Epigenetic and transcriptomic profiling of fibro adipogenic progenitors during Duchenne muscular dystrophy progression and histone deacetylase inhibitors treatment

Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutations in the Dystrophin gene. DMD is characterized by continuous cycles of muscle contraction/degeneration, leading to muscular tissue replacement by fibrotic and fat infiltrations deposed by the fibro-adipogenic progenitors (FAPs). Although there is currently no cure for DMD, the Histone Deacetylase Inhibitors (HDACi) represent the first generation of epigenetic drugs used to counteract DMD progression. Our lab has identified a regulatory network targeted by HDACi to repress FAPs differentiation into fibro-adipogenic cells, while activating a latent pro-myogenic phenotype (Saccone et al. 2014). However, HDACi pharmacological efficacy is restricted at early stage of DMD (Mozzetta et al. 2013). The mechanism during dystrophic FAPs aging that confers resistance to HDACi treatment is still unknown. To address this issue, we performed ChIP-seq for H3K9/14ac and H3K27ac in FAPs from early and late stage dystrophic mice, treated or not with HDACi. Coupling ChIP-seq with RNA-seq we identified differentially acetylated regions responsible of gene expression changes and unveiled the stage-specific epi-signature of both HDACi efficacy and resistance. This work paves the way to future diagnostic and therapeutic perspective for extending the efficacy of HDACi for the treatment of DMD.