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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 & Differentiationvolume 26pages426442 (2019) | Download Citation



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.

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This work was supported by Natural Scientific Foundation of China (31702105), Natural Scientific Foundation of China (31472090), the China Agriculture Research System (CARS-41-G03), and the Science and Technology Program of Guangzhou, China (201804020088).

Author information


  1. Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China

    • Wen Luo
    • , Jiahui Chen
    • , Limin Li
    • , Xueyi Ren
    • , Tian Cheng
    • , Shiyi Lu
    • , Qinghua Nie
    •  & Xiquan Zhang
  2. Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China

    • Wen Luo
    • , Jiahui Chen
    • , Limin Li
    • , Xueyi Ren
    • , Tian Cheng
    • , Shiyi Lu
    •  & Xiquan Zhang
  3. Cells, Organisms and Molecular Genetics Division, School of Life Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK

    • Raman Akinyanju Lawal
    • , Qinghua Nie
    •  & Olivier Hanotte


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The authors declare that they have no conflict of interest.

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Correspondence to Qinghua Nie or Xiquan Zhang.

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