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

Stephanie Dobersch, et al.

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Received Date: 31st March 20

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, Gergana Dobreva, Malgorzata Wygrecka, Thomas Braun, Dulce Papy-Garcia, Guillermo Barreto

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) 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 HMG proteins during transcription initiation remain unclear. Here we show that HMG AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT (facilitates chromatin transcription) 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 that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure the integrity of the genome.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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