Methylation of Structured RNA by the m6A Writer METTL16 Is Essential for Mouse Embryonic Development

Abstract

SummaryInternal modification of RNAs with N6-methyladenosine (m6A) is a highly conserved means of gene expression control. While the METTL3/METTL14 heterodimer adds this mark on thousands of transcripts in a single-stranded context, the substrate requirements and physiological roles of the second m6A writer METTL16 remain unknown. Here we describe the crystal structure of human METTL16 to reveal a methyltransferase domain furnished with an extra N-terminal module, which together form a deep-cut groove that is essential for RNA binding. When presented with a random pool of RNAs, METTL16 selects for methylation-structured RNAs where the critical adenosine is present in a bulge. Mouse 16-cell embryos lacking Mettl16 display reduced mRNA levels of its methylation target, the SAM synthetase Mat2a. The consequence is massive transcriptome dysregulation in ∼64-cell blastocysts that are unfit for further development. This highlights the role of an m6A RNA methyltransferase in facilitating early development via regulation of SAM availability.

Functions of N6-methyladenosine and its role in cancer

“…METTL16 binds a subset of mRNAs and methylates long noncoding RNA (lncRNA) and U6 small nuclear RNA (U6 snRNA) [59,60]. The UACAGAGAA sequence is required for METTL16-mediated-methylation and the Nterminal module of METTL16 is essential for RNA binding [61,62].…”

Occurrence and Functions of m6A and Other Covalent Modifications in Plant mRNA

“…The essential mammalian enzyme METTL16 methylates structured RNAs containing the nonamer UAC(A)GAGAA (Pendleton et al, 2017). Its few identified targets include the MAT2A mRNA encoding SAM synthetase, and the embryo-lethal phenotype of mettl16 mutants may indeed result from disrupted SAM homeostasis (Pendleton et al, 2017;Warda et al, 2017;Mendel et al, 2018). Interestingly, a clear METTL16 homolog, FIONA1 (FIO1), exists in plants.…”

N6-Methyladenosine: A Novel RNA Imprint in Human Cancer

“…Scientists have also reported some other proteins that modulate the cellular m 6 A landscape cooperatively. METTL16, a newly defined m 6 A writer targeting U6 spliceosomal small nuclear RNA, also regulates S-adenosylmethionine homeostasis by inducing the expression of S-adenosylmethionine synthetase upon methionine starvation (13)(14)(15)(16).…”