High Mobility Group protein mediated transcription requires DNA damage marker γ-H2AX

The eukaryotic genome is organized into chromatin, which constitutes the physiological template for DNA-dependent processes including replication, recombination, repair and transcription. Chromatin mediated transcription regulation involves histone modifications, chromatin remodeling and DNA methylation. However, the precise biological function of non-histone chromatin-associated proteins is still unclear. The high mobility group proteins are the most abundant non-histone chromatin-associated proteins. Here we combined proteomic, ChIP-seq and transcriptome data to decipher the mechanism of transcriptional regulation mediated by the high mobility group AT-hook protein 2 (HMGA2). We showed that HMGA2-induced transcription requires H2AX phosphorylation at S139 (H2AXS139ph; γ-H2AX), mediated by the kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrated the relevance of this mechanism within the biological context of TGFB1-signaling. Our results link H2AXS139ph, a marker for DNA damage, to transcription, which is a new function for this histone modification. The interplay between HMGA2, ATM and H2AX is a novel mechanism of transcription initiation. Chip-seq data of HMGA2, H2AXS139ph and ATM obtained from Mouse embryonic Fibroblast cells in wt and Ko of Hmga2