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., …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