2. Academic Validation
  3. Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation

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

  • Nat Commun. 2021 Feb 16;12(1):1072. doi: 10.1038/s41467-021-21227-y.
Stephanie Dobersch 1 2 3,  Karla Rubio 1 2 4 5,  Indrabahadur Singh 2 6,  Stefan Günther 7 8,  Johannes Graumann 9,  Julio Cordero 10 11,  Rafael Castillo-Negrete 1 2,  Minh Bao Huynh 12,  Aditi Mehta 2 13,  Peter Braubach 14 15,  Hector Cabrera-Fuentes 16 17 18 19,  Jürgen Bernhagen 20 21,  Cho-Ming Chao 22 23 24 25,  Saverio Bellusci 22 23 24 25,  Andreas Günther 24 25 26 27,  Klaus T Preissner 16 24,  Sita Kugel 3,  Gergana Dobreva 10 11,  Malgorzata Wygrecka 24 25 28,  Thomas Braun 8 24,  Dulce Papy-Garcia 12,  Guillermo Barreto 29 30 31 32 33 34
Affiliations

Affiliations

  • 1 Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE), Creteil, France.
  • 2 Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 3 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 4 Laboratoire IMoPA, UMR 7365 CNRS-Université de Lorraine, Biopôle de l'Université de Lorraine, Campus Biologie-Santé, Faculté de Médecine, Vandœuvre-lès-Nancy Cedex, France.
  • 5 International Laboratory EPIGEN, Universidad de la Salud del Estado de Puebla, Puebla, Mexico.
  • 6 Emmy Noether Research Group Epigenetic Machineries and Cancer, Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 7 ECCPS Bioinformatics and Deep Sequencing Platform, Bad Nauheim, Germany.
  • 8 Department of Cardiac Development, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 9 Biomolecular Mass Spectrometry, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 10 Anatomy and Developmental Biology, CBTM, Mannheim, Germany.
  • 11 European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • 12 Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), F-, Creteil, France.
  • 13 Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • 14 Institute for Pathology, Hannover Medical School, Hanover, Germany.
  • 15 Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) Research Network, Hanover, Germany.
  • 16 Faculty of Medicine, Department of Biochemistry, Justus Liebig University, Giessen, Germany.
  • 17 National Heart Research Institute, National Heart Centre Singapore, Singapore, Singapore.
  • 18 Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Monterrey, Mexico.
  • 19 Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
  • 20 Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • 21 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 22 Cardio-Pulmonary Institute, Giessen, Germany.
  • 23 International Collaborative Center on Growth Factor Research, School of Pharmaceutical Sciences, Wenzhou Medical University and Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang, China.
  • 24 Member of the Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany.
  • 25 German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Giessen, Germany.
  • 26 Pulmonary and Critical Care Medicine, Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
  • 27 Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, Germany.
  • 28 Center for Infection and Genomics of the Lung (CIGL), Universities Giessen and Marburg Lung Center, Giessen, Germany.
  • 29 Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE), Creteil, France. guillermo.barreto@u-pec.fr.
  • 30 Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany. guillermo.barreto@u-pec.fr.
  • 31 Laboratoire IMoPA, UMR 7365 CNRS-Université de Lorraine, Biopôle de l'Université de Lorraine, Campus Biologie-Santé, Faculté de Médecine, Vandœuvre-lès-Nancy Cedex, France. guillermo.barreto@u-pec.fr.
  • 32 International Laboratory EPIGEN, Universidad de la Salud del Estado de Puebla, Puebla, Mexico. guillermo.barreto@u-pec.fr.
  • 33 Member of the Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany. guillermo.barreto@u-pec.fr.
  • 34 German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Giessen, Germany. guillermo.barreto@u-pec.fr.
PMID: 33594057 DOI: 10.1038/s41467-021-21227-y
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.

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