RT Journal Article
SR Electronic
T1 Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.06.980912
DO 10.1101/2020.03.06.980912
A1 Stephanie Dobersch
A1 Karla Rubio
A1 Indrabahadur Singh
A1 Stefan Günther
A1 Johannes Graumann
A1 Julio Cordero
A1 Rafael Castillo-Negrete
A1 Minh Bao Huynh
A1 Aditi Mehta
A1 Peter Braubach
A1 Hector Cabrera-Fuentes
A1 Jürgen Bernhagen
A1 Cho-Ming Chao
A1 Saverio Bellusci
A1 Andreas Günther
A1 Klaus T Preissner
A1 Gergana Dobreva
A1 Malgorzata Wygrecka
A1 Thomas Braun
A1 Dulce Papy-Garcia
A1 Guillermo Barreto
YR 2020
UL http://biorxiv.org/content/early/2020/03/08/2020.03.06.980912.abstract
AB 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.