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Title: Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation
Authors: Dobersch, Stephanie
Rubio, Karla
Singh, Indrabahadur
Günther, Stefan
Graumann, Johannes
Cordero, Julio
Castillo-Negrete, Rafael
Huynh, Minh Bao
Mehta, Aditi
Braubach, Peter
Cabrera-Fuentes, Hector 
Bernhagen, Jurgen
Chao, Cho-Ming
Bellusci, Saverio
Günther, Andreas
Preissner, Klaus T.
Kugel, Sita
Dobreva, Gergana
Wygrecka, Malgorzata
Braun, Thomas
Papy-Garcia, Dulce
Barreto, Guillermo
Issue Date: 16-Feb-2021
Publisher: Nature Research
Citation: Dobersch, Stephanie, Rubio, Karla, Singh, Indrabahadur, Günther, Stefan, Graumann, Johannes, Cordero, Julio, Castillo-Negrete, Rafael, Huynh, Minh Bao, Mehta, Aditi, Braubach, Peter, Cabrera-Fuentes, Hector, Bernhagen, Jurgen, Chao, Cho-Ming, Bellusci, Saverio, Günther, Andreas, Preissner, Klaus T., Kugel, Sita, Dobreva, Gergana, Wygrecka, Malgorzata, Braun, Thomas, Papy-Garcia, Dulce, Barreto, Guillermo (2021-02-16). Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation. Nature Communications 12 (1) : 1072. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. © 2021, The Author(s).
Source Title: Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-021-21227-y
Rights: Attribution 4.0 International
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