Coordination of mRNA and tRNA methylations by TRMT10A

The posttranscriptional modification of messenger RNA (mRNA) and transfer RNA (tRNA) provides an additional layer of regulatory complexity during gene expression. Here, we show that a tRNA methyltransferase, TRMT10A, interacts with an mRNA demethylase FTO (ALKBH9), both in vitro and inside cells. TRMT10A installs N¹-methylguanosine (m¹G) in tRNA, and FTO performs demethylation on N⁶-methyladenosine (m⁶A) and N⁶,2'-O-dimethyladenosine (m⁶A_m) in mRNA. We show that TRMT10A ablation not only leads to decreased m¹G in tRNA but also significantly increases m⁶A levels in mRNA. Cross-linking and immunoprecipitation, followed by high-throughput sequencing results show that TRMT10A shares a significant overlap of associated mRNAs with FTO, and these mRNAs have accelerated decay rates potentially through the regulation by a specific m⁶A reader, YTHDF2. Furthermore, transcripts with increased m⁶A upon TRMT10A ablation contain an overrepresentation of m¹G9-containing tRNAs codons read by tRNA^Gln(TTG), tRNA^Arg(CCG), and tRNA^Thr(CGT) These findings collectively reveal the presence of coordinated mRNA and tRNA methylations and demonstrate a mechanism for regulating gene expression through the interactions between mRNA and tRNA modifying enzymes.