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Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation

Author

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  • Stephanie Dobersch

    (Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE)
    Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research
    Human Biology Division, Fred Hutchinson Cancer Research Center)

  • Karla Rubio

    (Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE)
    Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research
    UMR 7365 CNRS-Université de Lorraine, Biopôle de l’Université de Lorraine, Campus Biologie-Santé, Faculté de Médecine
    Universidad de la Salud del Estado de Puebla)

  • Indrabahadur Singh

    (Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research
    Emmy Noether Research Group Epigenetic Machineries and Cancer, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ))

  • Stefan Günther

    (ECCPS Bioinformatics and Deep Sequencing Platform
    Max-Planck-Institute for Heart and Lung Research)

  • Johannes Graumann

    (Biomolecular Mass Spectrometry, Max-Planck-Institute for Heart and Lung Research)

  • Julio Cordero

    (Anatomy and Developmental Biology, CBTM
    Heidelberg University)

  • Rafael Castillo-Negrete

    (Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE)
    Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research)

  • Minh Bao Huynh

    (Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), F-)

  • Aditi Mehta

    (Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research
    Ludwig-Maximilians-University (LMU) Munich)

  • Peter Braubach

    (Institute for Pathology, Hannover Medical School
    Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) Research Network)

  • Hector Cabrera-Fuentes

    (Justus Liebig University
    National Heart Research Institute, National Heart Centre Singapore
    Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA
    Duke-National University of Singapore Medical School)

  • Jürgen Bernhagen

    (Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich
    Munich Cluster for Systems Neurology (SyNergy))

  • Cho-Ming Chao

    (Cardio-Pulmonary Institute
    International Collaborative Center on Growth Factor Research, School of Pharmaceutical Sciences, Wenzhou Medical University and Institute of Life Sciences, Wenzhou University
    Member of the Universities of Giessen and Marburg Lung Center (UGMLC)
    German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL))

  • Saverio Bellusci

    (Cardio-Pulmonary Institute
    International Collaborative Center on Growth Factor Research, School of Pharmaceutical Sciences, Wenzhou Medical University and Institute of Life Sciences, Wenzhou University
    Member of the Universities of Giessen and Marburg Lung Center (UGMLC)
    German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL))

  • Andreas Günther

    (Member of the Universities of Giessen and Marburg Lung Center (UGMLC)
    German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL)
    Justus Liebig University
    Agaplesion Lung Clinic Waldhof Elgershausen)

  • Klaus T. Preissner

    (Justus Liebig University
    Member of the Universities of Giessen and Marburg Lung Center (UGMLC))

  • Sita Kugel

    (Human Biology Division, Fred Hutchinson Cancer Research Center)

  • Gergana Dobreva

    (Anatomy and Developmental Biology, CBTM
    Heidelberg University)

  • Malgorzata Wygrecka

    (Member of the Universities of Giessen and Marburg Lung Center (UGMLC)
    German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL)
    Universities Giessen and Marburg Lung Center)

  • Thomas Braun

    (Max-Planck-Institute for Heart and Lung Research
    Member of the Universities of Giessen and Marburg Lung Center (UGMLC))

  • Dulce Papy-Garcia

    (Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), F-)

  • Guillermo Barreto

    (Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE)
    Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research
    UMR 7365 CNRS-Université de Lorraine, Biopôle de l’Université de Lorraine, Campus Biologie-Santé, Faculté de Médecine
    Universidad de la Salud del Estado de Puebla)

Abstract

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.

Suggested Citation

  • Stephanie Dobersch & Karla Rubio & Indrabahadur Singh & Stefan Günther & Johannes Graumann & Julio Cordero & Rafael Castillo-Negrete & Minh Bao Huynh & Aditi Mehta & Peter Braubach & Hector Cabrera-Fu, 2021. "Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21227-y
    DOI: 10.1038/s41467-021-21227-y
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    Cited by:

    1. Naohiro Kuwayama & Tomoya Kujirai & Yusuke Kishi & Rina Hirano & Kenta Echigoya & Lingyan Fang & Sugiko Watanabe & Mitsuyoshi Nakao & Yutaka Suzuki & Kei-ichiro Ishiguro & Hitoshi Kurumizaka & Yukiko , 2023. "HMGA2 directly mediates chromatin condensation in association with neuronal fate regulation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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