Nature 526, 591–594 (2015)

N6-Methyladenosine (m6A) is the most abundant mRNA post-translational modification and is mediated by nuclear methyltransferase (MeT) proteins (including METTL3, METTl14 and WTAP). FTO is a demethylase that removes this modification. Once the modification occurs, m6A mRNA is specifically recognized in the cytoplasm by the RNA-binding protein YTHDF2, which regulates mRNA stability. In addition, m6A-modified mRNA regulates RNA-protein interactions and translational efficiency. However, it was not known whether this type of modification responds to environmental or cellular changes. To test this, Zhou et al. immunoprecipitated RNA with an m6A-specific antibody and used next-generation sequencing to examine changes in methylated RNA species in cells in the presence or absence of heat shock. Heat shock–upregulated genes, such as HSPA1A, exhibited an abundance of m6A, particularly in the 5′ UTR, whereas downregulated genes contained less methylation in the 5′ UTR. The authors found that heat-shock treatment did not alter the protein levels or activity of the nuclear MeT proteins but increased the transcription and nuclear translocation of YTHDF2. YTHDF2 knockdown decreased 5′ UTR m6A levels, indicating that YTHDF2 was necessary for the heat shock–induced m6A modification. YTHDF2 promoted m6A modification by effectively competing with FTO to prevent demethylation as knockdown of FTO increased 5′ UTR m6A levels in untreated conditions. Given that the 5′ UTR is involved in regulating mRNA translation, Zhou et al. performed ribosome profiling in heat shock–treated cells and noted that m6A 5′ UTR–modified mRNA exhibited increased ribosomal occupancy that was dependent on increased YTHDF2 levels. Because heat shock stress suppressed cap-dependent translation, the authors thought that the presence of m6A might act as a cap substitute to activate mRNA translation. Indeed, the addition of m6A to a 5′ UTR construct increased translational activity independent of the normal cap. Consistent with this hypothesis, mutation of the m6A site in Hsp70 mRNA or construction of an Hsp70 5′ UTR construct that failed to undergo m6A modification resulted in decreased translational efficiency. Overall, these findings reveal a role of m6A modification in providing a unique mode of mRNA translation.