Epigenetic Regulation of Secretome in Duchenne Muscular Dystrophy: role of the Histone Methyltransferase SETDB1 in TGFbeta-induced Fibrosis – EpiMuSe

By employing an efficient method to prepare skeletal myotubes from patient-specific induced pluripotent stem cells (iPSCs) and immortalized myoblasts, we study the molecular mechanisms underlying the TGF?-induced fibrosis in Duchenne Muscular Dystrophy (DMD). Moreover, the signaling pathways controlling fibrosis, and the signals coordinating diverse cell types to maintain or restore muscle tissue homeostasis, remain largely unknown. Since most of the data related to this were generated in mouse models, our system provides a human “disease in a dish” model for the elucidation of the molecular pro-fibrotic determinants in DMD, and identification of new therapeutic targets.

We have identified the WNT-regulated histone H3 lysine 9 lysine methyltransferase SETDB1 (published) as the key factor at the interface of TGF? and WNT signaling (unpublished). SETDB1 is associated with the abnormal TGF? signaling in DMD that can account for muscle dysfunction and fibrosis. Importantly, SETDB1 seems to control the TGF?-dependent pro-fibrotic secretome in DMD muscle. Thus, using our “disease in a dish” model, we will identify new regulators of the TGF?-induced fibrosis and provide unprecedented insight into the epigenetically-regulated cell communication networks linking the diverse muscle resident cell types. The elucidation of an integrated framework of the perturbed signaling events underlying fibrogenesis represents crucial missing information. Findings can potentially be transposed to other fibrotic diseases given the general implication of TGF? and SETDB1 in tissue homeostasis control. Overall, this project has the potential to unravel new therapeutic strategies to treat muscle fibrosis.