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

Dobersch, Stephanie; Rubio, Karla; Singh, Indrabahadur; Guenther, Stefan; Graumann, Johannes; Cordero, Julio; Castillo-Negrete, Rafael; Huynh, Minh Bao; Mehta, Aditi; Braubach, Peter; Cabrera-Fuentes, Hector; Bernhagen, Jürgen; Chao, Cho-Ming; Bellusci, Saverio; Guenther, Andreas; Preissner, Klaus T.; Kugel, Sita; Dobreva, Gergana; Wygrecka, Malgorzata; Braun, Thomas; Papy-Garcia, Dulce und Barreto, Guillermo (2021): Positioning of nucleosomes containing gamma-H2AX precedes active DNA demethylation and transcription initiation. In: Nature Communications, Bd. 12, Nr. 1, 1072

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 (gamma -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 gamma -H2AX, which is required for repair-mediated DNA demethylation and transcription.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department für Pharmazie - Zentrum für Pharmaforschung ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 2041-1723
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198