m6A甲基转移酶Mettl16在果蝇发育中的作用

Abstract

N 6 -methyladenosine (m 6 A), one of the most abundant chemical modifications on RNA, is installed by METTL3 and several other methyltransferases, including METTL16. Although METTL16 has been characterized in several model organisms, its function in Drosophila remains unknown. Here, we show that, unlike in mammals, Drosophila Mettl16 mutants are viable but exhibit multiple developmental and behavioral defects. Both male and female mutants are sterile, with severe gametogenesis defects. Mettl16 mutant germ cells can pass the mitotic and meiotic stages, but are defective in spermatid elongation and individualization. Mettl16-GFP localizes predominantly to the nucleus, and its absence does not impair global protein synthesis in wing disc epithelial cells. MeRIP-Seq analysis indicates that Mettl16 loss affects m 6 A on only a small subset of transcripts, in contrast to the broad effect of Mettl3. We further demonstrate that Mettl16 interacts with U6 snRNA and is required for its m 6 A modification. Accordingly, Mettl16 mutants display widespread alterations in alternative splicing. Together, the pleiotropic phenotypes of Mettl16 mutants likely stem from its role in m 6 A deposition and U6-dependent splicing regulation of specific target transcripts. RNA molecules carry chemical modifications that act as key regulators of their function. Among the most common is m 6 A, which is added by several “writer” proteins. One of these writers, Mettl16, is conserved across species, yet its in vivo role remains less understood, especially in the fruit fly Drosophila . In this study, we uncover the key functions of Mettl16 in fly development and reproduction. Flies lacking Mettl16 are viable but show a range of developmental and behavioral problems. Interestingly, both males and females are sterile, with severe defects in sperm and egg production. Mechanistically, Mettl16 only methylates a small subset of mRNAs, unlike the broad activity of the major writer Mettl3. Los