Organ regeneration requires a proper balance between self-renewal and differentiation of tissuespecific progenitor cells. Progenitor cell expansion and differentiation recapitulate many of the mechanisms regulating embryonic development. The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. They are present at high levels in various undifferentiated tissues during embryonic development and their levels are strongly reduced in the corresponding adult tissues, where they have been implicated in maintaining and activating stem/progenitor cells. Here, this study uncovered the role of the high mobility group AT-hook protein 2 (HMGA2) as a key regulator of branching morphogenesis and epithelial differentiation during embryonic lung development as well as in adult lung. Detailed analysis of the Hmga2 knockout (Hmga2-/-, KO) mice together with in vitro Hmga2 loss-of-function (LOF) experiments revealed enhanced canonical WNT signaling resulting not only in defective lung epithelial differentiation but also in increased numbers of bronchioalveolar stem cells (BASCs). Increased numbers of progenitor cells in the lung of Hmga2-/- mice generated an imbalance in cell differentiation that is reflected in a reduction of alveolar type II (ATII) cells, thereby affecting both lung morphology as well as lung functionality. It also showed that HMGA2 directly regulates Gata6 which is crucial for fine-tuning canonical WNT signaling in airway epithelium.In addition, this study deciphered the molecular mechanism of transcriptional activation mediated by HMGA2. It showed that Hmga2-induced transcriptional activation of Gata6 requires phosphorylation of the linker histone H1 at S65 (H1S65ph) and the core histone variant H2AX at S139 (H2AXS139ph), both mediated by the kinase, ataxia telangiectasia mutated (ATM). It also demonstrated the sequential order of events in which H1S65ph precedes H2AXS139ph and both are a prerequisite for the subsequent disassembly of promoter-associated nucleosomes and transcriptional activation. The functional interplay between HMGA2, ATM, H1 and H2AX is a novel mechanism of transcription initiation.Together, this data demonstrate that HMGA2-mediated changes in chromatin structure regulate canonical WNT signaling and control the balance between progenitor cells expansion and differentiation required for both lung development and homeostasis.
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