{"gene":"TMT1A","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2023,"finding":"METTL7A (TMT1A) is a SAM-dependent thiol methyltransferase responsible for microsomal alkyl S-thiol methyltransferase (TMT) activity in human liver. Purified recombinant His-GST-tagged METTL7A selectively methylates exogenous thiol-containing substrates including 7α-thiospironolactone, dithiothreitol, 4-chlorothiophenol, and mertansine. TMT activity in human liver microsomes correlates closely with METTL7A and METTL7B protein levels by quantitative proteomics, and gene modulation in HepG2 and HeLa cells confirmed this correlation.","method":"In vitro enzymatic assay with purified recombinant protein; quantitative proteomics of human liver microsomes; gene modulation (overexpression/knockdown) in HepG2 and HeLa cells","journal":"Drug metabolism and disposition: the biological fate of chemicals","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant protein plus orthogonal proteomics and cell-based gene modulation in a single rigorous study","pmids":["37137720"],"is_preprint":false},{"year":2024,"finding":"METTL7A (TMT1A) and METTL7B (TMT1B) confer resistance to thiol-based histone deacetylase inhibitors (romidepsin and related compounds) by methylating and inactivating the thiol zinc-binding moiety of these drugs. Overexpression of METTL7A in MCF-7 cells selected for romidepsin resistance (MCF-7 DpVp300) was identified by RNA-seq and confirmed to methylate thiol-containing HDACis directly.","method":"RNA-seq identification; overexpression in cancer cells; resistance assay; direct methylation of thiol-HDACi substrates demonstrated","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RNA-seq discovery plus functional overexpression plus direct substrate methylation assay in a single study with multiple orthogonal methods","pmids":["38151817"],"is_preprint":false},{"year":2024,"finding":"The thiol methyltransferase activity of TMT1A (METTL7A) is conserved across species (rat, mouse, chicken, zebrafish homologs). All species homologs expressed in HEK-293 cells conferred resistance to thiol-based HDACIs (NCH-51, KD-5170, romidepsin), blunted downstream HDACi effects (p21 induction, H3K27 acetylation, cell cycle arrest), and produced increased dimethylated romidepsin in culture medium.","method":"Heterologous expression of species homologs in HEK-293 cells; drug resistance assays; LC-MS detection of dimethylated romidepsin product","journal":"Chemico-biological interactions","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple species homologs tested, orthogonal readouts (resistance, biochemical downstream markers, product detection), replicated finding across homologs","pmids":["38574836"],"is_preprint":false},{"year":2023,"finding":"The thiol methyltransferase activity of TMT1A is conserved across species (preprint version confirming published finding); all species homologs expressed in HEK-293 cells conferred resistance to thiol-based HDACIs and produced dimethylated romidepsin.","method":"Heterologous expression; drug resistance assay; LC-MS product detection","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — same findings as peer-reviewed version but preprint; multiple orthogonal methods, single lab","pmids":["38076968"],"is_preprint":true},{"year":2025,"finding":"METTL7A functions as a mechanosensitive internal m7G mRNA methyltransferase in endothelial cells. Athero-protective unidirectional flow induces METTL7A expression; METTL7A promotes internal m7G methylation (not cap-associated m7G or other epitranscriptomic marks) of endothelial mRNAs. METTL7A preferentially binds AG-enriched motifs in protein-coding mRNAs (by CLIP-seq) and stabilizes KLF4 and NFKBIA transcripts by enhancing their internal m7G. Global or endothelial-specific Mettl7a1 knockout mice show exacerbated atherosclerosis; nanoparticle-mediated METTL7A restoration reduces lesion formation.","method":"CLIP-seq; LC-MS/MS epitranscriptomic profiling; RNA stability assays; CIRTS; endothelial-specific and global knockout mouse models; nanoparticle-mediated rescue in vivo","journal":"bioRxiv (preprint) / also published in PMID:40661507","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (CLIP-seq, LC-MS/MS, RNA stability, genetic KO, in vivo rescue) in a single comprehensive study","pmids":["40661507"],"is_preprint":false},{"year":2017,"finding":"DNA methylation of a CpG site within the METTL7A gene body (exon) regulates its transcriptional activity. Mutation of this CpG site (CG to CC) in an exogenous vector in papillary thyroid cancer cells resulted in higher RNA polymerase II recruitment and reduced methyl-CpG binding protein-2 (MeCP2) enrichment at the gene body. EZH2, a subunit of polycomb repressor complex 2, was identified as potentially responsible for regulating gene body methylation of METTL7A in thyroid cancer.","method":"Site-directed mutagenesis of CpG site in exogenous vector; ChIP for RNA Pol II and MeCP2; in vitro cell comparison (BCPAP vs normal thyroid cells)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus ChIP assays, single lab, two orthogonal methods, but EZH2 role described as suggestive rather than fully confirmed","pmids":["28416772"],"is_preprint":false},{"year":2021,"finding":"METTL7A is a direct target of miR-6807-5p (binding confirmed at the 3'UTR by dual-luciferase reporter assay and pull-down with biotinylated miRNA). SNRNP200 was identified as a co-binding protein of METTL7A by protein mass spectrometry and Co-IP. Knockdown of SNRNP200 inhibited odontogenic differentiation of dental pulp stem cells.","method":"Dual-luciferase reporter assay; biotinylated miRNA pull-down; protein mass spectrometry; co-immunoprecipitation (Co-IP)","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct binding confirmation by two orthogonal methods (luciferase + pull-down), Co-IP for SNRNP200 interaction; single lab","pmids":["34790668"],"is_preprint":false},{"year":2023,"finding":"METTL7A is localized to the endoplasmic reticulum and to lipid droplets in some cells, with a novel localization identified in GFAP-positive Bergmann glial cells of the human cerebellum, particularly enriched at the end-feet participating in the cerebrospinal fluid-brain parenchyma barrier and at contacts between Bergmann glia and Purkinje neurons.","method":"Immunohistochemistry; laser confocal microscopy; 3D reconstruction image analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunohistochemistry and confocal microscopy with 3D reconstruction, but no functional consequence directly linked in this study","pmids":["37176112"],"is_preprint":false},{"year":2024,"finding":"METTL7A modulates m6A modification of CORIN mRNA and thereby regulates corin expression during orofacial BMSC osteogenic differentiation. Cycloleucine (a non-selective m6A methylase inhibitor) blocked the corin-mediated promotion of differentiation, and METTL7A overexpression reversed bisphosphonate-impaired BMSC differentiation. The corin-mediated differentiation promotion operates via the ERK pathway (phos-ERK alteration; blocked by PD98059).","method":"m6A epitranscriptomic microarray; m6A inhibitor treatment; METTL7A overexpression/knockdown; ERK pathway inhibitor (PD98059); ALP and Alizarin Red staining","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — m6A microarray plus functional rescue experiments and pathway inhibitor, single lab, moderate mechanistic depth","pmids":["38782892"],"is_preprint":false},{"year":2025,"finding":"METTL7A drives MSC osteogenic differentiation by activating the YAP1-TEAD1 signaling pathway. METTL7A stabilizes YAP1 mRNA and recruits the eIF4F translation initiation complex to boost YAP1 translation efficiency. The YAP1/TEAD1 complex in turn transcriptionally regulates METTL7A expression, creating a positive feedback loop amplifying osteogenic differentiation.","method":"Western blotting; ALP and Alizarin Red S staining; in vivo bone regeneration studies; mRNA stability assays; eIF4F complex recruitment assay","journal":"International endodontic journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple functional and biochemical assays in single lab, pathway mechanism proposed with supporting data, but abstract-level description limits full method verification","pmids":["39815670"],"is_preprint":false},{"year":2025,"finding":"USP9X deubiquitinase stabilizes METTL7A protein by regulating its deubiquitination, thereby promoting AML cell growth and adriamycin resistance. USP9X knockdown decreased METTL7A protein stability, and METTL7A overexpression reversed growth inhibition caused by USP9X knockdown.","method":"Co-expression analysis; siRNA knockdown; overexpression rescue; colony formation; xenograft mouse model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional rescue and in vivo validation, but deubiquitination of METTL7A by USP9X is inferred rather than directly demonstrated by ubiquitination assay in the abstract","pmids":["41391677"],"is_preprint":false},{"year":2025,"finding":"METTL7A promotes Mettl7a-mediated m6A methylation of Oga mRNA, regulating O-GlcNAcylation of the ECM protein BSP (bone sialoprotein), thereby promoting BMSC osteogenic differentiation. Conditional knockout of Mettl7a in mesenchyme (Prx1-cre;Mettl7af/f) accelerated bone loss in OVX mice, and Mettl7a-AAV treatment alleviated the bone loss phenotype.","method":"Conditional knockout mouse model (Prx1-cre;Mettl7af/f); AAV overexpression in vivo; m6A methylation analysis; O-GlcNAcylation assays; osteogenic differentiation assays","journal":"Stem cells translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model with defined phenotype and molecular mechanism (m6A of Oga → O-GlcNAcylation of BSP), single lab","pmids":["40558384"],"is_preprint":false},{"year":2025,"finding":"METTL7A protein has a novel chromatin regulatory function in TKI-resistant lung adenocarcinoma cells: it binds to amplified oncogene loci, regulates cohesin recruitment, and modulates inter-TAD interactions, remodeling the chromatin landscape prior to large-scale copy number gains. METTL7A depletion prevents formation and maintenance of TKI-resistant clones without affecting chromatin structure or proliferation of drug-naïve cells.","method":"Chromatin binding assays; cohesin co-localization; Hi-C/inter-TAD interaction analysis; METTL7A depletion in drug-naïve vs. TKI-resistant cells; clone formation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, abstract-level description of chromatin binding and cohesin regulation without full methodological detail","pmids":["bio_10.1101_2025.01.26.634826"],"is_preprint":true},{"year":2026,"finding":"METTL7A directly binds SREBP1 and SCAP (by Co-IP and immunofluorescence), hindering nuclear translocation of SREBP1 and thereby reducing intracellular cholesterol content in colorectal cancer cells. Transcriptomic and proteomic analyses showed METTL7A affects genes in the cholesterol metabolism pathway (FDFT1, SQLE, CYP51A1).","method":"Co-immunoprecipitation; immunofluorescence; transcriptomics; proteomics; in situ tumor and spontaneous tumor mouse models","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus immunofluorescence plus multi-omics in single lab, direct binding to SREBP1/SCAP demonstrated","pmids":["42009961"],"is_preprint":false},{"year":2025,"finding":"TMT1A (METTL7A) inhibits M2 macrophage polarization in lung adenocarcinoma and downregulates PD-L1 expression in LUAD cells. In co-culture experiments, TMT1A knockdown suppressed T cell activation and reduced IFN-γ secretion; in vivo, TMT1A expression promoted CD8+ T cell infiltration.","method":"Co-culture experiments with LUAD cells and T cells; in vivo tumor models; functional assays (proliferation, migration); single-cell transcriptome analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — defined cellular mechanism (M2 polarization, PD-L1, T cell activation) with in vitro and in vivo validation, single lab","pmids":["41541671"],"is_preprint":false}],"current_model":"TMT1A (METTL7A) is an SAM-dependent methyltransferase with at least three distinct enzymatic activities: (1) a microsomal thiol methyltransferase that S-methylates exogenous aliphatic and phenolic thiol-containing substrates (including clinically relevant drugs such as romidepsin, captopril, and spironolactone metabolites), conferring resistance to thiol-based HDAC inhibitors; (2) a mechanosensitive internal m7G mRNA methyltransferase in endothelial cells that binds AG-enriched motifs, stabilizes KLF4 and NFKBIA transcripts, and protects against atherosclerosis; and (3) an m6A writer that regulates target mRNA stability and translation (including via eIF4F recruitment for YAP1 mRNA), promoting MSC osteogenic differentiation through the YAP1-TEAD1 axis and modulating ECM O-GlcNAcylation through Oga mRNA methylation; additionally, METTL7A protein has a novel chromatin-regulatory function binding amplified loci and regulating cohesin recruitment in TKI-resistant lung cancer cells, and directly binds SREBP1/SCAP to suppress cholesterol biosynthesis in colorectal cancer."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2017,"claim":"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","pmids":["28416772"],"confidence":"Medium","gaps":["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"]},{"year":2021,"claim":"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","pmids":["34790668"],"confidence":"Medium","gaps":["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"]},{"year":2023,"claim":"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","pmids":["37137720"],"confidence":"High","gaps":["Endogenous physiological thiol substrates not defined","No structural basis for substrate selectivity","Relative contributions of METTL7A vs METTL7B not separated"]},{"year":2023,"claim":"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","pmids":["37176112"],"confidence":"Medium","gaps":["No functional consequence linked to glial localization","Does not connect localization to enzymatic activity","Descriptive only"]},{"year":2024,"claim":"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","pmids":["38151817","38574836"],"confidence":"High","gaps":["Whether thiol methylation activity contributes to clinical HDACi resistance in patients unknown","Catalytic residues mediating drug methylation not mapped"]},{"year":2024,"claim":"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","pmids":["38782892"],"confidence":"Medium","gaps":["Direct m6A catalysis by METTL7A not demonstrated biochemically","Non-selective inhibitor cycloleucine cannot isolate METTL7A activity","Reader linking m6A to CORIN expression unidentified"]},{"year":2025,"claim":"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","pmids":["40661507"],"confidence":"High","gaps":["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"]},{"year":2025,"claim":"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","pmids":["39815670","40558384"],"confidence":"Medium","gaps":["Direct catalytic deposition of m6A on YAP1/Oga mRNA by METTL7A not shown enzymatically","Mechanism of eIF4F recruitment undefined","Single-lab mechanistic models"]},{"year":2025,"claim":"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)","pmids":["41391677","41541671"],"confidence":"Medium","gaps":["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"]},{"year":2026,"claim":"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","pmids":["42009961"],"confidence":"Medium","gaps":["Whether binding requires methyltransferase activity not tested","Reciprocal validation of SREBP1/SCAP interaction limited","Structural interface undefined"]},{"year":null,"claim":"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.","evidence":"No single study reconciles the distinct enzymatic and scaffolding activities","pmids":[],"confidence":"Low","gaps":["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"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,4]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[4,9,11]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,9,11]},{"term_id":"R-HSA-9748784","term_label":"Drug ADME","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13]}],"complexes":[],"partners":["METTL7B","SNRNP200","USP9X","SREBP1","SCAP","EIF4F"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H8H3","full_name":"Thiol S-methyltransferase TMT1A","aliases":["Methyltransferase-like protein 7A","N6-adenosine-methyltransferase TMT1A","Protein AAM-B","Thiol methyltransferase 1A"],"length_aa":244,"mass_kda":28.3,"function":"Thiol S-methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to alkyl and phenolic thiol-containing acceptor substrates. Together with TMT1B accounts for most of S-thiol methylation activity in the endoplasmic reticulum of hepatocytes (PubMed:37137720). Able to methylate the N6 position of adenosine residues in long non-coding RNAs (lncRNAs). May facilitate lncRNAs transfer into exosomes at the tumor-stroma interface (PubMed:34980213). Promotes osteogenic and odontogenic differentiation by regulating the expression of genes involved in stem cell differentiation and survival (PubMed:34226523, PubMed:34790668). Targeted from the endoplasmic reticulum to lipid droplets, where it recruits cellular proteins to form functional organelles (PubMed:19773358) (Microbial infection) May be involved in the assembly and release stages of hepatitis C virus (HCV) life cycle and thus play a crucial role in HCV propagation","subcellular_location":"Lipid droplet; Endoplasmic reticulum; Membrane; Microsome; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q9H8H3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMT1A","classification":"Not Classified","n_dependent_lines":174,"n_total_lines":1208,"dependency_fraction":0.14403973509933773},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMT1A","total_profiled":1310},"omim":[{"mim_id":"618338","title":"THIOL METHYLTRANSFERASE 1A; TMT1A","url":"https://www.omim.org/entry/618338"},{"mim_id":"601112","title":"THIOREDOXIN REDUCTASE 1; TXNRD1","url":"https://www.omim.org/entry/601112"}],"hpa":{"profiled":true,"resolved_as":"METTL7A","reliability":"Supported","locations":[{"location":"Lipid droplets","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":395.4}],"url":"https://www.proteinatlas.org/search/METTL7A"},"hgnc":{"alias_symbol":["DKFZP586A0522"],"prev_symbol":["METTL7A"]},"alphafold":{"accession":"Q9H8H3","domains":[{"cath_id":"3.40.50.150","chopping":"1-244","consensus_level":"medium","plddt":96.0969,"start":1,"end":244}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8H3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8H3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8H3-F1-predicted_aligned_error_v6.png","plddt_mean":96.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMT1A","jax_strain_url":"https://www.jax.org/strain/search?query=TMT1A"},"sequence":{"accession":"Q9H8H3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H8H3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H8H3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8H3"}},"corpus_meta":[{"pmid":"28416772","id":"PMC_28416772","title":"DNA methylation of METTL7A gene body regulates its transcriptional level in thyroid cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28416772","citation_count":39,"is_preprint":false},{"pmid":"34226523","id":"PMC_34226523","title":"Methyltransferase-like protein 7A (METTL7A) promotes cell survival and osteogenic differentiation under metabolic stress.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34226523","citation_count":26,"is_preprint":false},{"pmid":"38782892","id":"PMC_38782892","title":"METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs.","date":"2024","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/38782892","citation_count":20,"is_preprint":false},{"pmid":"37137720","id":"PMC_37137720","title":"METTL7A (TMT1A) and METTL7B (TMT1B) Are Responsible for Alkyl S-Thiol Methyl Transferase Activity in Liver.","date":"2023","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/37137720","citation_count":19,"is_preprint":false},{"pmid":"36830565","id":"PMC_36830565","title":"Evidence Based on an Integrative Analysis of Multi-Omics Data on METTL7A as a Molecular Marker in Pan-Cancer.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36830565","citation_count":18,"is_preprint":false},{"pmid":"38151817","id":"PMC_38151817","title":"The Methyltransferases METTL7A and METTL7B Confer Resistance to Thiol-Based Histone Deacetylase Inhibitors.","date":"2024","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/38151817","citation_count":16,"is_preprint":false},{"pmid":"34790668","id":"PMC_34790668","title":"miR-6807-5p Inhibited the Odontogenic Differentiation of Human Dental Pulp Stem Cells Through Directly Targeting METTL7A.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34790668","citation_count":14,"is_preprint":false},{"pmid":"37176112","id":"PMC_37176112","title":"A Novel Localization of METTL7A in Bergmann Glial Cells in Human Cerebellum.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37176112","citation_count":7,"is_preprint":false},{"pmid":"37547717","id":"PMC_37547717","title":"Transcriptomic characterization revealed that METTL7A inhibits melanoma progression via the p53 signaling pathway and immunomodulatory pathway.","date":"2023","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/37547717","citation_count":6,"is_preprint":false},{"pmid":"39883095","id":"PMC_39883095","title":"METTL7A improves bovine IVF embryo competence by attenuating oxidative stress†.","date":"2025","source":"Biology of 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Purified recombinant His-GST-tagged METTL7A selectively methylates exogenous thiol-containing substrates including 7α-thiospironolactone, dithiothreitol, 4-chlorothiophenol, and mertansine. TMT activity in human liver microsomes correlates closely with METTL7A and METTL7B protein levels by quantitative proteomics, and gene modulation in HepG2 and HeLa cells confirmed this correlation.\",\n      \"method\": \"In vitro enzymatic assay with purified recombinant protein; quantitative proteomics of human liver microsomes; gene modulation (overexpression/knockdown) in HepG2 and HeLa cells\",\n      \"journal\": \"Drug metabolism and disposition: the biological fate of chemicals\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant protein plus orthogonal proteomics and cell-based gene modulation in a single rigorous study\",\n      \"pmids\": [\"37137720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL7A (TMT1A) and METTL7B (TMT1B) confer resistance to thiol-based histone deacetylase inhibitors (romidepsin and related compounds) by methylating and inactivating the thiol zinc-binding moiety of these drugs. Overexpression of METTL7A in MCF-7 cells selected for romidepsin resistance (MCF-7 DpVp300) was identified by RNA-seq and confirmed to methylate thiol-containing HDACis directly.\",\n      \"method\": \"RNA-seq identification; overexpression in cancer cells; resistance assay; direct methylation of thiol-HDACi substrates demonstrated\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq discovery plus functional overexpression plus direct substrate methylation assay in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"38151817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The thiol methyltransferase activity of TMT1A (METTL7A) is conserved across species (rat, mouse, chicken, zebrafish homologs). All species homologs expressed in HEK-293 cells conferred resistance to thiol-based HDACIs (NCH-51, KD-5170, romidepsin), blunted downstream HDACi effects (p21 induction, H3K27 acetylation, cell cycle arrest), and produced increased dimethylated romidepsin in culture medium.\",\n      \"method\": \"Heterologous expression of species homologs in HEK-293 cells; drug resistance assays; LC-MS detection of dimethylated romidepsin product\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple species homologs tested, orthogonal readouts (resistance, biochemical downstream markers, product detection), replicated finding across homologs\",\n      \"pmids\": [\"38574836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The thiol methyltransferase activity of TMT1A is conserved across species (preprint version confirming published finding); all species homologs expressed in HEK-293 cells conferred resistance to thiol-based HDACIs and produced dimethylated romidepsin.\",\n      \"method\": \"Heterologous expression; drug resistance assay; LC-MS product detection\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — same findings as peer-reviewed version but preprint; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38076968\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL7A functions as a mechanosensitive internal m7G mRNA methyltransferase in endothelial cells. Athero-protective unidirectional flow induces METTL7A expression; METTL7A promotes internal m7G methylation (not cap-associated m7G or other epitranscriptomic marks) of endothelial mRNAs. METTL7A preferentially binds AG-enriched motifs in protein-coding mRNAs (by CLIP-seq) and stabilizes KLF4 and NFKBIA transcripts by enhancing their internal m7G. Global or endothelial-specific Mettl7a1 knockout mice show exacerbated atherosclerosis; nanoparticle-mediated METTL7A restoration reduces lesion formation.\",\n      \"method\": \"CLIP-seq; LC-MS/MS epitranscriptomic profiling; RNA stability assays; CIRTS; endothelial-specific and global knockout mouse models; nanoparticle-mediated rescue in vivo\",\n      \"journal\": \"bioRxiv (preprint) / also published in PMID:40661507\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (CLIP-seq, LC-MS/MS, RNA stability, genetic KO, in vivo rescue) in a single comprehensive study\",\n      \"pmids\": [\"40661507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DNA methylation of a CpG site within the METTL7A gene body (exon) regulates its transcriptional activity. Mutation of this CpG site (CG to CC) in an exogenous vector in papillary thyroid cancer cells resulted in higher RNA polymerase II recruitment and reduced methyl-CpG binding protein-2 (MeCP2) enrichment at the gene body. EZH2, a subunit of polycomb repressor complex 2, was identified as potentially responsible for regulating gene body methylation of METTL7A in thyroid cancer.\",\n      \"method\": \"Site-directed mutagenesis of CpG site in exogenous vector; ChIP for RNA Pol II and MeCP2; in vitro cell comparison (BCPAP vs normal thyroid cells)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus ChIP assays, single lab, two orthogonal methods, but EZH2 role described as suggestive rather than fully confirmed\",\n      \"pmids\": [\"28416772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL7A is a direct target of miR-6807-5p (binding confirmed at the 3'UTR by dual-luciferase reporter assay and pull-down with biotinylated miRNA). SNRNP200 was identified as a co-binding protein of METTL7A by protein mass spectrometry and Co-IP. Knockdown of SNRNP200 inhibited odontogenic differentiation of dental pulp stem cells.\",\n      \"method\": \"Dual-luciferase reporter assay; biotinylated miRNA pull-down; protein mass spectrometry; co-immunoprecipitation (Co-IP)\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct binding confirmation by two orthogonal methods (luciferase + pull-down), Co-IP for SNRNP200 interaction; single lab\",\n      \"pmids\": [\"34790668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL7A is localized to the endoplasmic reticulum and to lipid droplets in some cells, with a novel localization identified in GFAP-positive Bergmann glial cells of the human cerebellum, particularly enriched at the end-feet participating in the cerebrospinal fluid-brain parenchyma barrier and at contacts between Bergmann glia and Purkinje neurons.\",\n      \"method\": \"Immunohistochemistry; laser confocal microscopy; 3D reconstruction image analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunohistochemistry and confocal microscopy with 3D reconstruction, but no functional consequence directly linked in this study\",\n      \"pmids\": [\"37176112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL7A modulates m6A modification of CORIN mRNA and thereby regulates corin expression during orofacial BMSC osteogenic differentiation. Cycloleucine (a non-selective m6A methylase inhibitor) blocked the corin-mediated promotion of differentiation, and METTL7A overexpression reversed bisphosphonate-impaired BMSC differentiation. The corin-mediated differentiation promotion operates via the ERK pathway (phos-ERK alteration; blocked by PD98059).\",\n      \"method\": \"m6A epitranscriptomic microarray; m6A inhibitor treatment; METTL7A overexpression/knockdown; ERK pathway inhibitor (PD98059); ALP and Alizarin Red staining\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — m6A microarray plus functional rescue experiments and pathway inhibitor, single lab, moderate mechanistic depth\",\n      \"pmids\": [\"38782892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL7A drives MSC osteogenic differentiation by activating the YAP1-TEAD1 signaling pathway. METTL7A stabilizes YAP1 mRNA and recruits the eIF4F translation initiation complex to boost YAP1 translation efficiency. The YAP1/TEAD1 complex in turn transcriptionally regulates METTL7A expression, creating a positive feedback loop amplifying osteogenic differentiation.\",\n      \"method\": \"Western blotting; ALP and Alizarin Red S staining; in vivo bone regeneration studies; mRNA stability assays; eIF4F complex recruitment assay\",\n      \"journal\": \"International endodontic journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple functional and biochemical assays in single lab, pathway mechanism proposed with supporting data, but abstract-level description limits full method verification\",\n      \"pmids\": [\"39815670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP9X deubiquitinase stabilizes METTL7A protein by regulating its deubiquitination, thereby promoting AML cell growth and adriamycin resistance. USP9X knockdown decreased METTL7A protein stability, and METTL7A overexpression reversed growth inhibition caused by USP9X knockdown.\",\n      \"method\": \"Co-expression analysis; siRNA knockdown; overexpression rescue; colony formation; xenograft mouse model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional rescue and in vivo validation, but deubiquitination of METTL7A by USP9X is inferred rather than directly demonstrated by ubiquitination assay in the abstract\",\n      \"pmids\": [\"41391677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL7A promotes Mettl7a-mediated m6A methylation of Oga mRNA, regulating O-GlcNAcylation of the ECM protein BSP (bone sialoprotein), thereby promoting BMSC osteogenic differentiation. Conditional knockout of Mettl7a in mesenchyme (Prx1-cre;Mettl7af/f) accelerated bone loss in OVX mice, and Mettl7a-AAV treatment alleviated the bone loss phenotype.\",\n      \"method\": \"Conditional knockout mouse model (Prx1-cre;Mettl7af/f); AAV overexpression in vivo; m6A methylation analysis; O-GlcNAcylation assays; osteogenic differentiation assays\",\n      \"journal\": \"Stem cells translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model with defined phenotype and molecular mechanism (m6A of Oga → O-GlcNAcylation of BSP), single lab\",\n      \"pmids\": [\"40558384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL7A protein has a novel chromatin regulatory function in TKI-resistant lung adenocarcinoma cells: it binds to amplified oncogene loci, regulates cohesin recruitment, and modulates inter-TAD interactions, remodeling the chromatin landscape prior to large-scale copy number gains. METTL7A depletion prevents formation and maintenance of TKI-resistant clones without affecting chromatin structure or proliferation of drug-naïve cells.\",\n      \"method\": \"Chromatin binding assays; cohesin co-localization; Hi-C/inter-TAD interaction analysis; METTL7A depletion in drug-naïve vs. TKI-resistant cells; clone formation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, abstract-level description of chromatin binding and cohesin regulation without full methodological detail\",\n      \"pmids\": [\"bio_10.1101_2025.01.26.634826\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"METTL7A directly binds SREBP1 and SCAP (by Co-IP and immunofluorescence), hindering nuclear translocation of SREBP1 and thereby reducing intracellular cholesterol content in colorectal cancer cells. Transcriptomic and proteomic analyses showed METTL7A affects genes in the cholesterol metabolism pathway (FDFT1, SQLE, CYP51A1).\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence; transcriptomics; proteomics; in situ tumor and spontaneous tumor mouse models\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus immunofluorescence plus multi-omics in single lab, direct binding to SREBP1/SCAP demonstrated\",\n      \"pmids\": [\"42009961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMT1A (METTL7A) inhibits M2 macrophage polarization in lung adenocarcinoma and downregulates PD-L1 expression in LUAD cells. In co-culture experiments, TMT1A knockdown suppressed T cell activation and reduced IFN-γ secretion; in vivo, TMT1A expression promoted CD8+ T cell infiltration.\",\n      \"method\": \"Co-culture experiments with LUAD cells and T cells; in vivo tumor models; functional assays (proliferation, migration); single-cell transcriptome analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — defined cellular mechanism (M2 polarization, PD-L1, T cell activation) with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"41541671\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMT1A (METTL7A) is an SAM-dependent methyltransferase with at least three distinct enzymatic activities: (1) a microsomal thiol methyltransferase that S-methylates exogenous aliphatic and phenolic thiol-containing substrates (including clinically relevant drugs such as romidepsin, captopril, and spironolactone metabolites), conferring resistance to thiol-based HDAC inhibitors; (2) a mechanosensitive internal m7G mRNA methyltransferase in endothelial cells that binds AG-enriched motifs, stabilizes KLF4 and NFKBIA transcripts, and protects against atherosclerosis; and (3) an m6A writer that regulates target mRNA stability and translation (including via eIF4F recruitment for YAP1 mRNA), promoting MSC osteogenic differentiation through the YAP1-TEAD1 axis and modulating ECM O-GlcNAcylation through Oga mRNA methylation; additionally, METTL7A protein has a novel chromatin-regulatory function binding amplified loci and regulating cohesin recruitment in TKI-resistant lung cancer cells, and directly binds SREBP1/SCAP to suppress cholesterol biosynthesis in colorectal cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMT1A (METTL7A) is a SAM-dependent methyltransferase with dual roles in xenobiotic metabolism and epitranscriptomic gene regulation [#0, #4]. Its best-defined activity is as the microsomal alkyl thiol methyltransferase of human liver, S-methylating exogenous thiol-containing substrates including 7\\u03b1-thiospironolactone, dithiothreitol, 4-chlorothiophenol, and mertansine, with enzymatic activity tracking METTL7A/METTL7B protein abundance across liver microsomes [#0]. 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 [#1, #2]. 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 [#4]. 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 [#9, #11]. METTL7A protein is localized to the endoplasmic reticulum and lipid droplets [#7], and additional regulatory functions in cancer have been described, including direct binding of SREBP1/SCAP to suppress cholesterol biosynthesis in colorectal cancer [#13] and modulation of tumor immune responses in lung adenocarcinoma [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Site-directed CpG mutagenesis in an exogenous vector with ChIP for RNA Pol II and MeCP2 in papillary thyroid cancer cells\",\n      \"pmids\": [\"28416772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Post-transcriptional and protein-interaction regulation of METTL7A was probed, identifying a targeting miRNA and a candidate binding partner.\",\n      \"evidence\": \"Dual-luciferase reporter, biotinylated miRNA pull-down, mass spectrometry and Co-IP in dental pulp stem cells\",\n      \"pmids\": [\"34790668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro assay with purified recombinant protein, quantitative proteomics of liver microsomes, and gene modulation in HepG2/HeLa cells\",\n      \"pmids\": [\"37137720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological thiol substrates not defined\", \"No structural basis for substrate selectivity\", \"Relative contributions of METTL7A vs METTL7B not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Subcellular and tissue localization of METTL7A was mapped, placing the protein at the ER and lipid droplets and in cerebellar Bergmann glia.\",\n      \"evidence\": \"Immunohistochemistry, confocal microscopy, and 3D reconstruction of human cerebellum\",\n      \"pmids\": [\"37176112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence linked to glial localization\", \"Does not connect localization to enzymatic activity\", \"Descriptive only\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The thiol-methyltransferase activity was extended to clinical relevance and evolutionary conservation, showing METTL7A/B inactivate thiol-based HDAC inhibitors to drive resistance.\",\n      \"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\",\n      \"pmids\": [\"38151817\", \"38574836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether thiol methylation activity contributes to clinical HDACi resistance in patients unknown\", \"Catalytic residues mediating drug methylation not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A second, RNA-directed activity emerged, implicating METTL7A as an m6A regulator of osteogenic differentiation through CORIN and ERK signaling.\",\n      \"evidence\": \"m6A microarray, m6A-inhibitor and ERK-inhibitor treatments, and overexpression/knockdown rescue in orofacial BMSCs\",\n      \"pmids\": [\"38782892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct m6A catalysis by METTL7A not demonstrated biochemically\", \"Non-selective inhibitor cycloleucine cannot isolate METTL7A activity\", \"Reader linking m6A to CORIN expression unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The epitranscriptomic role was sharpened by defining METTL7A as a mechanosensitive internal m7G writer that stabilizes athero-protective transcripts.\",\n      \"evidence\": \"CLIP-seq, LC-MS/MS epitranscriptomic profiling, RNA stability assays, endothelial-specific and global knockout mice, and nanoparticle rescue in vivo\",\n      \"pmids\": [\"40661507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"mRNA stability and eIF4F recruitment assays, YAP1/TEAD1 readouts, and conditional Mettl7a knockout (Prx1-cre) and AAV rescue in OVX mice\",\n      \"pmids\": [\"39815670\", \"40558384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct catalytic deposition of m6A on YAP1/Oga mRNA by METTL7A not shown enzymatically\", \"Mechanism of eIF4F recruitment undefined\", \"Single-lab mechanistic models\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Protein-level regulation and non-enzymatic functions in cancer were uncovered, including USP9X-mediated stabilization, chromatin/cohesin regulation, and tumor immune modulation.\",\n      \"evidence\": \"siRNA/overexpression rescue and xenografts (USP9X); chromatin binding, cohesin co-localization and Hi-C (chromatin); co-culture and single-cell transcriptomics (immune)\",\n      \"pmids\": [\"41391677\", \"41541671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A non-catalytic scaffolding role in lipid metabolism was defined, with METTL7A binding SREBP1/SCAP to block SREBP1 nuclear translocation and suppress cholesterol synthesis.\",\n      \"evidence\": \"Co-IP, immunofluorescence, transcriptomics/proteomics, and in situ and spontaneous tumor mouse models in colorectal cancer\",\n      \"pmids\": [\"42009961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether binding requires methyltransferase activity not tested\", \"Reciprocal validation of SREBP1/SCAP interaction limited\", \"Structural interface undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"No single study reconciles the distinct enzymatic and scaffolding activities\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [4, 9, 11]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 9, 11]},\n      {\"term_id\": \"R-HSA-9748784\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"METTL7B\", \"SNRNP200\", \"USP9X\", \"SREBP1\", \"SCAP\", \"eIF4F\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}