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

Jiadong Liu; Mingwei Gao; Shuyang Xu; Yaping Chen; Kaixin Wu; He Liu; Jie Wang; Xuejie Yang; Junwei Wang; Weiwei Liu; Xichen Bao; Jiekai Chen

doi:10.1016/j.celrep.2020.108120

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

Jiadong Liu^#; Mingwei Gao^#; Shuyang Xu; Yaping Chen; Kaixin Wu; He Liu; Jie Wang; Xuejie Yang; Junwei Wang; Weiwei Liu; Xichen Bao; Jiekai Chen^*

Cell Reports, 2020, 32(10): 108120.

DOI: 10.1016/j.celrep.2020.108120

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Summary

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 Tgfbl, 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 Tgfbl 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.

Keywords

HIPPO SIGNALING PATHWAY; MESSENGER-RNA; M(6)A RNA; READ ALIGNMENT; NUCLEAR-RNA; YTH DOMAIN; STEM; BINDING; N-6-METHYLADENOSINE; TRANSCRIPTION

Institution

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences

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