N⁶-methyladenosine (m⁶A), the most abundant reversible modification on eukaryote messenger RNA, is recognized by a series of readers, including the YT521-B homology domain family (YTHDF) proteins, which are coupled to perform physiological functions. Here, we report that YTHDF2 and YTHDF3, but not YTHDF1, are required for reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). Mechanistically, we found that YTHDF3 recruits the PAN2-PAN3 deadenylase complex and conduces to reprogramming by promoting mRNA clearance of somatic genes, including Tead2 and Tgfb1, which parallels the activity of the YTHDF2-CCR4-NOT deadenylase complex. Ythdf2/3 deficiency represses mesenchymal-to-epithelial transition (MET) and chromatin silencing at loci containing the TEAD motif, contributing to decreased reprogramming efficiency. Moreover, RNA interference of Tgfb1 or the Hippo signaling effectors Yap1, Taz, and Tead2 rescues Ythdf2/3-defective reprogramming. Overall, YTHDF2/3 couples RNA deadenylation and regulation with the clearance of somatic genes and provides insights into iPSC reprogramming at the posttranscriptional level.

N ⁶ -甲基腺苷 (m ⁶ A) 是真核生物信使 RNA 上最丰富的可逆修饰，被一系列阅读器识别，包括 YT521-B 同源域家族 (YTHDF) 蛋白，它们偶联以执行生理功能。在这里，我们报告 YTHDF2 和 YTHDF3，而不是 YTHDF1，是将体细胞重编程为诱导多能干细胞 (iPSC) 所必需的。从机制上讲，我们发现 YTHDF3 募集 PAN2-PAN3 脱腺苷酸酶复合物，并通过促进体细胞基因（包括Tead2和Tgfb1）的mRNA 清除来促进重编程，这与 YTHDF2-CCR4-NOT 脱腺苷酸酶复合物的活性平行。Ythdf2/3缺乏抑制间充质到上皮转化 (MET) 和染色质沉默在含有 TEAD 基序的位点，导致重编程效率降低。此外，Tgfb1或 Hippo 信号效应子Yap1、Taz和Tead2 的RNA 干扰挽救了Ythdf2/3缺陷的重编程。总体而言，YTHDF2/3 将 RNA 去腺苷酸化和调节与体细胞基因的清除结合起来，并提供了对转录后水平的 iPSC 重编程的见解。