Histone 3 lysine 9 methyltransferases G9a and GLP as potential pharmacological targets in skeletal muscle regeneration and Duchenne Muscular Dystrophy

Histone Lysine Methyltransferases (KMTs) are epigenetic modifiers that dynamically control gene expression during stem cell differentiation. Among the different KMTs, EHMT2/G9a and EHMT1/GLP, responsible of mono- and di-methylation of Lysine 9 of histone H3 (H3K9), are of particular relevance in the context of myogenesis since they have been shown to control the repression of muscle-specific genes in myogenic precursors and to prevent their premature differentiation. Modulation of their activity might therefore be exploited to promote the expression of muscle-specific genes and to enhance muscle differentiation in tissues whose myogenic capacity is compromised due to a pathological condition, as in the case of muscles affected by Duchenne Muscular Dystrophy (DMD). DMD is a severe X-linked neuromuscular degenerative disorder that leads to progressive muscle weakness associated with loss of muscle tissue and replacement with adipose and connective infiltrates, in coincidence with the final stages of disease. Despite recent progresses in genome editing approaches, the cure for DMD is still a big challenge and pharmacological therapies aimed to counteract the fibro-adipogenic degeneration and to promote the compensatory regeneration, typical of the early stages of disease, hold great promise to slow-down DMD progression. Here we provide evidence of the pro-regenerative effect of G9a/GLP specific inhibitors in vivo. Our results show that in vivo inhibition of G9a/GLP-mediated H3K9me2 improves skeletal muscle regeneration. This is caused by an accelerated myogenic capacity of muscle stem cells (MuSCs) and by an impaired adipogenic differentiation of fibro-adipogenic progenitors (FAPs), which rather unmasks a previously silent myogenic capacity. Our preliminary results provide proof of concept of the use of H3K9 KMTs specific inhibitors as potential pharmacological strategy to promote the regenerative response of diseased, dystrophic, muscles, while concomitantly blocking their fibro-adipogenic degeneration.