YTHDF2/3 Are Required for Somatic Reprogramming through Different RNA Deadenylation Pathways

Abstract

N 6 -methyladenosine (m 6 A), 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.

N6‐Methyladenosine mRNA methylation is important for salt stress tolerance in Arabidopsis

“…Results obtained in the present study show that the loss of m 6 A modification contributes to lengthening the 3ʹ‐UTR of ATAF1 , GI and GSTU17 transcripts via alterations in poly(A) site usage (Figure 5). Given that the m 6 A marks in the 3ʹ‐UTR are recognized by the m 6 A reader proteins YTHDF2 and YTHDF3, which are involved in mRNA decay via the YTHDF2‐CCR4‐NOT and YTHDF3‐PAN2‐PAN3 pathways, respectively, in mammals (Du et al , 2016; Liu et al , 2020), it is highly likely that the loss of the m 6 A marks in the 3ʹ‐UTRs of the ATAF1 , GI and GSTU17 transcripts in the vir‐1 mutant renders them unrecognizable by m 6 A reader proteins, which results in 3ʹ‐UTR lengthening and a concomitant increase in the stability of these transcripts. Because the stability and integrity of m 6 A‐containing transcripts can be modulated by specific reader proteins (Pontier et al , 2019; Wei et al , 2018), it is of primary importance to further determine how different m 6 A marks are recognized by specific reader proteins, and how this interaction is associated with the stability of m 6 A‐containing transcripts.…”

ALKBH5 regulates somatic cell reprogramming in a phase specific manner

“…A recent study reported that YTHDF2/3, but not YTHDF1, regulate the MET event in somatic cell reprogramming in an m 6 A dependent manner through the Hippo signaling pathway effector Tead2 [44]. Other studies have shown redundancy among the three paralogs Ythdf1/2/3, suggesting they can have adequate functional compensation at least in some biological contexts [45,46].…”

Emerging Perspectives of RNA N6-methyladenosine (m6A) Modification on Immunity and Autoimmune Diseases

“…Additionally, m 6 A-methylated mRNAs can be also decayed by YTHDF2-Heat-responsive protein 12 (HRSP12)-RNase P/MRP-mediated endoribonucleolytic cleavage (20). Moreover, YTHDF3 can induce m 6 A-decorated mRNAs deadenylation and sequent decay by recruiting PAN2-PAN3 deadenylase complex (28). Nonetheless, accumulating evidence also indicate that several m 6 A-readers, including IGF2BPs, FMRP and Prrc2a, can conversely enhance stability of m 6 A-containg mRNA (29)(30)(31).…”