A fast Myosin super enhancer dictates muscle fiber phenotype through competitive interactions with Myosin genes

Matthieu Santos, Stéphanie Backer, Frédéric Auradé, Matthew Man-Kin Wong, Maud Wurmser, Rémi Pierre, Francina Langa, Marcio Cruzeiro, Alain Schmitt, Jean-Paul Concordet, Athanassia Sotiropoulos, F. Jeffrey Dilworth, Daan Noordermeer, Frédéric Relaix, Iori Sakakibara () and Pascal Maire ()
Additional contact information
Matthieu Santos: Université de Paris, Institut Cochin, INSERM, CNRS
Stéphanie Backer: Université de Paris, Institut Cochin, INSERM, CNRS
Frédéric Auradé: Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB
Matthew Man-Kin Wong: Regenerative Medicine Program. Ottawa Hospital Research Institute
Maud Wurmser: Université de Paris, Institut Cochin, INSERM, CNRS
Rémi Pierre: Université de Paris, Institut Cochin, INSERM, CNRS
Francina Langa: Institut Pasteur
Marcio Cruzeiro: Université de Paris, Institut Cochin, INSERM, CNRS
Alain Schmitt: Université de Paris, Institut Cochin, INSERM, CNRS
Jean-Paul Concordet: MNHN
Athanassia Sotiropoulos: Université de Paris, Institut Cochin, INSERM, CNRS
F. Jeffrey Dilworth: Regenerative Medicine Program. Ottawa Hospital Research Institute
Daan Noordermeer: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Frédéric Relaix: Univ Paris Est Creteil, INSERM, EnvA, EFS, AP-HP, IMRB
Iori Sakakibara: Université de Paris, Institut Cochin, INSERM, CNRS
Pascal Maire: Université de Paris, Institut Cochin, INSERM, CNRS

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract The contractile properties of adult myofibers are shaped by their Myosin heavy chain isoform content. Here, we identify by snATAC-seq a 42 kb super-enhancer at the locus regrouping the fast Myosin genes. By 4C-seq we show that active fast Myosin promoters interact with this super-enhancer by DNA looping, leading to the activation of a single promoter per nucleus. A rainbow mouse transgenic model of the locus including the super-enhancer recapitulates the endogenous spatio-temporal expression of adult fast Myosin genes. In situ deletion of the super-enhancer by CRISPR/Cas9 editing demonstrates its major role in the control of associated fast Myosin genes, and deletion of two fast Myosin genes at the locus reveals an active competition of the promoters for the shared super-enhancer. Last, by disrupting the organization of fast Myosin, we uncover positional heterogeneity within limb skeletal muscles that may underlie selective muscle susceptibility to damage in certain myopathies.

Date: 2022
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DOI: 10.1038/s41467-022-28666-1

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