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 -methylguanosine (mG) in tRNA, and FTO performs demethylation on -methyladenosine (mA) and ,2'--dimethyladenosine (mA) in mRNA. We show that TRMT10A ablation not only leads to decreased mG in tRNA but also significantly increases mA 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 mA reader, YTHDF2. Furthermore, transcripts with increased mA upon TRMT10A ablation contain an overrepresentation of mG9-containing tRNAs codons read by tRNA, tRNA, and tRNA 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.