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    Identification of coordinated transcriptional activity of nuclei within mammalian myofibers

    Team Maire, Sotiropoulos

    Identification of coordinated transcriptional activity of nuclei within mammalian myofibers

     

    In a study published in Nature communications, the team directed by Pascal Maire and Athanassia Sotiropoulos (Neuromuscular Development, Genetics and Physiopathology) identifies for the first time the transcription profiles of various myonuclei types in adult myofibers and show that the majority of myonuclei within a myofiber are synchronized. This study also highlights a previously undefined mechanism of coordination of gene expression in a syncytium.

     

    Myofibers from skeletal muscles are syncytia composed of hundreds of post-mitotic nuclei sharing the same cytoplasm, generated by the fusion of myoblasts during development. Along the myofibers different regions (body, myotendinous junctions, neuromuscular junctions) exhibit different protein expression profiles, suggesting distinct transcriptional regulations. In body myonuclei that constitute the vast majority of myonuclei in the fiber, heterogeneity in nuclear protein import and stochastic gene expression have been proposed to occur, suggesting that body myonuclei along the myofiber are not equivalent. Whether the hundreds of body nuclei along the myofiber are transcriptionally active at the same time and express the same set of genes remained debated.

     

    The authors developed a method of single-nucleus RNA sequencing (snRNA-seq) using a droplet-based platform on purified nuclei from different skeletal muscles of adult mice. They also used single nucleus ATAC sequencing (snATAC-seq) to study chromatin accessibility and transcription factors motif accessibility between the different myonuclei. 

    Results show that the different populations of myonuclei - namely neuromuscular junctions, myotendinous junctions, and body myonuclei - each exhibit specific transcriptional profiles and chromatin accessibilities.

     

    Figure legend: Uniform Manifold Approximation and Projection (Umap) diagram from snRNA-seq from adult skeletal muscle showing the nuclei of the different cells present in adult muscles. MTJ, myotendinous; NMJ, neuromuscular junctions, MuSC, myogenic stem cells; FAPS, fibroadipogenic cells.

     © Nature communications 

     

     

     

    Adult skeletal muscles are composed mainly of slow- and fast-twitch contracting myofibers according to their MYH (myosin heavy chain) content. In adult mice, identified myofiber types predominantly express either a slow or one of the three fast isoforms of MYH proteins.  By snRNA-seq and FISH, the authors show that the majority of myonuclei within a myofiber are synchronized, coordinately expressing only one fast Myh isoform with a preferential panel of muscle-specific genes. Thus in fast skeletal muscles, the transcriptional activity of nuclei within each myofiber is finely coordinated.

    Furthermore, the authors show that this coordination is dependent upon innervation of the myofiber, and that it is established early during development.

    In addition to defining the exact transcriptional landscape within skeletal muscle, the snRNA-seq and snATAC-seq methods presented here open new perspectives to characterize in the future the crosstalk between myofibers and their environment, such as with associated myogenic stem cells in pathophysiological conditions, to date poorly investigated due to technical limits.

     

    Further information

    Dos Santos M, Backer S, Saintpierre B, Izac B, Andrieu M, Letourneur F, Relaix F, Sotiropoulos A, Maire P.  Single-nucleus RNA-seq and FISH identify coordinated transcriptional activity in mammalian myofibers. Nat Commun 11:5102 (2020). https://doi.org/10.1038/s41467-020-18789-8

     

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