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

-methyladenosine (mA) is an abundant post-transcriptional modification that can impact RNA fate via interactions with mA-specific RNA binding proteins. Despite accumulating evidence that mA plays an important role in modulating pluripotency, the influence of mA reader proteins in pluripotency is less clear. Here, we report that YTHDF2, an mA 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 mA-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.