Nature 540, 242–247 (2016)

Nature 540, 301–304 (2016)

N6-Methyladenosine (m6A) RNA modification is mediated by components of a methyltransferase complex (including METTL3, METTL14 and WTAP) and is subsequently recognized by YTH domain RNA-binding proteins. METTL3 depletion in mice and plants results in embryonic lethality that precludes elucidation of additional functions of m6A modifications past embryogenesis. Lence et al. and Haussmann et al. characterized the Drosophila METTL3 (Ime4) and METTl14 (dMettl14) homologs and revealed a role for m6A in regulating sex determination and dosage compensation. Although these mutant flies were viable, there was a significant decrease in female mutants compared to males due to impaired dosage compensation in females. Transcriptome analysis of Drosophila ime4 mutants exhibited alterations in alternative splicing of Sex-lethal (sxl), the master regulator of female sex determination and dosage compensation. Alternative splicing of Sxl ensures production of functional Sxl protein in females only. Surviving adult female flies that were deficient in Ime4 exhibited defects in female-specific Sxl alternative splicing that resulted in sexual transformations. m6A directly modulates Sxl splicing as Sxl mRNA is m6A methylated and the m6A reader YTH–521-B was found to bind to a region near the regulated exon within the flanking Sxl intron. Overall, these findings reveal an important role of m6A in regulating sex determination and dosage compensation.