Lysines Methyltransferases (KMTs) have recently raised increased interest as potential targets of therapeutic value thanks to the possibility to revert aberrant epigenetic states associated with human diseases. KMTs catalyzing mono-and di-methylation of lysine 9 on histone 3 (H3K9me1/2) are typically involved in gene repression and heterochromatin formation. In the context of muscle differentiation, the H3K9 KMTs G9a and GLP are emerging as critical epigenetic modulators able to maintain the repression of muscle-specific genes in embryonic precursors and in myoblasts, therefore preventing their premature differentiation.1,2 Our preliminary data suggest that H3K9 KMTs are also involved in the epigenetic control of lineage choice of a population of muscle-resident mesenchymal stem cells, called fibro- adipogenic progenitors (FAPs). FAPs play key roles in Duchenne Muscular Dystrophy (DMD) by both supporting the myogenic differentiation of muscle stem cells in the regenerating phase or by contributing to fibrosis and fat deposition in advanced stages of disease.3,4 However, the molecular regulation governing their lineage determination is largely unknown. We show here that pharmacological inhibition of G9a/GLP, by the use of its specific inhibitor (UNC0642), induce a FAPs’ lineage switch. Indeed, FAPs isolated from young dystrophic (mdx) mice, cultured ex vivo in the presence of UNC0642 unmask a myogenic potential, as suggested by the appearance of MyoD positive cells and increased expression of myogenic genes. This is paralleled by an impaired adipogenic differentiation, as confirmed by a decreased number of FAPs-derived adipocytes, upon UNC0642 treatment. In sum, our preliminary evidence suggest that the H3K9 KMTs G9a/GLP might be involved in maintaining silent the capacity of FAPs to give rise to myogenic cells and indicate these proteins as possible
pharmacological targets for therapeutic approaches aimed to promote regeneration, and to prevent fibro-adipogenic degeneration, of dystrophic muscles
