Defective plasticity in dermatomyositis patients muscle stem cells is associated with sustained intrinsic inflammatory signaling and disruption of the histone H3.3 chromatin loading pathway [RNA-seq]

Skeletal muscle regeneration is driven by muscle stem cells (MuSC). They proliferate then differentiate to restore muscle function. This process, known as myogenesis, is driven both by intrinsic properties of MuSCs and by extrinsic inflammatory signals. While proinflammatory signals are necessary for healthy muscle regeneration, chronic inflammation participates in different pathologies affecting the skeletal muscle, including cancer-associated cachexia, Duchenne muscular dystrophy (DMD) or auto-immune disorders. Dermatomyositis (DM) is characterized by infiltration of immune cells in the peri-fascicular area which is associated with chronic inflammation. Although anti-inflammatory treatments are commonly used to combat the disease, most patients never fully regain their muscle strength. MuSCs derived from dermatomyositis patients exhibit impaired myogenesis in vitro, indicating that these cells may have acquired intrinsic defects that contribute to the disease. We compared the transcriptomes of MuSCs from healthy individuals and DM patients, finding that the latter are unable to effectively execute the myogenic transcriptomic program during ex vivo differentiation. Additionally, they exhibit an intrinsically activated canonical TNF signaling. MuSC from DM patients also exhibit reduced expression of H3.3 and its chaperone genes, coupled with a decrease in H3.3 deposition across the entire genome. The global loss of H3.3 combined with elevated intrinsic TNF signaling is associated with a failure of DM-derived MuSCs to suppress inflammatory signals and achieve proper myogenesis, suggesting a mechanistic link between epigenetic dysregulation and defective muscle regeneration. RNA-seq profiling of human skeletal muscle stem cells derived from either healthy control or dermatomyositis patients grown in vitro in either proliferating condition and after day 1 and day 3 of switch to differentiating condition.