YTHDF2/3 are required for somatic reprogramming through different RNA deadenylation pathways

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 the 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 further represses mesenchymal-to-epithelial transition (MET) and chromatin silencing at loci containing the TEAD motif, contributing to decreased reprogramming efficiency. Moreover, we reveal that RNA interference of Tgfb1 or the Hippo signaling effectors Yap1 , Taz , and Tead2 rescues Ythdf2/3 deficiency-initiated defects in reprogramming. Overall, the compensatory mechanism by which YTHDF2/3 couple RNA deadenylation and regulation with the clearance of genes, in particular, Tead2 and Tgfb1 , in somatic cells provides novel insights into iPSC reprogramming at the posttranscriptional level.