YTHDF2 destabilizes m⁶A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells

Abstract

N 6 -methyladenosine (m 6 A) is an abundant post-transcriptional modification that can impact RNA fate via interactions with m 6 A-specific RNA binding proteins. Despite accumulating evidence that m 6 A plays an important role in modulating pluripotency, the influence of m 6 A reader proteins in pluripotency is less clear. Here, we report that YTHDF2, an m 6 A reader associated with mRNA degradation, is highly expressed in induced pluripotent stem cells (iPSCs) and down-regulated during neural differentiation. Through RNA sequencing, we identified a group of m 6 A-modified transcripts associated with neural development that are directly regulated by YTDHF2. Depletion of YTHDF2 in iPSCs leads to stabilization of these transcripts, loss of pluripotency, and induction of neural-specific gene expression. Collectively, our results suggest YTHDF2 functions to restrain expression of neural-specific mRNAs in iPSCs and facilitate their rapid and coordinated up-regulation during neural induction. These effects are both achieved by destabilization of the targeted transcripts.