The histone methyltransferase Whsc1 regulates TGFβ-driven macrophage to myofibroblast transition

Abstract In normal wound healing, macrophages regulate early and late inflammation, allowing for resolution of tissue injury subsequent healing. During repair, undergo transition to myofibroblasts, which promote While this critical is impaired in diabetic wounds, the underlying mechanisms responsible are unknown. Our group others have identified that epigenetic regulation controls their phenotype wounds. Since TGFβ drives macrophage myofibroblast transition, we performed an superarray identify key chromatin modifying enzymes (CD11b+CD3− CD19-NK1.1-Ly6G-) from diet (ND) diabetic-induced obese (DIO) murine wounds treated ex vivo with TGFβ. The histone methyltransferase Whsc1, mediates di- tri-methylation at H3K36, was significantly increased DIO treatment compared ND (p<0.05). siRNA knockdown Whsc1 BMDMs decreased TGFβ-dependent expression fibrotic (Acta2, Col1a1, Col3a1) inflammatory genes (IL-1b, IL-6, IL-12) ChIP experiments, enriched Col1a1 Col3a1 promoters but not BMDMs, inhibited binding as well H3K36me2 H3K36me3 gene promoters. Additionally, were Whsc1-knockdown Col3a1, validating H3K36 regulates expression. These results suggest conversion via a switch repair potentially important therapeutic target F32 DK131799-01, 2022 American College Surgeons Resident Research Scholarship, VESS/Medtronic Award