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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 & Differentiation (2018) | Download Citation

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Abstract

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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Acknowledgements

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).

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Affiliations

  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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DOI

https://doi.org/10.1038/s41418-018-0129-0