Cytoplasmic m1A reader YTHDF3 inhibits trophoblast invasion by downregulation of m1A-methylated IGF1R

N-1-methyladenosine (m(1)A) is one of the important post-transcriptional modifications in RNA and plays an important role in promoting translation or decay of m(1)A-methylated messenger RNA (mRNA), but the reader protein and the exact biological role of m(1)A remain to be determined. Here, we identified that nine potential m(1)A reader proteins including YTH domain family and heterogeneous nuclear ribonucleoprotein by mass spectrometry, and among them, YTH domain-containing protein 3 (YTHDF3), could bind directly to m(1)A-carrying RNA. YTHDF3 was then identified to negatively regulate invasion and migration of trophoblast. Mechanistically, we found that the m(1)A reader YTHDF3 bound to certain m(1)A-methylated transcripts, such as insulin-like growth factor 1 receptor (IGF1R), with the combination of iCLIP-seq (individual-nucleotide resolution ultraviolet crosslinking and immunoprecipitation high-throughput sequencing) and m(1)A-seq. Furthermore, YTHDF3 could promote IGF1R mRNA degradation and thus inhibit IGF1R protein expression along with its downstream matrix metallopeptidase 9 signaling pathway, consequently decreasing migration and invasion of trophoblast. Thus, we demonstrated that YTHDF3 as an m(1)A reader decreased invasion and migration of trophoblast by inhibiting IGF1R expression. Our study outlines a new m(1)A epigenetic way to regulate the trophoblast activity, which suggests a novel therapeutic target for trophoblast-associated pregnancy disorders.