Bouchereau, W.; Chenane, L.; Lessard, L.; Weiss-Gayet, M.; Cardona, Y.; Mounier, R.; Gallay, L.; Allenbach, Y.; Benveniste, O.; Corpet, A.; Chazaud, B.; Lomonte, P.

Skeletal muscle regeneration is driven by muscle stem cells (MuSCs), which proliferate, differentiate and fuse to reform myofibers and restore muscle function. This myogenesis process is driven both by intrinsic MuSC properties and extrinsic cues. While coordinated inflammatory signals are necessary for healthy regeneration, chronic inflammation participates in various pathologies affecting the skeletal muscle. In the idiopathic inflammatory myopathy dermatomyositis (DM), MuSCs exhibit impaired myogenesis in vitro, indicating that they may have acquired intrinsic defects, contributing to the disease and providing a mechanism for sustained patient muscle weakness despite efficient anti-inflammatory treatments. Here, we investigated the transcriptomic regulation of DM-derived MuSCs, with a focus on the H3.3 histone variant which regulates myogenesis progression. DM-derived MuSCs were unable to effectively execute the myogenic transcriptional program during in vitro differentiation. They exhibited an activated canonical TNF- signaling. They also showed reduced expression of H3.3 and its chaperone genes, coupled with a decrease in H3.3 deposition across the entire genome, and particularly at myogenic regulatory factor loci. The loss of H3.3 combined with elevated TNF- signaling was associated with a failure of DM-derived MuSCs to achieve myogenesis, suggesting a mechanistic link between epigenetic dysregulation and defective muscle regeneration in humans.