c-Myc inhibits myoblast differentiation and promotes myoblast proliferation and muscle fibre hypertrophy by regulating the expression of its target genes, miRNAs and lincRNAs

Luo, Wen; Chen, Jiahui; Li, Limin; Ren, Xueyi; Cheng, Tian; Lu, Shiyi; Lawal, Raman Akinyanju; Nie, Qinghua; Zhang, Xiquan; Hanotte, Olivier

Abstract

© 2018, ADMC Associazione Differenziamento e Morte Cellulare. The transcription factor c-Myc is an important regulator of cellular proliferation, differentiation and embryogenesis. While c-Myc can inhibit myoblast differentiation, the underlying mechanisms remain poorly understood. Here, we found that c-Myc does not only inhibits myoblast differentiation but also promotes myoblast proliferation and muscle fibre hypertrophy. By performing chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), we identified the genome-wide binding profile of c-Myc in skeletal muscle cells. c-Myc achieves its regulatory effects on myoblast proliferation and differentiation by targeting the cell cycle pathway. Additionally, c-Myc can regulate cell cycle genes by controlling miRNA expression of which dozens of miRNAs can also be regulated directly by c-Myc. Among these c-Myc-associated miRNAs (CAMs), the roles played by c-Myc-induced miRNAs in skeletal muscle cells are similar to those played by c-Myc, whereas c-Myc-repressed miRNAs play roles that are opposite to those played by c-Myc. The cell cycle, ERK–MAPK and Akt-mediated pathways are potential target pathways of the CAMs during myoblast differentiation. Interestingly, we identified four CAMs that can directly bind to the c-Myc 3' UTR and inhibit c-Myc expression, suggesting that a negative feedback loop exists between c-Myc and its target miRNAs during myoblast differentiation. c-Myc also potentially regulates many long intergenic noncoding RNAs (lincRNAs). Linc-2949 and linc-1369 are directly regulated by c-Myc, and both lincRNAs are involved in the regulation of myoblast proliferation and differentiation by competing for the binding of muscle differentiation-related miRNAs. Our findings do not only provide a genome-wide overview of the role the c-Myc plays in skeletal muscle cells but also uncover the mechanism of how c-Myc and its target genes regulate myoblast proliferation and differentiation, and muscle fibre hypertrophy.

Citation

Luo, W., Chen, J., Li, L., Ren, X., Cheng, T., Lu, S., Lawal, R. A., Nie, Q., Zhang, X., & Hanotte, O. (2019). c-Myc inhibits myoblast differentiation and promotes myoblast proliferation and muscle fibre hypertrophy by regulating the expression of its target genes, miRNAs and lincRNAs. Cell Death and Differentiation, 26(3), 426-442. https://doi.org/10.1038/s41418-018-0129-0

• Journal Article Type: Article
• Acceptance Date: May 2, 2018
• Publication Date: Mar 1, 2019
• Deposit Date: Jan 22, 2021
• Journal: Cell Death and Differentiation
• Print ISSN: 1350-9047
• Electronic ISSN: 1476-5403
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 26
• Issue: 3
• Pages: 426-442
• DOI: https://doi.org/10.1038/s41418-018-0129-0
• Public URL: https://nottingham-repository.worktribe.com/output/3119214
• Publisher URL: https://www.nature.com/articles/s41418-018-0129-0