CRISPR gene editing in pluripotent stem cells reveals the function of MBNL proteins during human in vitro myogenesis


Alternative splicing has emerged as a fundamental mechanism for the spatiotemporal control of development. A better understanding of how this mechanism is regulated has the potential not only to elucidate fundamental biological principles, but also to decipher pathological mechanisms implicated in diseases where normal splicing networks are misregulated. Here, we took advantage of human pluripotent stem cells to decipher during human myogenesis the role of muscleblind-like (MBNL) proteins, a family of tissue-specific splicing regulators whose loss of function is associated with myotonic dystrophy type 1 (DM1), an inherited neuromuscular disease. Thanks to the CRISPR/Cas9 technology, we generated human-induced pluripotent stem cells (hiPSCs) depleted in MBNL proteins and evaluated the consequences of their losses on the generation of skeletal muscle cells. Our results suggested that MBNL proteins are required for the late myogenic maturation. In addition, loss of MBNL1 and MBNL2 recapitulated the main features of DM1 observed in hiPSC-derived skeletal muscle cells. Comparative transcriptomic analyses also revealed the muscle-related processes regulated by these proteins that are commonly misregulated in DM1. Together, our study reveals the temporal requirement of MBNL proteins in human myogenesis and should facilitate the identification of new therapeutic strategies capable to cope with the loss of function of these MBNL proteins. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email:

Authors Mérien A, Tahraoui-Bories J, Cailleret M, Dupont JB, Leteur C, Polentes J, Carteron A, Polvèche H, Concordet JP, Pinset C, Jarrige M, Furling D, Martinat C
Journal Human molecular genetics
Publication Date 2021 Dec 17;31(1):41-56
PubMed 34312665
PubMed Central PMC8682758
DOI 10.1093/hmg/ddab218

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