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

Stephanie Dobersch, Karla Rubio, Indrabahadur Singh, Stefan Günther, Johannes Graumann, Julio Cordero, Rafael Castillo-Negrete, Minh Bao Huynh, Aditi Mehta, Peter Braubach, Hector Cabrera-Fuentes, Jürgen Bernhagen, Cho-Ming Chao, Saverio Bellusci, Andreas Günther, Klaus T. Preissner, Sita Kugel, Gergana Dobreva, Malgorzata Wygrecka, Thomas Braun, Dulce Papy-Garcia and Guillermo Barreto ()
Additional contact information
Stephanie Dobersch: Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE)
Karla Rubio: Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE)
Indrabahadur Singh: Lung Cancer Epigenetic, Max-Planck-Institute for Heart and Lung Research
Stefan Günther: ECCPS Bioinformatics and Deep Sequencing Platform
Johannes Graumann: Biomolecular Mass Spectrometry, Max-Planck-Institute for Heart and Lung Research
Julio Cordero: Anatomy and Developmental Biology, CBTM
Rafael Castillo-Negrete: Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Brain and Lung Epigenetics (BLUE)
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
Peter Braubach: Institute for Pathology, Hannover Medical School
Hector Cabrera-Fuentes: Justus Liebig University
Jürgen Bernhagen: Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich
Cho-Ming Chao: Cardio-Pulmonary Institute
Saverio Bellusci: Cardio-Pulmonary Institute
Andreas Günther: Member of the Universities of Giessen and Marburg Lung Center (UGMLC)
Klaus T. Preissner: Justus Liebig University
Sita Kugel: Human Biology Division, Fred Hutchinson Cancer Research Center
Gergana Dobreva: Anatomy and Developmental Biology, CBTM
Malgorzata Wygrecka: Member of the Universities of Giessen and Marburg Lung Center (UGMLC)
Thomas Braun: Max-Planck-Institute for Heart and Lung Research
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)

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21227-y

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