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  Selective Mediator dependence of cell-type-specifying transcription

Jaeger, M. G., Schwalb, B., Mackowiak, S. D., Velychko, T., Hanzl, A., Imrichova, H., et al. (2020). Selective Mediator dependence of cell-type-specifying transcription. Nature Genetics, In Press. doi:10.1038/s41588-020-0635-0.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-9373-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-937B-A
Genre: Journal Article

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Jaeger, M. G., Author
Schwalb, B.1, Author              
Mackowiak, S. D., Author
Velychko, T.1, Author              
Hanzl, A., Author
Imrichova, H., Author
Brand, M., Author
Agerer, B., Author
Chorn, S., Author
Nabet, B., Author
Ferguson, F. M., Author
Müller, A. C., Author
Bergthaler, A., Author
Gray, N. S., Author
Bradner, J. E., Author
Bock, C., Author
Hnisz, D., Author
Cramer, P.1, Author              
Winter, G. E., Author
Affiliations:
1Department of Molecular Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_1863498              

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Free keywords: Gene expression; Gene regulation; Genetic engineering; Transcriptomics
 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.

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Language(s): eng - English
 Dates: 2020-06-01
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/s41588-020-0635-0
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Title: Nature Genetics
Source Genre: Journal
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Pages: 12 Volume / Issue: - Sequence Number: In Press Start / End Page: - Identifier: -