Epigenetic control of myogenic identity of human muscle stem cells in Duchenne muscular dystrophy
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 <i>CBX3</i>, <i>SMC3</i>, <i>H2AFV</i>, and <i>H3F3B</i> prevented the MuSC identity drift. Among epigenetic changes, a closing of chromatin at the transcription factor <i>MEF2B</i> 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.
Authors
- Hina Bandukwala (ORCID: https://orcid.org/0000-0002-3340-6774)
- Wilhelm Bouchereau (ORCID: https://orcid.org/0000-0002-0152-3239)
- Isabelle Desguerre (ORCID: https://orcid.org/0000-0002-4074-5862)
- Bénédicte Chazaud (ORCID: https://orcid.org/0000-0002-1262-502X)
- Jimmy Massenet (ORCID: https://orcid.org/0000-0001-9699-5580)
- Stéphanie Gobert (ORCID: https://orcid.org/0000-0002-9475-9397)
- Arnaud Hubas
- F. Jeffrey Dilworth (ORCID: https://orcid.org/0000-0002-6265-8102)
- Patrick Nusbaum
- Michèle Weiss‐Gayet
- Cyril Gitiaux (ORCID: https://orcid.org/0000-0002-2190-6843)
- Mélanie Magnan
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Ottawa Hospital (CA)
- Assistance Publique – Hôpitaux de Paris (FR)
- Institut NeuroMyoGène (FR)
- Institut Cochin (FR)
- Institut des Maladies Génétiques Imagine (FR)
- Ottawa Hospital Research Institute (CA)
Publication Details
- Journal
- iScience
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1016/j.isci.2024.111350
- Citations
- 10
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- French Muscular Dystrophy Association
- Institut National de la Santé et de la Recherche Médicale
- Mitacs
- Centre National de la Recherche Scientifique
- Canadian Institutes of Health Research