ZFP217 regulates adipogenesis by controlling mitotic clonal expansion in a METTL3-m⁶A dependent manner

Obesity is becoming a global problem. Research into the detailed mechanism of adipocyte development is crucial for the treatment of excess fat. Zinc finger protein 217 plays roles in adipogenesis. However, the underlying mechanism remains unclear. Here, we demonstrated that ZFP217 knockdown prevented the mitotic clonal expansion process and caused adipogenesis inhibition. Depletion of ZFP217 increased the expression of the m6A methyltransferase METTL3, which upregulated the m6A level of cyclin D1 mRNA. METTL3 knockdown rescued the siZFP217-inhibited MCE and promoted CCND1 expression. YTH domain family 2 recognized and degraded the methylated CCND1 mRNA, leading to the downregulation of CCND1. Consequently, cell-cycle progression was blocked, and adipogenesis was inhibited. YTHDF2 knockdown relieved siZFP217-inhibited adipocyte differentiation. These findings reveal that ZFP217 knockdown–induced adipogenesis inhibition was caused by CCND1, which was mediated by METTL3 and YTHDF2 in an m6A-dependent manner. We have provided novel insight into the underlying molecular mechanisms by which m6A methylation is involved in the ZFP217 regulation of adipogenesis.肥胖正日益成为全球性公共健康问题。深入探究脂肪细胞发育的详细机制，对于过量脂肪的临床治疗具有关键意义。锌指蛋白217（Zinc finger protein 217, ZFP217）已被证实参与脂肪生成过程，但其具体的分子调控机制仍未阐明。本研究证实，敲低ZFP217会阻断有丝分裂克隆扩增（mitotic clonal expansion, MCE）过程，进而抑制脂肪生成。敲低ZFP217可上调m6A甲基转移酶（m6A methyltransferase）METTL3的表达，进而提升细胞周期蛋白D1（cyclin D1）mRNA的m6A修饰水平。敲低METTL3可逆转siZFP217介导的有丝分裂克隆扩增抑制，并恢复CCND1的表达水平。YTH结构域家族2（YTH domain family 2, YTHDF2）可识别并降解发生m6A修饰的CCND1 mRNA，最终导致CCND1表达下调。由此，细胞周期进程被阻断，脂肪生成过程亦受到抑制。敲低YTHDF2可缓解siZFP217对脂肪细胞分化的抑制作用。本研究结果表明，ZFP217敲低所引发的脂肪生成抑制，是通过METTL3与YTHDF2依赖m6A修饰的方式调控CCND1表达所介导的。本研究为m6A甲基化参与ZFP217调控脂肪生成的潜在分子机制提供了全新的研究视角。