Coordination of mRNA and tRNA methylations by TRMT10A

The post-transcriptional modification of mRNA and tRNA provides an additional layer of regulatory complexity during gene expression. TRMT10A is a tRNA methyltransferase that installs N1-methylguanosine (m1G), while FTO performs demethylation on N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) in mRNA. We find that this tRNA methyltransferase TRMT10A interacts with mRNA demethylase FTO (ALKBH9), both in vitro and inside cells. Strikingly, depletion of TRMT10A not only led to decreased m1G in tRNA but also significantly increased m6A levels in mRNA. CLIP-seq results showed that TRMT10A shares a significant overlap of associated mRNAs with FTO, and these mRNAs have accelerated decay rates potentially through the regulation by specific m6A reader. Furthermore, transcripts with increased m6A upon TRMT10A ablation contain an overrepresentation of m1G9-containing tRNAs codons read by tRNAGln(TTG), tRNAArg(CCG), and tRNAThr(CGT). These findings collectively reveal the presence of coordinated mRNA and tRNA modifications and demonstrate a mechanism for regulating gene expression through the interactions between mRNA and tRNA modifying enzymes. Overall design: m6A profiling in TRMT10A knockdown and control cells, TRMT10A CLIP-seq and FTO CLIP-seq.