1. Developmental Biology
  2. Chromosomes and Gene Expression
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Fibroblast growth factors (FGFs) prime the limb specific Shh enhancer for chromatin changes that balance histone acetylation mediated by E26 transformation-specific (ETS) factors

  1. Silvia Peluso
  2. Adam Douglas
  3. Alison Hill
  4. Carlo De Angelis
  5. Benjamin L Moore
  6. Graeme Grimes
  7. Giulia Petrovich
  8. Abdelkader Essafi
  9. Robert E Hill  Is a corresponding author
  1. University of Edinburgh, United Kingdom
  2. University of Bristol, United Kingdom
Research Article
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Cite this article as: eLife 2017;6:e28590 doi: 10.7554/eLife.28590

Abstract

Sonic hedgehog (Shh) expression in the limb bud organizing center called the ZPA is regulated by the ZRS enhancer. Here, we examine in mouse and in a mouse limb-derived cell line the dynamic events that activate and restrict the spatial activity of the ZRS. FGF signalling in the distal limb primes the ZRS at early embryonic stages maintaining a poised, but inactive state broadly across the distal limb mesenchyme. The ETS transcription factor, ETV4, which is induced by FGF signalling and acts as a repressor of ZRS activity, interacts with the histone deacetylase HDAC2 and ensures that the poised ZRS remains transcriptionally inactive. Conversely, GABPα, an activator of the ZRS, recruits p300, which is associated with histone acetylation (H3K27ac) indicative of an active enhancer. Hence, the primed but inactive state of the ZRS is induced by FGF signalling and in combination with balanced histone modification events establishes the restricted, active enhancer responsible for patterning the limb bud during development.

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Author details

  1. Silvia Peluso

    MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1803-5300

  2. Adam Douglas

    MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Alison Hill

    MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Carlo De Angelis

    MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Benjamin L Moore

    MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4074-1933

  6. Graeme Grimes

    MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  7. Giulia Petrovich

    MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  8. Abdelkader Essafi

    School of Cellular and Molecular Medicine, Faculty of Biomedical Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  9. Robert E Hill

    MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    Bob.hill@igmm.ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2848-1080

Funding

Medical Research Council

  • Silvia Peluso
  • Adam Douglas
  • Alison Hill
  • Carlo De Angelis
  • Benjamin L Moore
  • Graeme Grimes
  • Giulia Petrovich
  • Abdelkader Essafi
  • Robert E Hill

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

Ethics

Animal experimentation: Experiments using mice were conducted in accordance with the UK Animals (Scientific Procedures) Act 1986, with appropriate personal and project licences in place.

Reviewing Editor

  1. Lee Niswander, University of Colorado Anschutz Medical Campus, United States

Publication history

  1. Received: May 12, 2017
  2. Accepted: September 25, 2017
  3. Accepted Manuscript published: September 26, 2017 (version 1)
  4. Version of Record published: October 27, 2017 (version 2)

Copyright

© 2017, Peluso 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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