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A novel long non-coding RNA Myolinc regulates myogenesis through TDP-43 and Filip1

Journal of Molecular Cell Biology 2018年第2期10卷 102-117页

作者： Giuseppe Militello Mohammed Rabiul Hosen yuliya ponomareva Pascal Gellerts Tyler Weirick David John Sajedah Mahmoud Hindi Kamel Mamchaoui Vincent Mouly Claudia Doring Lidan Zhang Miki Nakamura Ashok Kumar So-ichiro Fukada Stefanie Dimmeler Shizuka Uchida Institute of Cardiovascular Regeneration Centre for Molecular Medicine Goethe University Frankfurt Frankfurt am Main 60590 Germany German Center for Cardiovascular Research Partner side Rhein-Main Frankfurt am Main 60590 Germany Department of Biosciences Goethe University Frankfurt Frankfurt am Main 60438 Germany Cardiovascular Innovation Institute University of Louisville Louisville KY 40202 USA Breast Cancer Now Toby Robins Research Centre Institute of Cancer Research London SW3 6JB UK Department of Anatomical Sciences and Neurobiology University of Louisville School of Medicine Louisville KY 40202 USA Sorbonne Universites UPMC Univ Paris 06 INSERM UMRS974 CNRS FRE3617 Center for Research in Myology Paris 75013 France Dr. Senckenberg Institute of Pathology Goethe University Frankfurt Frankfurt am Main 60590 Germany Laboratory of Molecular and Cellular Physiology Graduate School of Pharmaceutical Sciences Osaka University Osaka 565-0871 Japan

Myogenesis is a complex process required for skeletal muscle formation during embryonic development and for regeneration and growth of myofibers in adults. Accumulating evidence suggests that long non-coding RNAs （IncRNAs） play key roles in regulating cell fate decision and function in various tissues. However, the role of IncRNAs in the regulation of myogenesis remains poorly understood. In this study, we identifed a novel muscle-enriched IncRNA called ＇Myolinc （AK142388）＇, which we functionally characterized in the C2C12 myoblast cell line. Myolinc is predominately localized in the nucleus, and its levels increase upon induction of the differ-entiation. Knockdown of Myolinc impairs the expression of myogenic regulatory factors and formation of multi-nucleated myotubes in cultured myoblasts. Myolinc also regulates the expression of Filipl in a cis-manner. Similar to MyoUnc, knockdown of FiUpl inhi-bits myogenic differentiation. Furthermore, Myolinc binds to TAR DNA-binding protein 43 （TDP-43）, a DNA/RNA-binding protein that regulates the expression of muscle genes （e.g. Actal and MyoD）. Knockdown of TDP-43 inhibits myogenic differentiation. We also show that Myolinc-TDP-43 interaction is essential for the binding of TDP-43 to the promoter regions of muscle marker genes. Finally, we show that silencing of Myolinc inhibits skeletal muscle regeneration in adult mice. Altogether, our study identifies a novel IncRNA that controls key regulatory networks of myogenesis.

关键词： long non-coding RNA skeletal muscle myoblasts differentiation transcriptional regulation

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