TMT1A

TMT1A (METTL7A) is a SAM-dependent methyltransferase with dual roles in xenobiotic metabolism and epitranscriptomic gene regulation (PMID:37137720, PMID:40661507). Its best-defined activity is as the microsomal alkyl thiol methyltransferase of human liver, S-methylating exogenous thiol-containing substrates including 7α-thiospironolactone, dithiothreitol, 4-chlorothiophenol, and mertansine, with enzymatic activity tracking METTL7A/METTL7B protein abundance across liver microsomes (PMID:37137720). By methylating and inactivating the thiol zinc-binding moiety of thiol-based HDAC inhibitors such as romidepsin, METTL7A confers drug resistance and blunts downstream HDACi effects including p21 induction and H3K27 acetylation, an activity conserved across vertebrate homologs (PMID:38151817, PMID:38574836). Independently, METTL7A acts as an RNA methyltransferase: in endothelial cells it deposits internal m7G on AG-enriched motifs of protein-coding mRNAs, stabilizing KLF4 and NFKBIA transcripts and protecting against atherosclerosis in a mechanosensitive, flow-induced manner (PMID:40661507). In mesenchymal stem cells it functions as an m6A writer that stabilizes target transcripts and recruits the eIF4F initiation complex to drive YAP1 translation, activating a YAP1-TEAD1 feedback loop, and methylates Oga mRNA to modulate ECM O-GlcNAcylation, collectively promoting osteogenic differentiation (PMID:39815670, PMID:40558384). METTL7A protein is localized to the endoplasmic reticulum and lipid droplets (PMID:37176112), and additional regulatory functions in cancer have been described, including direct binding of SREBP1/SCAP to suppress cholesterol biosynthesis in colorectal cancer (PMID:42009961) and modulation of tumor immune responses in lung adenocarcinoma (PMID:41541671).

1. 2017 Medium

   Before its catalytic role was known, the question of how METTL7A expression is controlled was addressed, establishing that gene-body DNA methylation tunes its transcription.

   Evidence Site-directed CpG mutagenesis in an exogenous vector with ChIP for RNA Pol II and MeCP2 in papillary thyroid cancer cells

   PMID:28416772

   Open questions at the time

   • EZH2's role in setting gene-body methylation described as suggestive, not confirmed
   • No link to enzymatic function of the protein
   • Mechanism studied on an exogenous vector rather than the endogenous locus
2. 2021 Medium

   Post-transcriptional and protein-interaction regulation of METTL7A was probed, identifying a targeting miRNA and a candidate binding partner.

   Evidence Dual-luciferase reporter, biotinylated miRNA pull-down, mass spectrometry and Co-IP in dental pulp stem cells

   PMID:34790668

   Open questions at the time

   • Functional consequence of the SNRNP200 interaction for METTL7A activity not defined
   • Single-lab Co-IP without reciprocal validation
   • No demonstration of an enzymatic role in this system
3. 2023 High

   The long-sought identity of the microsomal thiol methyltransferase was resolved by showing METTL7A is a SAM-dependent enzyme that S-methylates exogenous thiol substrates.

   Evidence In vitro assay with purified recombinant protein, quantitative proteomics of liver microsomes, and gene modulation in HepG2/HeLa cells

   PMID:37137720

   Open questions at the time

   • Endogenous physiological thiol substrates not defined
   • No structural basis for substrate selectivity
   • Relative contributions of METTL7A vs METTL7B not separated
4. 2023 Medium

   Subcellular and tissue localization of METTL7A was mapped, placing the protein at the ER and lipid droplets and in cerebellar Bergmann glia.

   Evidence Immunohistochemistry, confocal microscopy, and 3D reconstruction of human cerebellum

   PMID:37176112

   Open questions at the time

   • No functional consequence linked to glial localization
   • Does not connect localization to enzymatic activity
   • Descriptive only
5. 2024 High

   The thiol-methyltransferase activity was extended to clinical relevance and evolutionary conservation, showing METTL7A/B inactivate thiol-based HDAC inhibitors to drive resistance.

   Evidence RNA-seq discovery in romidepsin-resistant cells, heterologous expression of vertebrate homologs in HEK-293, resistance assays, and LC-MS detection of dimethylated romidepsin

   PMID:38151817 PMID:38574836

   Open questions at the time

   • Whether thiol methylation activity contributes to clinical HDACi resistance in patients unknown
   • Catalytic residues mediating drug methylation not mapped
6. 2024 Medium

   A second, RNA-directed activity emerged, implicating METTL7A as an m6A regulator of osteogenic differentiation through CORIN and ERK signaling.

   Evidence m6A microarray, m6A-inhibitor and ERK-inhibitor treatments, and overexpression/knockdown rescue in orofacial BMSCs

   PMID:38782892

   Open questions at the time

   • Direct m6A catalysis by METTL7A not demonstrated biochemically
   • Non-selective inhibitor cycloleucine cannot isolate METTL7A activity
   • Reader linking m6A to CORIN expression unidentified
7. 2025 High

   The epitranscriptomic role was sharpened by defining METTL7A as a mechanosensitive internal m7G writer that stabilizes athero-protective transcripts.

   Evidence CLIP-seq, LC-MS/MS epitranscriptomic profiling, RNA stability assays, endothelial-specific and global knockout mice, and nanoparticle rescue in vivo

   PMID:40661507

   Open questions at the time

   • Reconciliation of m7G versus m6A activity in different cell types unresolved
   • Structural basis for AG-motif recognition unknown
   • Whether the same active site catalyzes thiol and RNA methylation not established
8. 2025 Medium

   Mechanistic depth in osteogenesis was added, showing METTL7A couples mRNA stabilization to translation via eIF4F and operates within a YAP1-TEAD1 feedback loop and an Oga/O-GlcNAcylation axis.

   Evidence mRNA stability and eIF4F recruitment assays, YAP1/TEAD1 readouts, and conditional Mettl7a knockout (Prx1-cre) and AAV rescue in OVX mice

   PMID:39815670 PMID:40558384

   Open questions at the time

   • Direct catalytic deposition of m6A on YAP1/Oga mRNA by METTL7A not shown enzymatically
   • Mechanism of eIF4F recruitment undefined
   • Single-lab mechanistic models
9. 2025 Medium

   Protein-level regulation and non-enzymatic functions in cancer were uncovered, including USP9X-mediated stabilization, chromatin/cohesin regulation, and tumor immune modulation.

   Evidence siRNA/overexpression rescue and xenografts (USP9X); chromatin binding, cohesin co-localization and Hi-C (chromatin); co-culture and single-cell transcriptomics (immune)

   PMID:41391677 PMID:41541671

   Open questions at the time

   • Direct deubiquitination of METTL7A by USP9X inferred, not shown by ubiquitination assay
   • How a methyltransferase regulates cohesin recruitment is mechanistically unexplained
   • Chromatin function evidence is preprint-level
10. 2026 Medium

    A non-catalytic scaffolding role in lipid metabolism was defined, with METTL7A binding SREBP1/SCAP to block SREBP1 nuclear translocation and suppress cholesterol synthesis.

    Evidence Co-IP, immunofluorescence, transcriptomics/proteomics, and in situ and spontaneous tumor mouse models in colorectal cancer

    PMID:42009961

    Open questions at the time

    • Whether binding requires methyltransferase activity not tested
    • Reciprocal validation of SREBP1/SCAP interaction limited
    • Structural interface undefined

• It remains unresolved whether the thiol-methyltransferase, m7G, and m6A activities arise from a single catalytic site and how METTL7A is partitioned among xenobiotic metabolism, RNA modification, and non-catalytic scaffolding roles across tissues.
• No structure of the catalytic domain bound to RNA or thiol substrate
• No clean separation-of-function mutants distinguishing the activities
• Endogenous determinants of which activity dominates in a given cell type unknown