Journal
NATURE GENETICS
Volume 52, Issue 7, Pages 719-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-020-0635-0
Keywords
-
Categories
Funding
- Boehringer Ingelheim Fonds PhD fellowship
- International Max Planck Research School for Genome Science, Gottingen Graduate Center for Neurosciences, Biophysics and Molecular Biosciences
- Austrian Science Fund (FWF)
- Medical University of Vienna's joint PhD program in Inflammation and Immunity [FWF1212]
- New Frontiers Group award of the Austrian Academy of Sciences
- ERC Starting Grant (European Union) [679146]
- American Cancer Society Postdoctoral Fellowship [PF-17-010-01-CDD]
- Katherine L. and Steven C. Pinard Research Fund
- Deutsche Forschungsgemeinschaft (DFG) [HN 4/1-1]
- FWF Stand-Alone grant [P31690-B]
- European Research Council (ERC) [679146] Funding Source: European Research Council (ERC)
- Austrian Science Fund (FWF) [P31690] Funding Source: Austrian Science Fund (FWF)
Ask authors/readers for more resources
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. Analysis with alleles encoding pharmacologically degradable Mediator subunits shows that Mediator acts as a global coactivator that facilitates transcription globally but is acutely required for cell-type-specific gene regulatory circuits.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available