HMGA2 mediated epigenetic regulation of Gata6 controls epithelial WNT signaling during lung development

Organ regeneration requires a proper balance between self-renewal and differentiation of tissue specific progenitor cells. Progenitor expansion and differentiation recapitulate many of the mechanisms regulating embryonic development. Here, we uncovered the role of the high mobility group AT-hook protein 2 (HMGA2) as a key regulator of epithelial differentiation during embryonic lung development. Hmga2 loss-of-function increased WNT signaling resulting not only in defective epithelial differentiation but also expansion of progenitors in the developing lung. We found that HMGA2 direct regulation of Gata6 is crucial in fine-tuning WNT signaling in airway epithelium. Furthermore, we combined proteomic, ChIP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 (H2AXS139ph; γ-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). The interplay between HMGA2, ATM, and H2AX is a novel mechanism of transcription initiation. Our results also link H2AXS139ph to transcription, assigning a new function for this DNA damage marker. Together, our data demonstrate that HMGA2-mediated changes in chromatin structure regulate WNT signaling and control the balance between progenitor expansion and differentiation required for proper lung development. Ref: Singh I, et al., (2015) Cell Research; Jul;25(7):837-50 Singh I, et al., (2014) BMC Biol; Mar 24;12:21 Ozturk N, Singh I, et al., (2014) Front Cell Dev Biol.; Mar 6;2:5