A high-resolution map of transcriptional repression

  1. Ziwei Liang
  2. Karen Brown
  3. Thomas Carroll
  4. Benjamin Taylor
  5. Isabel Ferreirós Vidal
  6. Brian Hendrich
  7. David Rueda
  8. Amanda G Fisher
  9. Matthias Merkenschlager  Is a corresponding author
  1. MRC London Institute of Medical Sciences, United Kingdom
  2. Wellcome Trust - Medical Research Council Stem Cell Institute, United Kingdom

Abstract

Turning genes on and off is essential for development and homeostasis, yet little is known about the sequence and causal role of chromatin state changes during the repression of active genes. This is surprising, as defective gene silencing underlies developmental abnormalities and disease. Here we delineate the sequence and functional contribution of transcriptional repression mechanisms at high temporal resolution. Inducible entry of the NuRD-interacting transcriptional regulator Ikaros into mouse pre-B cell nuclei triggered immediate binding to target gene promoters. Rapid RNAP2 eviction, transcriptional shutdown, nucleosome invasion, and reduced transcriptional activator binding required chromatin remodeling by NuRD-associated Mi2beta/CHD4, but were independent of HDAC activity. Histone deacetylation occurred after transcriptional repression. Nevertheless, HDAC activity contributed to stable gene silencing. Hence, high resolution mapping of transcriptional repression reveals complex and interdependent mechanisms that underpin rapid transitions between transcriptional states, and elucidates the temporal order, functional role and mechanistic separation of NuRD-associated enzymatic activities.

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The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ziwei Liang

    Lymphocyte Development Group, MRC London Institute of Medical Sciences, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Karen Brown

    Lymphocyte Development Group, MRC London Institute of Medical Sciences, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Thomas Carroll

    Epigenetics Section, MRC London Institute of Medical Sciences, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Benjamin Taylor

    Lymphocyte Development Group, MRC London Institute of Medical Sciences, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6101-3786
  5. Isabel Ferreirós Vidal

    Lymphocyte Development Group, MRC London Institute of Medical Sciences, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Brian Hendrich

    Wellcome Trust - Medical Research Council Stem Cell Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0231-3073
  7. David Rueda

    Single Molecule Imaging Group, MRC London Institute of Medical Sciences, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Amanda G Fisher

    Lymphocyte Development Group, MRC London Institute of Medical Sciences, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Matthias Merkenschlager

    Lymphocyte Development Group, MRC London Institute of Medical Sciences, London, United Kingdom
    For correspondence
    matthias.merkenschlager@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2889-3288

Funding

Medical Research Council (MC-A652-5PY20)

  • David Rueda
  • Amanda G Fisher
  • Matthias Merkenschlager

Wellcome (099276/Z/12/Z)

  • Matthias Merkenschlager

UK-China Scholarships for Excellence

  • Ziwei Liang

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

Reviewing Editor

  1. David N Arnosti, Michigan State University, United States

Publication history

  1. Received: October 28, 2016
  2. Accepted: March 15, 2017
  3. Accepted Manuscript published: March 20, 2017 (version 1)
  4. Version of Record published: March 30, 2017 (version 2)

Copyright

© 2017, Liang 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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  1. Ziwei Liang
  2. Karen Brown
  3. Thomas Carroll
  4. Benjamin Taylor
  5. Isabel Ferreirós Vidal
  6. Brian Hendrich
  7. David Rueda
  8. Amanda G Fisher
  9. Matthias Merkenschlager
(2017)
A high-resolution map of transcriptional repression
eLife 6:e22767.
https://doi.org/10.7554/eLife.22767

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