N6-methyladenosine (m6A), as the most abundant internal modification with ubiquitous feature in eukaryotic mRNAs, has been connected with many fundamental aspects of RNA metabolism such as translation1,2,3, splicing4,5, stability and decay6. m6A modification is reversible and can be regulated by three groups of molecules commonly referred to as writers, erasers and readers. m6A writers are the components of the multi-complex methyltransferase catalyzing the formation of m6A methylation, among which METTL3, METTL14, WTAP and KIAA1429 are the key ones7,8,9,10,11. FTO and ALKBH5 (both belonging to AlkB family proteins) serve as the erasers of m6A modification12,13. The reader proteins can mediate biological function of the chemical modifications through recognizing and selectively binding to them. Several m6A readers with YTH domain located in the cytoplasmic compartment (YTHDF1, YTHDF2 and YTHDF3) and nuclear compartment (YTHDC1) have been identified and possess differential functions based on their molecular features and cellular localization. Cytoplasmic readers YTHDF1 and YTHDF2 were demonstrated to modulate translation of m6A-modified mRNA and mediate degradation of methylated mRNAs by targeting them to the decay sites, respectively2,6. Our recent study revealed that nuclear reader YTHDC1 regulates m6A-dependent mRNA splicing4. However, the detailed function of cytoplasmic reader YTHDF3 is still unclear. In this study, we show that YTHDF3 promotes translation, thus playing an important role in the initial stages of translation.

To explore the effect of YTHDF1 and YTHDF3 on each other's RNA-binding affinity, we performed PAR-CLIP (photoactivatable ribonucleoside crosslinking and immunoprecipitation) combined with in vitro RNA-end biotin-labeling assay. Intriguingly, YTHDF3 RNA-binding ability was significantly increased upon YTHDF1 knockdown (Figure 1C); and similarly, RNA-binding affinity of YTHDF1 was significantly enhanced when YTHDF3 was knocked down (Supplementary information, Figure S1B), suggesting that YTHDF1 and YTHDF3 negatively affect each other's RNA-binding affinity.

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