为一种全局性的共激活因子,可以选择性地保护细胞类型特定的转录网络功能。
 
据悉,中介体复合物利用DNA结合转录因子的信号来指导Pol II。尽管处于这一关键位置,但对人体细胞中介体的机制理解仍然不完整。
 
附:英文原文

Title: Selective Mediator dependence of cell-type-specifying transcription

Author: Martin G. Jaeger, Bjrn Schwalb, Sebastian D. Mackowiak, Taras Velychko, Alexander Hanzl, Hana Imrichova, Matthias Brand, Benedikt Agerer, Someth Chorn, Behnam Nabet, Fleur M. Ferguson, Andr C. Mller, Andreas Bergthaler, Nathanael S. Gray, James E. Bradner, Christoph Bock, Denes Hnisz, Patrick Cramer, Georg E. Winter

Issue&Volume: 2020-06-01

Abstract: The Mediator complex directs signals from DNA-binding transcription factors to RNA polymerase II (Pol II). Despite this pivotal position, mechanistic understanding of Mediator in human cells remains incomplete. Here we quantified Mediator-controlled Pol II kinetics by coupling rapid subunit degradation with orthogonal experimental readouts. In agreement with a model of condensate-driven transcription initiation, large clusters of hypophosphorylated Pol II rapidly disassembled upon Mediator degradation. This was accompanied by a selective and pronounced disruption of cell-type-specifying transcriptional circuits, whose constituent genes featured exceptionally high rates of Pol II turnover. Notably, the transcriptional output of most other genes was largely unaffected by acute Mediator ablation. Maintenance of transcriptional activity at these genes was linked to an unexpected CDK9-dependent compensatory feedback loop that elevated Pol II pause release rates across the genome. Collectively, our work positions human Mediator as a globally acting coactivator that selectively safeguards the functionality of cell-type-specifying transcriptional networks.

DOI: 10.1038/s41588-020-0635-0

Source: https://www.nature.com/articles/s41588-020-0635-0

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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