細胞類型特異性轉錄選擇性依賴中介體
作者：
小柯機器人發布時間：2020/6/2 20:47:09
奧地利科學院Georg E. Winter、德國馬普所Patrick Cramer等研究人員合作發現，細胞類型特異性轉錄選擇性依賴中介體。2020年6月1日，《自然—遺傳學》在線發表了這一成果。
研究人員通過耦合快速亞基降解與正交實驗讀數來量化了中介體調控的RNA聚合酶II（Pol II）動力學。與相分離驅動的轉錄起始模型相一致，在中介體降解後，大量低磷酸化的Pol II簇迅速分解。這伴隨著細胞類型特異性轉錄迴路的選擇性顯著破壞。
值得注意的是，大多數其他基因的轉錄輸出在很大程度上不受急性中介體敲低的影響。這些基因轉錄活性的維持與依賴CDK9的補償性反饋迴路有關，進而提高了基因組中Pol II暫停釋放的速率。
總的來說，這些工作將人類中介體定位為一種全局性的共激活因子，可以選擇性地保護細胞類型特定的轉錄網絡功能。
據悉，中介體複合物利用DNA結合轉錄因子的信號來指導Pol II。儘管處於這一關鍵位置，但對人體細胞中介體的機制理解仍然不完整。
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