Role of Histone H3 Lysine 9 (H3K9) methyltransferases G9a and GLP in the epigenetic regulation of Fibroadipogenic progenitors (FAPs) differentiation during Duchenne Muscular Dystrophy (DMD) progression

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular degenerative disorder that leads to progressive muscle weakness. This is due to loss of muscle tissue that culminates with its replacement with fat and fibrotic infiltrates, in coincidence with the final stages of disease. Despite recent progresses in genome editing approaches have demonstrated the possibility to correct the genetic defect in vivo, the cure for DMD is still a big challenge. Therefore, pharmacological therapies aimed to counteract the fibro-adipogenic degeneration and to promote the compensatory regeneration that is typical of the early stages of disease hold great promise to slow-down DMD progression. Fibroadipogenic progenitors, FAPs, have been shown to be responsible of fat and fibrotic tissue deposition in degenerating dystrophic muscles, while also contributing to muscle regeneration at early stages of the disease.1,2 As such, understanding the molecular basis of FAP’s differentiation might reveal possible pharmacological targets to manipulate their phenotypical plasticity in vivo, with the ultimate goal to promote muscle regeneration and concomitantly block fibro-adipogenic degeneration. Our results and data from the literature suggest that methylation of Lysine 9 of histone H3 (H3K9) by specific methyltransferases (KMTs), is one of the epigenetic pathway involved in the control of FAPs’ alternative fates. In particular, among the different H3K9 KMTs, the mono- and di- methyltransferases G9a and GLP are of particular relevance in controlling the repression of muscle-specific genes in myogenic precursors,3,4 and likely in FAPs. In fact, our preliminary data show that the in vitro inhibition of H3K9 KMTs in FAPs from mdx mice (the DMD murine model) induces myogenic differentiation at expenses of their adipogenic potential. We show here that FAPs isolated from injured wild type mice treated in vivo with G9a/GLP specific inhibitors display increased expression of myogenic markers and de- regulation of fibroadipogenic genes. Taken together, our results suggest that H3K9 KMTs inhibitors could promote the myogenic potential of muscle progenitor cells and might become a potential new therapeutic approach in the treatment of DMD.