Ccndbp1 is a new positive regulator of skeletal myogenesis
Ccndbp1 is a new positive regulator of skeletal myogenesis
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Ccndbp1 是骨骼肌生成的新正调节因子。
DOI：
10.1242/jcs.184234
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发表时间：
2016-07-15
影响因子：
4
通讯作者：
Ma, Wenbin
中科院分区：
文献类型：
--
作者：
Huang, Yan;Chen, Bohong;Ma, Wenbin
骨骼肌发生是一个多步骤的过程，其中碱性螺旋-环-螺旋（bHLH）转录因子，如MyoD（也称为MyoD 1），与E盒结合并激活下游基因。Ccndbp 1是一种缺乏DNA结合区的HLH蛋白，其在骨骼肌发生中的功能目前尚不清楚。我们通过使用CRISPR-Cas9产生Ccndbp 1-null小鼠。值得注意的是，在Ccndbp 1基因敲除小鼠中，与野生型相比，骨骼胫骨前肌的横截面积较小，肌肉再生能力和握力受损。这种表型类似于某些人类肌病或肌发育不全中的肌纤维萎缩。Ccndbp 1的表达在C2 C12肌发生过程中上调。Ccndbp 1的过表达促进肌细胞的发生，而Ccndbp 1的敲低抑制肌细胞的分化。Ccndbp 1与MyoD和/或E47（由TCF 3编码）的共转染显著增强了E-box依赖的转录。此外，Ccndbp 1与MyoD而不是E47物理相关。这些数据表明，Ccndbp 1通过与MyoD相互作用并增强其与靶基因的结合来调节肌肉分化。我们的研究新鉴定了Ccndbp 1作为体内和体外骨骼肌分化的正调节剂，为破译骨骼肌发育和相关疾病中涉及的复杂网络提供了新的见解。
Skeletal myogenesis is a multistep process in which basic helix-loop-helix (bHLH) transcription factors, such as MyoD (also known as MyoD1), bind to E-boxes and activate downstream genes. Ccndbp1 is a HLH protein that lacks a DNA-binding region, and its function in skeletal myogenesis is currently unknown. We generated Ccndbp1-null mice by using CRISPR-Cas9. Notably, in Ccndbp1-null mice, the cross sectional area of the skeletal tibialis anterior muscle was smaller, and muscle regeneration ability and grip strength were impaired, compared with those of wild type. This phenotype resembled that of myofiber hypotrophy in some human myopathies or amyoplasia. Ccndbp1 expression was upregulated during C2C12 myogenesis. Ccndbp1 overexpression promoted myogenesis, whereas knockdown of Ccndbp1 inhibited myogenic differentiation. Co-transfection of Ccndbp1 with MyoD and/or E47 (encoded by TCF3) significantly enhanced E-box-dependent transcription. Furthermore, Ccndbp1 physically associated with MyoD but not E47. These data suggest that Ccndbp1 regulates muscle differentiation by interacting with MyoD and enhancing its binding to target genes. Our study newly identifies Ccndbp1 as a positive modulator of skeletal myogenic differentiation in vivo and in vitro, providing new insights in order to decipher the complex network involved in skeletal myogenic development and related diseases.