CDK9-dependent RNA polymerase II pausing controls transcription initiation

Abstract
Data availability
Article and author information
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Abstract

Gene transcription can be activated by decreasing the duration of RNA polymerase II pausing in the promoter-proximal region, but how this is achieved remains unclear. Here we use a 'multi-omics' approach to demonstrate that the duration of polymerase pausing generally limits the productive frequency of transcription initiation in human cells ('pause-initiation limit'). We further engineer a human cell line to allow for specific and rapid inhibition of the P-TEFb kinase CDK9, which is implicated in polymerase pause release. CDK9 activity decreases the pause duration but also increases the productive initiation frequency. This shows that CDK9 stimulates release of paused polymerase and activates transcription by increasing the number of transcribing polymerases and thus the amount of mRNA synthesized per time. CDK9 activity is also associated with long-range chromatin interactions, suggesting that enhancers can influence the pause-initiation limit to regulate transcription.

Data availability

The following data sets were generated

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2. Schwalb B
3. Decker TM
4. Qin W
5. Leonhardt H
6. Eick D
7. Cramer P
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https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE96056

The following previously published data sets were used

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Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE27584).

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4. Crawford G
5. Giresi P
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https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70408

Article and author information

Author details

Saskia Gressel

Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0261-675X
Björn Schwalb

Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

For correspondence
bjoern.schwalb@mpibpc.mpg.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2987-2622
Tim Michael Decker

Department of Molecular Epigenetics, Helmholtz Center Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Weihua Qin

Department of Biology II, Ludwig-Maximilians-Universität München, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Heinrich Leonhardt

Department of Biology II, Ludwig-Maximilians-Universität München, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Dirk Eick

Department of Molecular Epigenetics, Helmholtz Center Munich, Munich, Germany

For correspondence
eick@helmholtz-muenchen.de

Competing interests
The authors declare that no competing interests exist.
Patrick Cramer

Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

For correspondence
patrick.cramer@mpibpc.mpg.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5454-7755

Funding

European Research Council (TRANSREGULON)

Patrick Cramer

Volkswagen Foundation

Patrick Cramer

Deutsche Forschungsgemeinschaft (SFB 1064 TP A17)

Heinrich Leonhardt

Deutsche Forschungsgemeinschaft (SFB 1064)

Dirk Eick

Max Planck Institute for Biophysical Chemistry (Open-access funding)

Patrick Cramer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.