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DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal

Author

Listed:
  • Paola Cattaneo

    (University of California San Diego
    Milan Unit, National Research Council of Italy
    Goethe University
    German Center for Cardiovascular Research (DZHK), Partner Site Rhein Main)

  • Michael G. B. Hayes

    (University of California San Diego)

  • Nina Baumgarten

    (Goethe University
    German Center for Cardiovascular Research (DZHK), Partner Site Rhein Main)

  • Dennis Hecker

    (Goethe University
    German Center for Cardiovascular Research (DZHK), Partner Site Rhein Main)

  • Sofia Peruzzo

    (Goethe University
    German Center for Cardiovascular Research (DZHK), Partner Site Rhein Main
    Goethe University Frankfurt)

  • Galip S. Aslan

    (Goethe University
    German Center for Cardiovascular Research (DZHK), Partner Site Rhein Main
    Goethe University Frankfurt
    Goethe University)

  • Paolo Kunderfranco

    (IRCCS Humanitas Research Hospital)

  • Veronica Larcher

    (Goethe University
    German Center for Cardiovascular Research (DZHK), Partner Site Rhein Main
    Goethe University Frankfurt)

  • Lunfeng Zhang

    (University of California San Diego)

  • Riccardo Contu

    (University of California San Diego)

  • Gregory Fonseca

    (McGill University)

  • Simone Spinozzi

    (University of California San Diego)

  • Ju Chen

    (University of California San Diego)

  • Gianluigi Condorelli

    (Milan Unit, National Research Council of Italy
    IRCCS Humanitas Research Hospital
    Humanitas University)

  • Stefanie Dimmeler

    (Goethe University
    German Center for Cardiovascular Research (DZHK), Partner Site Rhein Main
    Goethe University Frankfurt)

  • Marcel H. Schulz

    (Goethe University
    German Center for Cardiovascular Research (DZHK), Partner Site Rhein Main
    Goethe University Frankfurt)

  • Sven Heinz

    (University of California San Diego)

  • Nuno Guimarães-Camboa

    (University of California San Diego
    Goethe University
    German Center for Cardiovascular Research (DZHK), Partner Site Rhein Main
    Goethe University Frankfurt)

  • Sylvia M. Evans

    (University of California San Diego
    University of California San Diego)

Abstract

Mechanisms by which specific histone modifications regulate distinct gene networks remain little understood. We investigated how H3K79me2, a modification catalyzed by DOT1L and previously considered a general transcriptional activation mark, regulates gene expression during cardiogenesis. Embryonic cardiomyocyte ablation of Dot1l revealed that H3K79me2 does not act as a general transcriptional activator, but rather regulates highly specific transcriptional networks at two critical cardiogenic junctures: embryonic cardiogenesis, where it was particularly important for left ventricle-specific genes, and postnatal cardiomyocyte cell cycle withdrawal, with Dot1L mutants having more mononuclear cardiomyocytes and prolonged cardiomyocyte cell cycle activity. Mechanistic analyses revealed that H3K79me2 in two distinct domains, gene bodies and regulatory elements, synergized to promote expression of genes activated by DOT1L. Surprisingly, H3K79me2 in specific regulatory elements also contributed to silencing genes usually not expressed in cardiomyocytes. These results reveal mechanisms by which DOT1L successively regulates left ventricle specification and cardiomyocyte cell cycle withdrawal.

Suggested Citation

  • Paola Cattaneo & Michael G. B. Hayes & Nina Baumgarten & Dennis Hecker & Sofia Peruzzo & Galip S. Aslan & Paolo Kunderfranco & Veronica Larcher & Lunfeng Zhang & Riccardo Contu & Gregory Fonseca & Sim, 2022. "DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35070-2
    DOI: 10.1038/s41467-022-35070-2
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    References listed on IDEAS

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    1. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
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    3. Caryn S. Ross-Innes & Rory Stark & Andrew E. Teschendorff & Kelly A. Holmes & H. Raza Ali & Mark J. Dunning & Gordon D. Brown & Ondrej Gojis & Ian O. Ellis & Andrew R. Green & Simak Ali & Suet-Feung C, 2012. "Differential oestrogen receptor binding is associated with clinical outcome in breast cancer," Nature, Nature, vol. 481(7381), pages 389-393, January.
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