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

Abstract

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 (lncRNAs) play key roles in regulating cell fate decision and function in various tissues. However, the role of lncRNAs in the regulation of myogenesis remains poorly understood. In this study, we identified a novel muscle-enriched lncRNA 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 differentiation. 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 Filip1 in a cis-manner. Similar to Myolinc, knockdown of Filip1 inhibits 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. Acta1 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 lncRNA that controls key regulatory networks of myogenesis.

Long Non-Coding RNA H19 Promotes Porcine Satellite Cell Differentiation by Interacting with TDP43

“…Previous studies have shown that TDP43 promotes MYOD expression by directly binding to its promoter in C2C12 cells [32]. In the present study, TDP43 was also enriched in the promoter of MYOD in PSCs through the CHIP experiment, indicating the same mechanism in mice and pigs ( Figure 4A).…”

“…Among the different proteins detected by MS, TDP43 attracted our attention the most. TDP43, as a RNA/DNA binding protein, plays an important role in myoblast differentiation [32]. Western blot analysis was carried out to validate the interaction between H19 and TDP43 ( Figure 1B).…”

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

“…PPARA is activated by endogenous fatty acid metabolite ligands in response to fasting and promotes the uptake, utilization, and catabolism of fatty acids by regulating a wide range of genes that reprogram metabolic pathways to facilitate the use of lipids as an energy source. The direct regulation of protein-coding genes by PPARA is well characterized, but it was not known whether lncRNAswhich may influence gene expression through a variety of mechanisms Militello et al, 2018;Zhao et al, 2016) -also serve as direct targets contributing to physiological changes induced by PPARA activation. This possibility was suggested by the finding that several hundred liver-expressed lncRNAs are dysregulated in livers exposed to xenobiotic agonist ligands of the nuclear receptors CAR and PXR (Lodato et al, 2017), which contribute to the regulation of lipid metabolism and whose gene targets overlap with those of PPARA (Cui and Klaassen, 2016;Wada et al, 2009).…”

Roles of lncRNAs and circRNAs in regulating skeletal muscle development

“…41 In addition to the above ceRNA mechanism, some lncRNAs regulate gene expression in cis or trans. 45 Overexpression of lncRNA MyoD upstream non-coding (MUNC) induced from a heterologous promoter increased endogenous MyoD, MyoG and Myh3 mRNA, but not protein, expression, suggesting that it can act in trans to promote gene expression, albeit independently of MyoD protein. Yam-1 functions via cis regulation of miR-715, which in turn targets Wnt7b.…”

“…44 Myolinc recruits TAR DNA-binding protein 43 (TDP-43) to the promoter of Filip1 to regulate its transcription in cis, and the Myolinc and TDP-43 complex binds to the promoters of muscle marker genes (eg, MyoD and Acta1) to promote differentiation and regeneration. 45 Overexpression of lncRNA MyoD upstream non-coding (MUNC) induced from a heterologous promoter increased endogenous MyoD, MyoG and Myh3 mRNA, but not protein, expression, suggesting that it can act in trans to promote gene expression, albeit independently of MyoD protein. 46 MUNC can also act as an enhancer RNA (eRNA) of MyoD.…”