Open AccessSelective Mediator dependence of cell-type-specifying transcription
Author(s) -
Martin G. Jaeger,
Björn Schwalb,
Sebastian D. Mackowiak,
Taras Velychko,
Alexander Hanzl,
Hana Imrichová,
Matthias Brand,
Benedikt Agerer,
Someth Chorn,
Behnam Nabet,
Fleur M. Ferguson,
André C. Müller,
Andréas Bergthaler,
Nathanael S. Gray,
James E. Bradner,
Christoph Bock,
Denes Hnisz,
Patrick Cramer,
Georg E. Winter
Publication year - 2020
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-020-0635-0
Subject(s) - mediator , rna polymerase ii , coactivator , biology , transcription (linguistics) , transcriptional regulation , microbiology and biotechnology , gene , protein subunit , promoter , transcription factor , genetics , gene expression , linguistics , philosophy
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.