Dual histone methyl reader ZCWPW1 facilitates repair of meiotic double strand breaks in male mice

  1. Mohamed Mahgoub
  2. Jacob Paiano
  3. Melania Bruno
  4. Wei Wu
  5. Sarath Pathuri
  6. Xing Zhang
  7. Sherry Ralls
  8. Xiaodong Cheng
  9. André Nussenzweig
  10. Todd S Macfarlan  Is a corresponding author
  1. The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, United States
  2. National Cancer Institute, NIH, United States
  3. University of Texas MD Anderson Cancer Center, United States

Abstract

Meiotic crossovers result from homology-directed repair of DNA double-strand breaks (DSBs). Unlike yeast and plants, where DSBs are generated near gene promoters, in many vertebrates DSBs are enriched at hotspots determined by the DNA binding activity of the rapidly evolving zinc finger array of PRDM9 (PR domain zinc finger protein 9). PRDM9 subsequently catalyzes tri-methylation of lysine 4 and lysine 36 of Histone H3 in nearby nucleosomes. Here, we identify the dual histone methylation reader ZCWPW1, which is tightly co-expressed during spermatogenesis with Prdm9, as an essential meiotic recombination factor required for efficient repair of PRDM9-dependent DSBs and for pairing of homologous chromosomes in male mice. In sum, our results indicate that the evolution of a dual histone methylation writer/reader (PRDM9/ZCWPW1) system in vertebrates remodeled genetic recombination hotspot selection from an ancestral static pattern near genes towards a flexible pattern controlled by the rapidly evolving DNA binding activity of PRDM9.

Data availability

All data have been deposited to GEO with the accession number GSE139289.

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

Article and author information

Author details

  1. Mohamed Mahgoub

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jacob Paiano

    Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Melania Bruno

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8401-7744
  4. Wei Wu

    Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sarath Pathuri

    Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xing Zhang

    Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sherry Ralls

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiaodong Cheng

    Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. André Nussenzweig

    Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8952-7268
  10. Todd S Macfarlan

    The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, NIH, Bethesda, United States
    For correspondence
    todd.macfarlan@nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2495-9809

Funding

National Institutes of Health (1ZIAHD008933)

  • Todd S Macfarlan

National Institutes of Health (GM114306)

  • Xiaodong Cheng

National Institutes of Health (CPRIT RR160029)

  • Xiaodong Cheng

National Institutes of Health (Intramural Research Program)

  • André Nussenzweig

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

Reviewing Editor

  1. Bernard de Massy, CNRS UM, France

Ethics

Animal experimentation: All mice experiments were done in accordance with NIH approved animal study protocol (ASP18-026).

Version history

  1. Received: November 6, 2019
  2. Accepted: April 29, 2020
  3. Accepted Manuscript published: April 30, 2020 (version 1)
  4. Version of Record published: May 19, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Mohamed Mahgoub
  2. Jacob Paiano
  3. Melania Bruno
  4. Wei Wu
  5. Sarath Pathuri
  6. Xing Zhang
  7. Sherry Ralls
  8. Xiaodong Cheng
  9. André Nussenzweig
  10. Todd S Macfarlan
(2020)
Dual histone methyl reader ZCWPW1 facilitates repair of meiotic double strand breaks in male mice
eLife 9:e53360.
https://doi.org/10.7554/eLife.53360

Share this article

https://doi.org/10.7554/eLife.53360

Further reading

    1. Cell Biology
    2. Genetics and Genomics
    Tao Huang, Shenli Yuan ... Hongbin Liu
    Research Article Updated

    The histone modification writer Prdm9 has been shown to deposit H3K4me3 and H3K36me3 at future double-strand break (DSB) sites during the very early stages of meiosis, but the reader of these marks remains unclear. Here, we demonstrate that Zcwpw1 is an H3K4me3 reader that is required for DSB repair and synapsis in mouse testes. We generated H3K4me3 reader-dead Zcwpw1 mutant mice and found that their spermatocytes were arrested at the pachytene-like stage, which phenocopies the Zcwpw1 knock–out mice. Based on various ChIP-seq and immunofluorescence analyses using several mutants, we found that Zcwpw1's occupancy on chromatin is strongly promoted by the histone-modification activity of PRDM9. Zcwpw1 localizes to DMC1-labelled hotspots in a largely Prdm9-dependent manner, where it facilitates completion of synapsis by mediating the DSB repair process. In sum, our study demonstrates the function of ZCWPW1 that acts as part of the selection system for epigenetics-based recombination hotspots in mammals.

    1. Genetics and Genomics
    Mathilde Biot, Bernard de Massy
    Insight

    Three independent studies show that a protein called ZCWPW1 is able to recognize the histone modifications that initiate the recombination of genetic information during meiosis.