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.

肥胖正逐渐成为全球性公共健康问题。深入解析脂肪细胞发育的具体分子机制，对于过量脂肪堆积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调控，但其背后的核心分子机制仍未明确。本研究证实，敲低ZFP217可阻断有丝分裂克隆扩增（mitotic clonal expansion, MCE）过程，进而抑制脂肪生成。敲除ZFP217会上调N⁶-甲基腺苷（m⁶A）甲基转移酶样3（methyltransferase-like 3, METTL3）的表达水平，该酶可提升细胞周期蛋白D1（cyclin D1, CCND1）mRNA的m⁶A修饰丰度。进一步实验表明，敲低METTL3可逆转ZFP217敲低所抑制的MCE过程，并恢复CCND1的表达。YTH结构域家族2（YTH domain family 2, YTHDF2）能够识别并降解带有m⁶A修饰的CCND1 mRNA，导致CCND1表达下调，最终阻滞细胞周期进程，抑制脂肪生成。敲低YTHDF2则可缓解ZFP217敲低对脂肪细胞分化的抑制作用。本研究揭示，ZFP217敲低诱导的脂肪生成抑制，是通过METTL3与YTHDF2介导的m⁶A依赖式通路调控CCND1表达而实现的。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学术视角。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于ZFP217通过METTL3-m6A依赖机制调控脂肪生成的研究，揭示了ZFP217敲低通过增加METTL3表达、促进CCND1 mRNA的m6A甲基化，并由YTHDF2识别降解，从而阻断细胞周期和抑制脂肪生成的分子路径。数据集包括相关图表和补充材料，支持肥胖治疗的基础研究，并涉及生物化学、细胞生物学等多个学科领域。