Long noncoding RNA <i>SYISL</i> regulates myogenesis by interacting with polycomb repressive complex 2

Abstract

Although many long noncoding RNAs (lncRNAs) have been identified in muscle, their physiological function and regulatory mechanisms remain largely unexplored. In this study, we systematically characterized the expression profiles of lncRNAs during C2C12 myoblast differentiation and identified an intronic lncRNA, <i>SYISL</i> (<i>SYNPO2</i> intron sense-overlapping lncRNA), that is highly expressed in muscle. Functionally, <i>SYISL</i> promotes myoblast proliferation and fusion but inhibits myogenic differentiation. <i>SYISL</i> knockout in mice results in significantly increased muscle fiber density and muscle mass. Mechanistically, <i>SYISL</i> recruits the enhancer of zeste homolog 2 (EZH2) protein, the core component of polycomb repressive complex 2 (PRC2), to the promoters of the cell-cycle inhibitor gene <i>p21</i> and muscle-specific genes such as myogenin (<i>MyoG</i>), muscle creatine kinase (<i>MCK</i>), and myosin heavy chain 4 (<i>Myh4</i>), leading to H3K27 trimethylation and epigenetic silencing of target genes. Taken together, our results reveal that <i>SYISL</i> is a repressor of muscle development and plays a vital role in PRC2-mediated myogenesis.