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

Author

Listed:
  • 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
    Sorbonne Université, INSERM U974, Center for Research in Myology)

  • 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
    Tokushima University Graduate School)

  • Pascal Maire

    (Université de Paris, Institut Cochin, INSERM, CNRS)

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.

Suggested Citation

  • Matthieu Santos & Stéphanie Backer & Frédéric Auradé & Matthew Man-Kin Wong & Maud Wurmser & Rémi Pierre & Francina Langa & Marcio Cruzeiro & Alain Schmitt & Jean-Paul Concordet & Athanassia Sotiropou, 2022. "A fast Myosin super enhancer dictates muscle fiber phenotype through competitive interactions with Myosin genes," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28666-1
    DOI: 10.1038/s41467-022-28666-1
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    1. Matthieu Dos Santos & Akansha M. Shah & Yichi Zhang & Svetlana Bezprozvannaya & Kenian Chen & Lin Xu & Weichun Lin & John R. McAnally & Rhonda Bassel-Duby & Ning Liu & Eric N. Olson, 2023. "Opposing gene regulatory programs governing myofiber development and maturation revealed at single nucleus resolution," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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