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CDK9-dependent RNA polymerase II pausing controls transcription initiation

  1. Saskia Gressel
  2. Björn Schwalb  Is a corresponding author
  3. Tim Michael Decker
  4. Weihua Qin
  5. Heinrich Leonhardt
  6. Dirk Eick  Is a corresponding author
  7. Patrick Cramer  Is a corresponding author
  1. Max Planck Institute for Biophysical Chemistry, Germany
  2. Helmholtz Center Munich, Germany
  3. Ludwig-Maximilians-Universität München, Germany
Research Article
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Cite this article as: eLife 2017;6:e29736 doi: 10.7554/eLife.29736

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.

Article and author information

Author details

  1. Saskia Gressel

    Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0261-675X
  2. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2987-2622
  3. Tim Michael Decker

    Department of Molecular Epigenetics, Helmholtz Center Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Weihua Qin

    Department of Biology II, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Heinrich Leonhardt

    Department of Biology II, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. 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.
  7. 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.
    ORCID icon "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.

Reviewing Editor

  1. Katherine A Jones, Salk Institute for Biological Studies, United States

Publication history

  1. Received: June 19, 2017
  2. Accepted: October 6, 2017
  3. Accepted Manuscript published: October 10, 2017 (version 1)
  4. Version of Record published: November 3, 2017 (version 2)

Copyright

© 2017, Gressel et al.

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.

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