A Long Non-coding RNA, LncMyoD, Regulates Skeletal Muscle Differentiation by Blocking IMP2-mediated protein translation

Abstract

Long non-coding RNAs (LncRNA) constitute a new class of genes recently identified in various tissues1-8. LncRNAs play important roles in normal physiology as well as in many diseases, including embryonic stem cell maintenance, organ development and cancer progression 1,9-14. However, the various roles of LncRNAs in somatic stem cell maintenance and myogenesis remain largely unknown 15,16. For this study, hundreds of novel intergenic LncRNAs were identified that are expressed in myoblasts and regulated during muscle differentiation. One of these LncRNAs, termed LncMyoD, is encoded next to the Myod gene and is directly activated by MyoD during early myoblast differentiation. Knockdown of LncMyoD strongly inhibits terminal muscle differentiation largely due to a failure to exit the cell cycle. RNA pull-down experiments demonstrate that LncMyoD directly binds to IGF2-mRNA-binding-proteins (IMPs), which regulate translation of particular mRNAs, and thus negatively regulates IMP-mediated translation of proliferation genes such as N-Ras and c-Myc. While the sequence of LncMyoD is not well-conserved between human and mouse, its locus and mechanism is preserved. It was largely unclear how MyoD blocks proliferation to help create a permissive state for differentiation; elucidation of the MyoD-LncMyoD-IMP2 pathway provides this mechanism