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

Autor: Karla Rubio, Saverio Bellusci, C.-M. Chao, Thomas Braun, Malgorzata Wygrecka, Julio Cordero, M. B. Huynh, K. Preissner, Rafael Castillo-Negrete, Andreas Guenther, Hector A. Cabrera-Fuentes, Guillermo Barreto, Indrabahadur Singh, Stephanie Dobersch, Dulce Papy-Garcia, Stefan Guenther, Johannes Graumann, Gergana Dobreva, Jürgen Bernhagen, Aditi Mehta, P. Bruabach
Přispěvatelé: Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute for Heart and Lung Research (MPI-HLR), Max-Planck-Gesellschaft, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Medical Faculty [Mannheim], Ludwig-Maximilians-Universität München (LMU), Hannover Medical School [Hannover] (MHH), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), National Heart Centre Singapore (NHCS), Tecnológico de Monterrey (ITESM), Duke-National University of Singapore Graduate Medical School, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Wenzhou Medical University [Wenzhou, China] (WMU)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
[SDV]Life Sciences [q-bio]
General Physics and Astronomy
Ataxia Telangiectasia Mutated Proteins
Histones
chemistry.chemical_compound
Mice
Phosphoserine
0302 clinical medicine
Transcription (biology)
Histone post-translational modifications
Phosphorylation
Transcription Initiation
Genetic
Histone variants
0303 health sciences
Multidisciplinary
biology
Chemistry
030302 biochemistry & molecular biology
Hmg protein
Chromatin
3. Good health
Cell biology
Nucleosomes
DNA Demethylation
Histone
DNA methylation
Epigenetics
RNA Polymerase II
Transcription Initiation Site
Transcriptional Activation
DNA repair
Science
Chromatin structure
General Biochemistry
Genetics and Molecular Biology
Article
Transforming Growth Factor beta1
03 medical and health sciences
Nucleosome
Animals
Humans
030304 developmental biology
HMGA2 Protein
General Chemistry
Idiopathic Pulmonary Fibrosis
030104 developmental biology
DNA demethylation
HEK293 Cells
biology.protein
030217 neurology & neurosurgery
DNA
Zdroj: Nature Communications
Nature Communications, Nature Publishing Group, 2021, 12 (1), ⟨10.1038/s41467-021-21227-y⟩
Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.1072. ⟨10.1038/s41467-021-21227-y⟩
Nature Communications, Vol 12, Iss 1, Pp 1-20 (2021)
ISSN: 2041-1723
DOI: 10.1038/s41467-021-21227-y⟩
Popis: 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.
The order of DNA methylation and histone modifications during transcription remained unclear. Here the authors show that HMGA2 induces DNA nicks at TGFB1-responsive genes, promoting nucleosome incorporation containing γ-H2AX, which is required for repair-mediated DNA demethylation and transcription.
Databáze: OpenAIRE
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