Zfp422 promotes skeletal muscle differentiation by regulating EphA7 to induce appropriate myoblast apoptosis
Zfp422 promotes skeletal muscle differentiation by regulating EphA7 to induce appropriate myoblast apoptosis
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Zfp422通过调节EphA7诱导适当的成肌细胞凋亡促进骨骼肌分化
DOI：
10.1038/s41418-019-0448-9
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发表时间：
2020-05-01
影响因子：
12.4
通讯作者：
Mo, Delin
中科院分区：
文献类型：
--
作者：
Nie, Yaping;Cai, Shufang;Mo, Delin
锌指蛋白422（Zfp 422）是一种广泛表达的锌指蛋白，作为转录因子调节下游基因的表达，但目前对其在肌肉发生中的作用知之甚少。我们发现Zfp 422在骨骼肌发育和再生中起着关键作用。在小鼠胚胎发育过程中，它在骨骼肌中高度表达。Zfp 422在骨骼肌中的特异性敲除损害胚胎肌肉形成。卫星细胞特异性Zfp 422缺失严重抑制肌肉再生。成肌细胞分化和肌管形成在Zfp 422缺失的C2 C12细胞、分离的原代成肌细胞和卫星细胞中受到抑制。染色质免疫沉淀测序（ChIP-Seq）显示Zfp 422通过结合上游169-bp的DNA序列来调节Ephrin type-A receptor 7（EphA 7）的表达，该序列被证明是EphA 7的增强子。敲低C2 C12细胞中的EphA 7或缺失成肌细胞中的Zfp 422将抑制成肌细胞分化所需的细胞凋亡。这些结果表明，Zfp 422通过调节EphA 7表达以维持适当的凋亡，对于骨骼肌分化和融合是必需的。
Zinc finger protein 422 (Zfp422) is a widely expressed zinc finger protein that serves as a transcriptional factor to regulate downstream gene expression, but until now, little is known about its roles in myogenesis. We found here that Zfp422 plays a critical role in skeletal muscle development and regeneration. It highly expresses in mouse skeletal muscle during embryonic development. Specific knockout of Zfp422 in skeletal muscle impaired embryonic muscle formation. Satellite cell-specific Zfp422 deletion severely inhibited muscle regeneration. Myoblast differentiation and myotube formation were suppressed in Zfp422-deleted C2C12 cells, isolated primary myoblasts, and satellite cells. Chromatin Immunoprecipitation Sequencing (ChIP-Seq) revealed that Zfp422 regulated ephrin type-A receptor 7 (EphA7) expression by binding an upstream 169-bp DNA sequence, which was proved to be an enhancer ofEphA7. Knocking EphA7 down in C2C12 cells or deleting Zfp422 in myoblasts will inhibit cell apoptosis which is required for myoblast differentiation. These results indicate that Zfp422 is essential for skeletal muscle differentiation and fusion, through regulating EphA7 expression to maintain proper apoptosis.