Epigenetic control of myogenic identity of human muscle stem cells in Duchenne muscular dystrophy

• Published in: iScience 2024-12, Vol.27 (12), p.111350, Article 111350
• Main Authors: Massenet, Jimmy, Weiss-Gayet, Michèle, Bandukwala, Hina, Bouchereau, Wilhelm, Gobert, Stéphanie, Magnan, Mélanie, Hubas, Arnaud, Nusbaum, Patrick, Desguerre, Isabelle, Gitiaux, Cyril, Dilworth, F. Jeffrey, Chazaud, Bénédicte
• Format: Article
• Language: English
• Subjects: Epigenetics; Integrative aspects of cell biology; Stem cells research
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.111350

In Duchenne muscular dystrophy (DMD), muscle stem cells’ (MuSCs) regenerative capacities are overwhelmed leading to fibrosis. Whether MuSCs have intrinsic defects or are disrupted by their environment is unclear. We investigated cell behavior and gene expression of MuSCs from DMD or healthy human muscles. Proliferation, differentiation, and fusion were unaltered in DMD-MuSCs, but with time, they lost their myogenic identity twice as fast as healthy MuSCs. The rapid drift toward a fibroblast-like cell identity was observed at the clonal level, and resulted from altered expression of epigenetic enzymes. Re-expression of CBX3, SMC3, H2AFV, and H3F3B prevented the MuSC identity drift. Among epigenetic changes, a closing of chromatin at the transcription factor MEF2B locus caused downregulation of its expression and loss of the myogenic fate. Re-expression of MEF2B in DMD-MuSCs restored their myogenic fate. MEF2B is key in the maintenance of myogenic identity in human MuSCs, which is altered in DMD. [Display omitted] •Duchenne muscular dystrophy muscle stem cells (DMD-MuSCs) exhibit unaltered myogenesis•DMD-MuSCs loose myogenicity faster than normal cells due to epigenetic enzyme downexpression•Re-expression of CBX3, SMC3, H2AFV, and H3F3B prevent the MuSC identity drift•MEF2B transcription factor is key in the maintenance of myogenic identity in human MuSCs Epigenetics; Stem cells research; Integrative aspects of cell biology