Epigenetic control of myogenic identity of human muscle stem cells in Duchenne muscular dystrophy
Jimmy Massenet,
Michèle Weiss-Gayet,
Hina Bandukwala,
Wilhelm Bouchereau,
Stéphanie Gobert,
Mélanie Magnan,
Arnaud Hubas,
Patrick Nusbaum,
Isabelle Desguerre,
Cyril Gitiaux,
F. Jeffrey Dilworth,
Bénédicte Chazaud
Affiliations
Jimmy Massenet
Institut NeuroMyoGène, Physiopathologie et Génétique du Neurone et du Muscle Université Claude Bernard Lyon 1, CNRS U5261, Inserm U1315, University Lyon, Lyon, France; Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
Michèle Weiss-Gayet
Institut NeuroMyoGène, Physiopathologie et Génétique du Neurone et du Muscle Université Claude Bernard Lyon 1, CNRS U5261, Inserm U1315, University Lyon, Lyon, France
Hina Bandukwala
Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
Wilhelm Bouchereau
Institut NeuroMyoGène, Physiopathologie et Génétique du Neurone et du Muscle Université Claude Bernard Lyon 1, CNRS U5261, Inserm U1315, University Lyon, Lyon, France
Stéphanie Gobert
Institut NeuroMyoGène, Physiopathologie et Génétique du Neurone et du Muscle Université Claude Bernard Lyon 1, CNRS U5261, Inserm U1315, University Lyon, Lyon, France
Mélanie Magnan
Institut Cochin, Université Paris-Cité, Inserm U1016, CNRS UMR8104, Paris, France
Arnaud Hubas
Hôpital Cochin – Port-Royal, Centre de Ressources Biologiques, Paris, France
Patrick Nusbaum
Hôpital Cochin – Port-Royal, Centre de Ressources Biologiques, Paris, France
Isabelle Desguerre
Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, AP-HP, Hôpital Necker Enfants Malades, Université Paris-Cité, Paris, France; Université Paris Cité, IHU Imagine, 75015 Paris, France
Cyril Gitiaux
Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, AP-HP, Hôpital Necker Enfants Malades, Université Paris-Cité, Paris, France; Service d’explorations Fonctionnelles, Unité de Neurophysiologie Clinique, AP-HP, Hôpital Necker Enfants Malades, Paris, France
F. Jeffrey Dilworth
Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Cell and Regenerative Biology, University of Wisconsin – Madison, Madison WI 53705, USA; Corresponding author
Bénédicte Chazaud
Institut NeuroMyoGène, Physiopathologie et Génétique du Neurone et du Muscle Université Claude Bernard Lyon 1, CNRS U5261, Inserm U1315, University Lyon, Lyon, France; Corresponding author
Summary: 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.
