1. Chromosomes and Gene Expression
  2. Genetics and Genomics
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PRDM9 activity depends on HELLS and promotes local 5-hydroxymethylcytosine enrichment

  1. Yukiko Imai
  2. Mathilde Biot
  3. Julie Clément
  4. Mariko Teragaki
  5. Serge Urbach
  6. Thomas Robert
  7. Frédéric Baudat
  8. Corinne Grey
  9. Bernard de Massy  Is a corresponding author
  1. National Institute of Genetics, Japan
  2. CNRS UM, France
  3. CNRS INSERM UM, France
Research Article
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Cite this article as: eLife 2020;9:e57117 doi: 10.7554/eLife.57117

Abstract

Meiotic recombination starts with the formation of DNA double-strand breaks (DSBs) at specific genomic locations that correspond to PRDM9 binding sites. The molecular steps occurring from PRDM9 binding to DSB formation are unknown. Using proteomic approaches to find PRDM9 partners, we identified HELLS, a member of the SNF2-like family of chromatin remodelers. Upon functional analyses during mouse male meiosis, we demonstrated that HELLS is required for PRDM9 binding and DSB activity at PRDM9 sites. However, HELLS is not required for DSB activity at PRDM9-independent sites. HELLS is also essential for 5-hydroxymethylcytosine (5hmC) enrichment at PRDM9 sites. Analyses of 5hmC in mice deficient for SPO11, which catalyzes DSB formation, and in PRDM9 methyltransferase deficient mice reveal that 5hmC is triggered at DSB-prone sites upon PRDM9 binding and histone modification, but independent of DSB activity. These findings highlight the complex regulation of the chromatin and epigenetic environments at PRDM9-specified hotspots.

Article and author information

Author details

  1. Yukiko Imai

    Department of Gene Function and Phenomics, National Institute of Genetics, Mishima, Japan
    Competing interests
    No competing interests declared.
  2. Mathilde Biot

    Institute of Human Genetics UMR9002, CNRS UM, Montpellier, France
    Competing interests
    No competing interests declared.
  3. Julie Clément

    Institut de Génétique Humaine, CNRS UM, Montpellier, France
    Competing interests
    No competing interests declared.
  4. Mariko Teragaki

    Institute of Human Genetics UMR9002, CNRS UM, Montpellier, France
    Competing interests
    No competing interests declared.
  5. Serge Urbach

    Institut de Génomique Fonctionnelle, CNRS INSERM UM, Montpellier, France
    Competing interests
    No competing interests declared.
  6. Thomas Robert

    Centre de Biologie Structurale, CNRS INSERM UM, Montpellier, France
    Competing interests
    No competing interests declared.
  7. Frédéric Baudat

    Institute of Human Genetics, CNRS UPR1142, CNRS UM, Montpellier, France
    Competing interests
    No competing interests declared.
  8. Corinne Grey

    Institute of Human Genetics UMR9002, CNRS UM, Montpellier, France
    Competing interests
    No competing interests declared.
  9. Bernard de Massy

    Institute of Human Genetics UMR9002, CNRS UM, Montpellier, France
    For correspondence
    bernard.de-massy@igh.cnrs.fr
    Competing interests
    Bernard de Massy, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0950-2758

Funding

ERC (322788)

  • Bernard de Massy

MSDAVenir (Gene-IGH)

  • Bernard de Massy

Fondation Bettencourt Schueller

  • Bernard de Massy

Fondation pour la Recherche Médicale

  • Mathilde Biot

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

Ethics

Animal experimentation: All experiments were carried out according to the CNRS guidelines and were approved by the ethics committee on live animals (project CE-LR-0812 and 1295).

Reviewing Editor

  1. Adèle L Marston, University of Edinburgh, United Kingdom

Publication history

  1. Received: March 20, 2020
  2. Accepted: September 16, 2020
  3. Accepted Manuscript published: October 13, 2020 (version 1)

Copyright

© 2020, Imai 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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