c-Myc inhibits myoblast differentiation and promotes myoblast proliferation and muscle fibre hypertrophy by regulating the expression of its target genes, miRNAs and lincRNAs
c-Myc inhibits myoblast differentiation and promotes myoblast proliferation and muscle fibre hypertrophy by regulating the expression of its target genes, miRNAs and lincRNAs
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c-Myc通过调节其靶基因、miRNA和lincRNA的表达，抑制成肌细胞分化，促进成肌细胞增殖和肌纤维肥大
DOI：
10.1038/s41418-018-0129-0
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发表时间：
2019-02-01
影响因子：
12.4
通讯作者：
Hanotte，Olivier
中科院分区：
文献类型：
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作者：
Luo，Wen;Chen，Jiahui;Hanotte，Olivier
转录因子c-Myc是细胞增殖、分化和胚胎发生的重要调节因子。虽然 c-Myc 可以抑制成肌细胞分化，但其潜在机制仍知之甚少。在这里，我们发现c-Myc不仅抑制成肌细胞分化，而且促进成肌细胞增殖和肌纤维肥大。通过进行染色质免疫沉淀和高通量测序 (ChIP-seq)，我们鉴定了骨骼肌细胞中 c-Myc 的全基因组结合谱。 c-Myc 通过靶向细胞周期途径实现对成肌细胞增殖和分化的调节作用。此外，c-Myc还可以通过控制miRNA的表达来调控细胞周期基因，其中数十种miRNA也可以被c-Myc直接调控。在这些c-Myc相关miRNA（CAM）中，c-Myc诱导的miRNA在骨骼肌细胞中所起的作用与c-Myc所起的作用相似，而c-Myc抑制的miRNA所起的作用与c-Myc所起的作用相反。细胞周期、ERK-MAPK 和 Akt 介导的途径是成肌细胞分化过程中 CAM 的潜在靶途径。有趣的是，我们发现了四种可以直接结合c-Myc 3' UTR并抑制c-Myc表达的CAM，这表明在成肌细胞分化过程中c-Myc与其目标miRNA之间存在负反馈环。 c-Myc 还可能调节许多长基因间非编码 RNA (lincRNA)。 Linc-2949和linc-1369均受c-Myc直接调控，两种lincRNA都通过竞争与肌肉分化相关miRNA的结合来参与成肌细胞增殖和分化的调节。我们的研究结果不仅提供了 c-Myc 在骨骼肌细胞中的作用的全基因组概述，而且揭示了 c-Myc 及其靶基因如何调节成肌细胞增殖和分化以及肌纤维肥大的机制。
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.