{"gene":"METTL14","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2013,"finding":"METTL14 forms a stable heterodimer core complex with METTL3 that together catalyzes N6-methyladenosine (m6A) deposition on mammalian nuclear RNAs; WTAP interacts with this complex and affects methylation activity.","method":"Biochemical co-purification, in vitro methylation assay, Co-IP","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — foundational discovery using in vitro assays and pulldown; independently replicated across many subsequent studies","pmids":["24316715"],"is_preprint":false},{"year":2016,"finding":"Crystal structures of the METTL3-METTL14 heterodimer (MTase domains) in ligand-free, SAM-bound, and SAH-bound states revealed that METTL3 is the catalytic core (SAM binds only in METTL3 pocket) while METTL14 serves as an RNA-binding platform; they interact via an extensive hydrogen-bonding network forming a positively charged RNA-binding groove.","method":"X-ray crystallography (1.61–1.9 Å resolution) combined with biochemical mutational analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structures in three states plus biochemical validation; landmark study","pmids":["27281194"],"is_preprint":false},{"year":2018,"finding":"The C-terminal RGG repeats of METTL14 are required for RNA substrate binding and for METTL3/METTL14 methyltransferase activity; monomeric METTL3 is soluble but inactive alone, and the catalytic center of METTL14 is degenerate and inactive alone. WTAP is required for nuclear speckle localization of METTL3/METTL14. Phosphorylation sites on endogenous METTL3 and METTL14 were identified.","method":"Recombinant protein binding-surface mapping, in vitro methylation assay, nuclear localization signal identification, phosphorylation site mapping, immunofluorescence","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical methods (in vitro reconstitution, mutagenesis of RGG repeats, localization) in a single focused study","pmids":["29348140"],"is_preprint":false},{"year":2022,"finding":"METTL14 binds RNA G-quadruplex (rG4) structures via its C-terminal RGG repeats, and the METTL3/METTL14 heterodimer selectively methylates adenosines proximal to rG4 sequences, suggesting a mechanism for direct recruitment of the complex to specific methylation sites.","method":"In vitro RNA-binding assay, selective methylation assay with rG4-containing substrates","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro biochemical assay, single laboratory study","pmids":["34908152"],"is_preprint":false},{"year":2021,"finding":"The MettL3-METTL14 complex is active in vitro on double-stranded DNA containing cyclopyrymidine dimers, abasic sites, or mismatches; N6-methyladenine in DNA decreases misincorporation of 8-oxoG opposite N6mA and inhibits N6mA excision by the adenine DNA glycosylase MYH from the template strand.","method":"In vitro methyltransferase assay on dsDNA substrates, structural analysis of YTHDC1 with gapped duplex DNA","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro biochemical reconstitution but single study, no in vivo confirmation of DNA methylation activity","pmids":["34086966"],"is_preprint":false},{"year":2022,"finding":"RNA binding to the METTL3-METTL14 complex largely restricts N6-deoxyadenosine methylation of DNA in vitro; the complex preferentially catalyzes m6dA in single-stranded DNA despite weaker binding to DNA, and binds structured RNAs with high affinity but methylates RNA adenosine less efficiently than ssDNA adenosine.","method":"Systematic in vitro methylation activity and binding affinity assays on panels of RNA/DNA oligonucleotides","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro biochemistry, single study","pmids":["35060905"],"is_preprint":false},{"year":2023,"finding":"METTL14, but not METTL3, directly binds H3K27me3 chromatin marks and recruits KDM6B (H3K27me3 demethylase) to induce H3K27me3 demethylation independently of METTL3 and of m6A methyltransferase activity; depletion of METTL14 leads to globally increased H3K27me3 and suppressed gene transcription in mouse embryonic stem cells.","method":"ChIP-seq, nascent RNA synthesis assay, KDM6B co-IP/pulldown, Mettl14-KO mESCs, enzymatic-inactive METTL14 mutant rescue","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, and functional KO with multiple orthogonal readouts in single study demonstrating m6A-independent chromatin function","pmids":["37030005"],"is_preprint":false},{"year":2023,"finding":"METTL14 specifically binds bivalent chromatin domains (H3K27me3 + H3K4me3) independently of METTL3 or m6A, enhances H3K27me3 by recruiting PRC2, and reduces H3K4me3 by recruiting KDM5B; Mettl14 knockout in mESCs decreases H3K27me3 and increases H3K4me3 at bivalent genes, increasing their transcription.","method":"ChIP-seq, Co-IP, Mettl14-KO mESCs, transcriptional analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with PRC2/KDM5B, ChIP-seq in KO cells, consistent with independent parallel study (PMID 37030005)","pmids":["37314930"],"is_preprint":false},{"year":2023,"finding":"STUB1 (E3 ubiquitin ligase) directly interacts with METTL14 and ubiquitinates it at lysine residues K148, K156, and K162, promoting its proteasomal degradation and decreasing global m6A levels; METTL3 competes with STUB1 for METTL14 binding (via METTL3 residues 450–454 and 464–480) to stabilize METTL14 and maintain m6A homeostasis.","method":"Co-IP, ubiquitination assay, site-directed mutagenesis of K148/K156/K162, domain-mapping of METTL3 interaction surface","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-specific mutagenesis of ubiquitination sites combined with reciprocal Co-IP and functional rescue; single laboratory but multiple orthogonal methods","pmids":["36597993"],"is_preprint":false},{"year":2023,"finding":"PRMT1 asymmetrically methylates arginine residues at the C-terminus of METTL14; the m6A reader SPF30 recognizes this arginine methylation; PRMT1-mediated arginine methylation on METTL14 is required for its m6A catalytic function and promotes cell proliferation.","method":"Co-IP, arginine methylation assay, functional rescue with PRMT1 inhibitor MS023","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP and functional inhibitor experiment; single laboratory, limited mutagenesis detail in abstract","pmids":["37269817"],"is_preprint":false},{"year":2023,"finding":"PRMT3 interacts with METTL14 and mediates its arginine methylation; PRMT3 inhibition leads to METTL14 overexpression, which promotes m6A modification of GPX4 mRNA via YTHDF2-dependent mechanism reducing GPX4 mRNA stability and increasing ferroptosis.","method":"Co-IP, arginine methylation assay, MeRIP, functional rescue experiments in endometrial carcinoma cells","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP demonstrating PRMT3-METTL14 interaction and downstream m6A mechanistic assay; single laboratory","pmids":["37973560"],"is_preprint":false},{"year":2024,"finding":"The HSV-1 immediate-early protein ICP0 interacts with METTL14 within ND10 nuclear bodies and acts as an E3 ubiquitin ligase, ubiquitinating METTL14 at lysine 156 and 162, leading to its proteasomal degradation and decreased global m6A levels; METTL14 stabilizes ISG15 mRNA via IGF2BP3 to promote antiviral immunity.","method":"Co-IP, ubiquitination assay with site-specific mutants (K156/K162), RIP assay for IGF2BP3-ISG15 interaction, functional rescue","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, site-specific ubiquitination mutagenesis, and RIP; single laboratory","pmids":["39325621"],"is_preprint":false},{"year":2019,"finding":"EBV latent oncoprotein EBNA3C activates METTL14 transcription and directly interacts with METTL14 protein to promote its stability; METTL14 knockdown decreases expression of latent EBV transcripts, demonstrating that EBV hijacks METTL14-mediated m6A modification to stabilize viral transcripts.","method":"Co-IP (EBNA3C-METTL14), transcriptional activation assay, METTL14 knockdown with viral transcript quantification, xenograft tumor model","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP and functional KD with in vivo xenograft; single laboratory","pmids":["31226160"],"is_preprint":false},{"year":2021,"finding":"UVB irradiation downregulates METTL14 protein through NBR1-dependent selective autophagy; METTL14 promotes global genome nucleotide excision repair (GGR) by increasing m6A methylation and translation of DDB2 mRNA, an effect dependent on its methyltransferase activity (enzymatically inactive mutant fails to rescue); YTHDF1 (m6A reader promoting translation) also binds DDB2 transcript and is required for normal DDB2 levels.","method":"METTL14 KD/OE with enzymatically inactive mutant, m6A MeRIP of DDB2 mRNA, YTHDF1 RIP, GGR repair assay, mouse skin-specific heterozygous KO","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — enzymatic-inactive mutant rescue, MeRIP, RIP, and mouse in vivo KO with defined phenotype; multiple orthogonal methods","pmids":["34452996"],"is_preprint":false},{"year":2024,"finding":"Mycobacterium tuberculosis secreted antigen EsxB interacts with p38 MAPK and disrupts TAB1-mediated autophosphorylation of p38, thereby inhibiting p38-mediated phosphorylation of METTL14 at Thr72; loss of pThr72 impairs liquid-liquid phase separation (LLPS) of METTL14 and its interaction with METTL3, preventing m6A modification of Nox2 mRNA and its stabilization by IGF2BP1.","method":"Co-IP (EsxB-p38, p38-METTL14), phosphorylation assay at Thr72, METTL14 LLPS assay, MeRIP of Nox2 mRNA, RIP (IGF2BP1), site-directed mutation of phosphorylation site, mouse infection model","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple mechanistic experiments including phospho-site mutagenesis and LLPS assay; single laboratory","pmids":["38548762"],"is_preprint":false},{"year":2021,"finding":"NF-κB directly transactivates the METTL14 gene (and METTL3) upon LPS challenge in Kupffer cells, increasing global m6A; METTL14-dependent m6A on the 5′UTR of TGF-β1 mRNA promotes cap-independent translation of TGF-β1; this mechanism is abolished in myeloid lineage cell-specific Mettl14-KO mice.","method":"ChIP-PCR (NF-κB on METTL14 promoter), dual-luciferase reporter with m6A site mutations in TGF-β1 5′UTR, m6A-seq, METTL14-deficient KCs and myeloid-specific KO mice","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP validation of NF-κB binding, m6A site mutagenesis in reporter, and KO mouse confirmation; multiple orthogonal methods","pmids":["33992834"],"is_preprint":false},{"year":2017,"finding":"Germ cell-specific inactivation of Mettl14 (with Vasa-Cre) depletes spermatogonial stem cells and causes loss of m6A; this dysregulates translation of transcripts required for SSC proliferation/differentiation. Combined deletion of Mettl3 and Mettl14 in advanced germ cells (Stra8-GFPCre) disrupts spermiogenesis and impairs translation of haploid-specific genes.","method":"Conditional Mettl14-KO mice, ribosome profiling/translation assay, m6A sequencing across spermatogenic cell stages","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with translational readout; replicated across multiple Cre lines; multiple spermatogenic stages analyzed","pmids":["28914256"],"is_preprint":false},{"year":2017,"finding":"METTL14 regulates m6A modification of MYB and MYC mRNAs in AML cells; the transcription factor SPI1 negatively regulates METTL14 protein expression, defining a SPI1-METTL14-MYB/MYC signaling axis in myelopoiesis.","method":"MeRIP of MYB/MYC mRNAs upon METTL14 silencing, RNA-seq, ChIP for SPI1, gain/loss-of-function in AML cells and mouse models","journal":"Cell stem cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MeRIP and ChIP with functional KD/KO; single laboratory","pmids":["29290617"],"is_preprint":false},{"year":2020,"finding":"METTL14 promotes m6A methylation of lncRNA XIST, enabling recognition by YTHDF2 and mediating XIST degradation; knockdown of METTL14 reduces m6A on XIST, increases XIST expression, and enhances CRC proliferation and invasion.","method":"Me-RIP, RNA pulldown, RIP, rescue experiment with YTHDF2","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP and RIP validation; single laboratory","pmids":["32111213"],"is_preprint":false},{"year":2020,"finding":"METTL14-mediated m6A modification of SOX4 mRNA promotes its degradation via YTHDF2; KDM5C-mediated demethylation of H3K4me3 at the METTL14 promoter inhibits METTL14 transcription in CRC.","method":"MeRIP-Seq, RIP, ChIP (KDM5C on METTL14 promoter), YTHDF2 functional rescue","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MeRIP, RIP, ChIP; single laboratory","pmids":["32552762"],"is_preprint":false},{"year":2019,"finding":"Mettl14 promotes m6A modification of Notch1 mRNA, reducing its stability; Mettl14 knockout increases Notch1 mRNA stability and promotes bladder tumor-initiating cell self-renewal.","method":"RNA stability assay, Me-RIP of Notch1 mRNA, gain/loss-of-function in bladder TICs","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP and RNA stability assay; single laboratory","pmids":["31760940"],"is_preprint":false},{"year":2021,"finding":"METTL14 directly binds FOXO1 mRNA via RIP assay, increases its m6A modification, and enhances FOXO1 translation through YTHDF1 recognition; METTL14 also interacts with FOXO1 protein to act on VCAM-1 and ICAM-1 promoters to promote their transcription in endothelial cells; METTL14 knockout in mice reduces atherosclerotic plaque formation.","method":"MeRIP-seq, RIP (METTL14-FOXO1 mRNA), Co-IP (METTL14-FOXO1 protein), luciferase reporter, METTL14-KO mouse atherosclerosis model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — RIP, MeRIP, Co-IP, and KO mouse; single laboratory","pmids":["32802173"],"is_preprint":false},{"year":2022,"finding":"METTL14 mediates m6A modification of Myd88 mRNA to regulate its stability, promoting NF-κB/IL-6 inflammatory signaling in macrophages; Mettl14 knockout reduces macrophage inflammation and atherosclerosis in mice.","method":"MeRIP (Myd88 mRNA stability), Mettl14-KD THP-1 cells, Mettl14-KO mice with atherosclerosis model","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP and in vivo KO; single laboratory","pmids":["35598196"],"is_preprint":false},{"year":2021,"finding":"METTL14 overexpression (but not an MTase-inactive mutant) blocks exercise-induced physiological cardiac hypertrophy; cardiac-specific METTL14 knockdown attenuates ischemia-reperfusion injury; METTL14 silencing suppresses Phlpp2 mRNA m6A modifications and activates Akt-S473 signaling to regulate cardiomyocyte growth and apoptosis.","method":"Wild-type vs. MTase-inactive mutant METTL14 OE, cardiac-specific KD, MeRIP of Phlpp2 mRNA, Akt-S473 phosphorylation assay, in vivo exercise and IR models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — enzymatically inactive mutant distinguishes m6A-dependent mechanism; in vivo cardiac-specific KD with defined signaling readout; multiple orthogonal methods","pmids":["36351918"],"is_preprint":false},{"year":2021,"finding":"Loss of METTL14 in tumor-associated macrophages decreases m6A abundance on Ebi3 mRNA and increases Ebi3 transcript and EBI3 cytokine subunit levels, which drives CD8+ T cell dysfunctional differentiation; neutralization of EBI3 reinvigorates dysfunctional CD8+ T cells.","method":"Macrophage-specific METTL14-KO mice, MeRIP of Ebi3 mRNA, EBI3 neutralization rescue, flow cytometry of CD8+ T cell states","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — macrophage-specific KO with MeRIP of specific target and functional rescue by neutralization; rigorous mechanistic dissection","pmids":["34019807"],"is_preprint":false},{"year":2021,"finding":"METTL14 knockdown in podocytes upregulates Sirt1 by relieving m6A-dependent Sirt1 mRNA degradation; podocyte-specific METTL14-KO mice show improved glomerular function with activated autophagy and reduced apoptosis; MeRIP-qPCR and dual-luciferase assay confirmed METTL14 promotes Sirt1 mRNA m6A modification and degradation.","method":"Podocyte-specific Mettl14-KO mice, MeRIP-qPCR, dual-luciferase reporter, gain/loss-of-function in cultured podocytes","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MeRIP, luciferase, and in vivo KO; single laboratory","pmids":["34580283"],"is_preprint":false},{"year":2021,"finding":"Mettl14 loss in liver-specific KO mice disrupts liver regeneration and causes G1 cell-cycle arrest; key ER stress response transcripts (Hsp90b1, Erp29, Stt3a, P4hb, Lman1) are m6A-hypomethylated and their levels decrease, resulting in unresolved ER stress and hepatocyte death; Mettl3 loss does not reproduce this phenotype.","method":"Hepatocyte-specific Mettl14-KO and Mettl3-KO mice, m6A-seq of regenerating liver, biochemical ER stress markers","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo conditional KO with m6A-seq; single laboratory; comparison with Mettl3 KO strengthens specificity","pmids":["33848642"],"is_preprint":false},{"year":2024,"finding":"METTL14-mediated m6A modification of GluN2A (GRIN2A) mRNA stabilizes it via IGF2BP2 recognition, enhancing NMDAR activity in DRG neurons; overexpression of METTL14 upregulates m6A and facilitates pain hypersensitivity; DBP transcription factor drives METTL14 upregulation in CINP.","method":"Gain/loss-of-function in DRG neurons, m6A dot blot, MeRIP of GluN2A mRNA, IGF2BP2 RIP, behavioral pain assays, human DRG validation","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MeRIP and RIP with in vivo and in vitro functional assays; single laboratory","pmids":["38319733"],"is_preprint":false},{"year":2023,"finding":"The cancer-associated METTL14 R298P mutation reduces m6A modification at canonical DRACH motifs and induces m6A at aberrant GGAU motifs; aberrant GGAU-context m6A is recognized normally by YTH readers but demethylated less efficiently by ALKBH5; one consequence is hypermethylation of c-MET mRNA at canonical sites near aberrant sites, destabilizing c-MET mRNA and reducing c-Myc expression.","method":"MeRIP-seq of WT vs. R298P cell lines, in vitro methyltransferase assay on GGAU substrates, structural modeling, mRNA stability assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro biochemistry plus MeRIP-seq; single laboratory","pmids":["37355987"],"is_preprint":false},{"year":2024,"finding":"Biochemical and structural data show that the METTL14 R298P cancer mutation shifts substrate selectivity toward noncanonical GGAU motifs in vitro and in vivo, and GGAU-context m6A is demethylated less efficiently by ALKBH5 than canonical sites; structural analysis provides a model for cognate RNA sequence selection by METTL3-METTL14.","method":"Biochemical in vitro methylation assay, MeRIP-seq, structural analysis, transgenic mouse model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution combined with structural data, MeRIP-seq, and transgenic mouse; multiple orthogonal approaches","pmids":["39705353"],"is_preprint":false},{"year":2024,"finding":"METTL3/METTL14 complex acts as an essential adapter for CRL4 E3 ubiquitin ligase to target SUV39H1/H2 histone methyltransferases for polyubiquitination and proteasomal degradation, preventing H3K9me3 accumulation in nucleoli and maintaining nucleolar integrity and LLPS in human embryonic stem cells.","method":"Co-IP (METTL3/METTL14 with CRL4 and SUV39H1/H2), ubiquitination assay, METTL3/METTL14 KO hESCs, nucleolar LLPS analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assay with KO phenotype; single laboratory","pmids":["39169036"],"is_preprint":false},{"year":2022,"finding":"METTL14 promotes m6A modification of TNFAIP3 mRNA (a NF-κB pathway suppressor) and regulates TNFAIP3 mRNA stability and protein translocation in coding-sequence context; METTL14 knockdown reduces TNFAIP3, increases IL-6 and IL-17, and worsens joint inflammation in CAIA mice.","method":"MeRIP-seq, RIP assay, METTL14 KD in PBMCs and CAIA mouse model","journal":"Arthritis & rheumatology (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP-seq and RIP with in vivo KD; single laboratory","pmids":["37327357"],"is_preprint":false},{"year":2022,"finding":"METTL14 promotes m6A modification of LASP1 mRNA, increasing LASP1 mRNA stability and protein expression; LASP1 activates the SRC/AKT signaling axis to promote fibroblast-like synoviocyte migration, invasion, and inflammation in rheumatoid arthritis.","method":"MeRIP, RIP, mRNA stability assay, METTL14 shRNA in vitro and RA rat model","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP and RIP with in vivo model; single laboratory","pmids":["36878846"],"is_preprint":false},{"year":2024,"finding":"METTL14 mediates m6A modification of FTH1 mRNA, reducing its stability and expression via YTHDF2-dependent degradation, thereby promoting sorafenib-induced ferroptosis in cervical cancer cells; this operates through the PI3K/Akt signaling pathway.","method":"MeRIP, luciferase reporter, mRNA stability assay (qRT-PCR), in vivo xenograft","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP and luciferase reporter with in vivo xenograft; single laboratory","pmids":["38738555"],"is_preprint":false},{"year":2023,"finding":"METTL14 mediates m6A modification of FOXO3a mRNA, stabilizing it and increasing FOXO3a expression; loss of METTL14 reduces FOXO3a, impairing autophagic flux and increasing inflammation in T cells from ankylosing spondylitis patients.","method":"MeRIP, RNA stability assay, gain/loss-of-function in T cells","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single MeRIP and stability assay; single laboratory","pmids":["37935312"],"is_preprint":false},{"year":2022,"finding":"METTL14 mediates m6A modification on Lnc-LSG1, enabling binding by YTHDC1 (m6A reader) which blocks Lnc-LSG1 interaction with ESRP2 protein; without m6A, Lnc-LSG1 binds ESRP2 and promotes its ubiquitination-dependent degradation, facilitating ccRCC metastasis.","method":"MeRIP-seq, RIP, ESRP2 ubiquitination assay, rescue experiments in ccRCC cells","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP-seq and RIP with functional rescue; single laboratory","pmids":["35036065"],"is_preprint":false},{"year":2024,"finding":"METTL14 overexpression in adipocytes decreases m6A on Adrb2, Adrb3, Atgl, and Cgi-58 transcripts; Mettl14 adipocyte-specific KO decreases m6A on these transcripts, increasing their protein levels and thereby enhancing β-adrenergic signaling and lipolysis; mice with adipocyte-specific Mettl14 deletion are resistant to HFD-induced obesity, insulin resistance, and NAFLD.","method":"Adipocyte-specific Mettl14-KO mice (HFD model), MeRIP of specific transcripts, lipolysis assays, metabolic phenotyping","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo conditional KO with MeRIP and metabolic readouts; single laboratory","pmids":["37526326"],"is_preprint":false},{"year":2022,"finding":"Mettl14 loss in retinal rod cells causes ectopic accumulation of outer segment proteins in the inner segment and progressive degeneration; Mettl14 loss in cone cells causes mislocalization of cone opsin proteins and cone cell death; mechanistically, m6A depletion reduces expression of phototransduction- and cilium-associated genes, impairing ciliogenesis and OS protein synthesis/transport.","method":"Retina-specific Mettl14-KO mouse models (Rho-Cre and HRGP-Cre), MeRIP-seq, transcriptomic analysis, immunofluorescence for protein localization","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — cell-type-specific KO with MeRIP-seq; single laboratory","pmids":["35698136"],"is_preprint":false},{"year":2019,"finding":"Beta-cell-specific Mettl14 KO mice develop glucose intolerance, decreased glucose-stimulated insulin secretion, increased beta-cell death, and reduced beta-cell mass; HFD-fed KO mice also show decreased beta-cell proliferation, AKT hyperactivation (insulin sensitivity) and altered lipid metabolism.","method":"Conditional Mettl14-KO mice (RIP-Cre), glucose tolerance tests, GSIS assays, islet RNA-seq, histology","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional KO with defined metabolic phenotype; single laboratory","pmids":["31029827"],"is_preprint":false},{"year":2023,"finding":"METTL14 regulates m6A modification and maturation of pri-miR-17 by reducing YTHDC2 recognition of the GGACC binding site, thereby inhibiting pri-miR-17 mRNA decay; this increases pri-miR-17 and mature miR-17-5p levels, which targets Mitofusin 2 (MFN2) to decrease mitochondrial fusion and promote 5-FU resistance.","method":"MeRIP (pri-miR-17), YTHDC2 RIP, MFN2 3'UTR reporter assay, mitochondrial morphology analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP and RIP mechanistic assays; single laboratory","pmids":["36810285"],"is_preprint":false},{"year":2023,"finding":"METTL14 transcriptional activation by wild-type p53 suppresses colorectal tumor growth by promoting m6A-YTHDF2-dependent processing of pri-miR-6769b and pri-miR-499a into mature miRNAs, which repress SLC2A3 and PGAM1 to restrain aerobic glycolysis; enzymatic activity of METTL14 is required for this effect.","method":"ChIP (p53 on METTL14 promoter), MeRIP of pri-miRNAs, YTHDF2 rescue, intestinal epithelial cell-specific METTL14-KO mouse models (AOM/DSS and AOM)","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP, MeRIP, and in vivo KO; single laboratory","pmids":["36794620"],"is_preprint":false},{"year":2021,"finding":"The CLK1 kinase phosphorylates SRSF5 at Ser250, which inhibits METTL14 exon 10 skipping; aberrant METTL14 exon10 skipping (when CLK1-SRSF5 axis is disrupted) enhances m6A modification levels and promotes pancreatic cancer metastasis.","method":"Phosphorylation mass spec (SRSF5-Ser250), RNA-seq (alternative splicing), RIP, RNA pulldown, CLIP-qPCR","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — phospho-mass spec, RIP/pulldown; single laboratory","pmids":["33849617"],"is_preprint":false},{"year":2022,"finding":"METTL14 increases m6A modification of UCHL5 mRNA and promotes its expression via YTHDF1 recognition; UCHL5 deubiquitinates NLRP3 to enhance its protein stability, activating NLRP3 inflammasome and promoting VSMC phenotypic switching in atherosclerosis.","method":"MeRIP, RIP, Co-IP (UCHL5-NLRP3), ubiquitination assay, dual-luciferase reporter","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP, RIP, Co-IP and ubiquitination; single laboratory","pmids":["37044315"],"is_preprint":false},{"year":2022,"finding":"METTL14 promotes m6A modification of NLRP3 transcripts; IGF2BP2 (m6A reader) recognizes and stabilizes METTL14-methylated NLRP3 mRNA, activating NLRP3 inflammasome in macrophages during acute lung injury.","method":"MeRIP, RIP (IGF2BP2-NLRP3), METTL14 KD in macrophages, ALI mouse model with IGF2BP2 KD","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP and RIP with in vivo model; single laboratory","pmids":["38218935"],"is_preprint":false},{"year":2023,"finding":"METTL14 enhances m6A modification and expression of KAT3B mRNA; KAT3B (a histone acetyltransferase) increases STING expression via H3K27ac on the STING promoter; this METTL14-KAT3B-STING axis promotes M1 microglia/macrophage polarization and NLRP3 inflammasome activation after ischemic stroke.","method":"MeRIP (KAT3B mRNA), ChIP (H3K27ac on STING promoter), METTL14 KD in MCAO rat model and OGD/R cells","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP and ChIP with in vivo KD; single laboratory","pmids":["37541353"],"is_preprint":false},{"year":2022,"finding":"METTL14 increases m6A modification of SMAD1 mRNA; IGF2BP1 acts as the m6A reader stabilizing SMAD1 mRNA; METTL14 knockdown reduces SMAD1 m6A and stability, suppressing osteogenic differentiation of BMSCs and reducing bone mass in OVX mice.","method":"Me-RIP, RIP (IGF2BP1-SMAD1), luciferase reporter, METTL14 KD in BMSCs, OVX mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Me-RIP, RIP, luciferase; single laboratory","pmids":["36319624"],"is_preprint":false},{"year":2022,"finding":"Loss of Mettl14 in the uterus causes infertility due to implantation failure; Mettl14-deficient uteri show aberrant upregulation of ERα signaling and ERα phosphorylation, abnormal innate immune pathway activation with macrophage/dendritic cell infiltration; MeRIP-seq shows decreased m6A peaks on innate immune response genes.","method":"Uterine-specific Mettl14-KO mice, MeRIP-seq, immunofluorescence for immune cell infiltration, ERα signaling assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional KO with MeRIP-seq; single laboratory","pmids":["37440278"],"is_preprint":false},{"year":2021,"finding":"DDX41 promotes YTHDC1 recruitment to R-loops by facilitating METTL3-YTHDC1 binding; DDX41 KO/KI leads to increased m6A-methylated R-loops and impaired YTHDC1-dependent R-loop resolution, contributing to genomic instability in MDS.","method":"Co-IP (DDX41-METTL3-METTL14 complex), DDX41-KO and KI (R525H, Y259C) cell lines, m6A R-loop quantification","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP and KO/KI cell lines; single laboratory","pmids":["38514771"],"is_preprint":false},{"year":2024,"finding":"METTL14 mediates m6A modification of MN1 mRNA in the CDS region; this is recognized by IGF2BP2, which prevents MN1 mRNA degradation and promotes its translation; elevated MN1 contributes to osteosarcoma progression and ATRA resistance.","method":"MeRIP-seq, RNA-seq, RNA pulldown, RIP (IGF2BP2), RNA stability and polysome analysis","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MeRIP-seq combined with polysome profiling and RIP; single laboratory","pmids":["35810559"],"is_preprint":false},{"year":2020,"finding":"LNC942 (LINC00942) directly recruits METTL14 protein by harboring a specific recognition sequence (+176–+265), thereby increasing METTL14-mediated m6A methylation and stabilizing CXCR4 and CYP1B1 mRNAs in breast cancer cells.","method":"RNA pulldown, RIP, m6A quantification, RNA stability assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — RNA pulldown and RIP; single laboratory","pmids":["32576970"],"is_preprint":false},{"year":2022,"finding":"METTL14-mediated m6A modification of ITGB4 3′UTR promotes ITGB4 mRNA degradation via YTHDF2 recognition, reducing ITGB4 expression and inhibiting EMT and PI3K/AKT signaling in ccRCC.","method":"MeRIP, RIP (YTHDF2-ITGB4), luciferase reporter, METTL14 KD/OE in vitro and in vivo","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP, RIP, luciferase; single laboratory","pmids":["35305660"],"is_preprint":false},{"year":2022,"finding":"METTL14 increases m6A modification of α-klotho mRNA and downregulates α-klotho expression; overexpression of METTL14 aggravates renal injury in diabetic nephropathy mice; α-klotho supplementation partially rescues METTL14-driven injury.","method":"MeRIP (α-klotho mRNA), in vitro HRGECs and db/db mouse model, α-klotho rescue","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MeRIP without detailed mechanistic validation; single laboratory","pmids":["34503454"],"is_preprint":false},{"year":2024,"finding":"METTL14 decreases GLS2 translation efficiency via YTHDF1 in hepatocytes in an m6A-dependent manner; hepatocyte-specific Mettl14 depletion aggravates MAFLD by creating an oxidative stress microenvironment that recruits Cx3cr1+Ccr2+ monocyte-derived macrophages, which activate hepatic stellate cells via CX3CR1/MyD88/NF-κB/S100A4 signaling.","method":"Hepatocyte-specific Mettl14-KO and OE mice, MeRIP (GLS2), YTHDF1 RIP, in vivo and in vitro mechanistic studies","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo KO/OE with MeRIP and YTHDF1 RIP; single laboratory","pmids":["38627387"],"is_preprint":false},{"year":2022,"finding":"METTL14 promotes m6A modification of circORC5, reducing its abundance; reduced circORC5 decreases sponging of miR-30c-2-3p, reducing AKT1S1 and EIF4B expression to suppress gastric cancer progression.","method":"m6A-circRNA epitranscriptomic microarray, Me-RIP of circORC5, luciferase (circORC5-miR-30c-2-3p sponge), RIP","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Me-RIP and luciferase; single laboratory","pmids":["35164771"],"is_preprint":false},{"year":2023,"finding":"METTL14 promotes m6A modification of Mettl14-mediated α-synuclein (SNCA) mRNA; this reduces α-syn mRNA stability; YTHDF2 recognizes m6A-modified α-syn mRNA, facilitating its degradation; overexpression of Mettl14 in PD cell models significantly increases m6A on α-syn CDS and weakens its stability.","method":"RIP (METTL14-α-syn mRNA), m6A modification analysis, RNA stability assay, YTHDF2 recognition assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — RIP and stability assay; single laboratory","pmids":["37309980"],"is_preprint":false},{"year":2022,"finding":"METTL14 promotes m6A modification of MALAT1 lncRNA, increasing its nuclear stability and expression; MALAT1 sponges miR-224-5p to promote KDM2A expression and OSCC cell proliferation.","method":"MeRIP (MALAT1), m6A level quantification, subcellular fractionation, RNA stability assay, in vivo xenograft","journal":"Oral diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MeRIP and subcellular fractionation; single laboratory","pmids":["35467063"],"is_preprint":false},{"year":2022,"finding":"METTL14 promotes m6A modification of METTL14-mediated NIXLRP3 transcript stabilization via IGF2BP2 in cardiomyocytes; in diabetic cardiomyopathy METTL14 decreases m6A of TINCR lncRNA; YTHDF2 recognizes m6A-modified TINCR and mediates its degradation; lower TINCR reduces NLRP3 mRNA stability, suppressing pyroptosis.","method":"RIP (YTHDF2-TINCR), MeRIP (TINCR m6A), RNA pulldown, NLRP3 mRNA stability assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — MeRIP, RIP, and stability assay; single laboratory","pmids":["35013106"],"is_preprint":false}],"current_model":"METTL14 is an RNA-binding scaffold subunit that heterodimerizes with the catalytic METTL3 to form the core m6A methyltransferase complex (with WTAP as a localization/activity co-factor), where METTL14's positively charged surface recognizes RNA substrates—including via RGG-repeat-dependent G-quadruplex binding—while METTL3 carries out catalysis using SAM; beyond m6A writing, METTL14 independently binds H3K27me3 chromatin and recruits KDM6B/KDM5B and PRC2 to regulate bivalent domain histone marks, and its stability is controlled by competitive ubiquitination (STUB1 at K148/K156/K162) versus METTL3-dependent protection, as well as by arginine methylation (PRMT1/PRMT3) and phosphorylation (p38 at Thr72); through m6A deposition, METTL14 controls mRNA stability, translation, and miRNA maturation of a broad set of target transcripts (including MYB, MYC, DDB2, TGF-β1, Phlpp2, GluN2A, and many others) in a context- and cell-type-specific manner, with downstream consequences for hematopoiesis, spermatogenesis, cardiac homeostasis, immune function, DNA repair, and tumorigenesis."},"narrative":{"mechanistic_narrative":"METTL14 is the RNA-binding scaffold subunit of the mammalian N6-methyladenosine (m6A) writer, forming a stable heterodimer with the catalytic METTL3 that deposits m6A on nuclear RNAs, with WTAP modulating activity and localization [PMID:24316715]. Crystal structures resolved the division of labor: SAM binds only METTL3's pocket while METTL14's degenerate catalytic center and extensive interface with METTL3 build a positively charged groove that engages RNA [PMID:27281194]; the complex is inactive when either subunit is monomeric, and METTL14's C-terminal RGG repeats are required for substrate binding and methyltransferase activity, including recognition of RNA G-quadruplex structures that can recruit the complex to specific sites [PMID:29348140, PMID:34908152]. Through m6A deposition, METTL14 governs the stability, translation, and processing of a broad target set—stabilizing or destabilizing transcripts through m6A readers (YTHDF1/2, IGF2BP1/2/3, YTHDC1) to control DDB2-dependent nucleotide excision repair [PMID:34452996], TGF-β1 cap-independent translation [PMID:33992834], and pri-miRNA maturation [PMID:36810285, PMID:36794620]—with cell-type-specific consequences for spermatogenesis [PMID:28914256], cardiac homeostasis [PMID:36351918], macrophage-driven immunity and CD8+ T-cell function [PMID:34019807], and tumorigenesis [PMID:29290617]. Beyond catalysis, METTL14 carries m6A-independent activities: it directly binds H3K27me3 and bivalent chromatin and recruits KDM6B, KDM5B, and PRC2 to set histone marks and gene transcription [PMID:37030005, PMID:37314930]. METTL14 protein levels are set by competitive ubiquitination—STUB1 ubiquitinates K148/K156/K162 to drive degradation while METTL3 binding protects it [PMID:36597993]—and by arginine methylation (PRMT1, PRMT3) and p38-mediated Thr72 phosphorylation that promotes its phase separation and METTL3 association [PMID:37269817, PMID:37973560, PMID:38548762]. A cancer-associated R298P mutation shifts substrate selectivity from canonical DRACH motifs toward aberrant GGAU sites that are demethylated poorly by ALKBH5 [PMID:37355987, PMID:39705353].","teleology":[{"year":2013,"claim":"Established that m6A on mammalian mRNA is written by a defined protein complex rather than a single enzyme, identifying METTL14 as a core partner of METTL3.","evidence":"Biochemical co-purification, in vitro methylation, and Co-IP defining a METTL3-METTL14 heterodimer with WTAP","pmids":["24316715"],"confidence":"High","gaps":["Did not resolve which subunit is catalytic","Substrate sequence/structural determinants not defined"]},{"year":2016,"claim":"Resolved the structural basis of the writer, showing METTL3 is the catalytic SAM-binding subunit and METTL14 an RNA-binding platform.","evidence":"X-ray crystallography of the MTase domains in ligand-free, SAM- and SAH-bound states with mutational validation","pmids":["27281194"],"confidence":"High","gaps":["Did not include the disordered C-terminal RGG region","How the complex selects specific adenosines in vivo unresolved"]},{"year":2018,"claim":"Defined METTL14's RGG repeats as the RNA-substrate-binding element required for activity and pinned WTAP to nuclear speckle localization, clarifying the functional roles of each subunit.","evidence":"Recombinant binding-surface mapping, in vitro methylation, NLS identification, and immunofluorescence","pmids":["29348140"],"confidence":"High","gaps":["Which specific RNA features the RGG region recognizes not yet defined","Functional role of mapped phosphorylation sites unestablished"]},{"year":2021,"claim":"Tested whether the writer acts on DNA, showing in vitro activity on dsDNA and ssDNA but with RNA binding restricting DNA methylation.","evidence":"In vitro methyltransferase and binding-affinity assays on RNA/DNA oligonucleotide panels","pmids":["34086966","35060905"],"confidence":"Medium","gaps":["No in vivo confirmation of physiological DNA methylation","Biological relevance of m6dA activity unestablished"]},{"year":2022,"claim":"Addressed how the complex finds specific sites, showing RGG-dependent binding to RNA G-quadruplexes directs methylation of proximal adenosines.","evidence":"In vitro RNA-binding and selective methylation assays on rG4-containing substrates","pmids":["34908152"],"confidence":"Medium","gaps":["Single-laboratory in vitro study without in vivo validation","Generality of rG4-directed targeting across the transcriptome unknown"]},{"year":2017,"claim":"Demonstrated in vivo physiological requirements for METTL14-dependent m6A in germ cell biology and myeloid m6A target control, moving from biochemistry to function.","evidence":"Conditional Mettl14-KO mice with ribosome profiling and m6A-seq; MeRIP/ChIP in AML cells defining a SPI1-METTL14-MYB/MYC axis","pmids":["28914256","29290617"],"confidence":"High","gaps":["Direct targets driving phenotypes only partially mapped","Reader specificity for individual transcripts not fully resolved"]},{"year":2021,"claim":"Showed that METTL14-deposited m6A directs reader-dependent fate decisions across diverse tissues, establishing it as a context-specific post-transcriptional regulator.","evidence":"Enzymatic-inactive mutant rescue, MeRIP, reader RIP and tissue-specific KO mice across DNA repair (DDB2/YTHDF1), TGF-β1 translation, and tumor-macrophage immunity (Ebi3)","pmids":["34452996","33992834","34019807"],"confidence":"High","gaps":["Determinants of reader selection (YTHDF1 vs YTHDF2 vs IGF2BPs) per transcript unclear","Why the same writer stabilizes some targets and destabilizes others not mechanistically unified"]},{"year":2023,"claim":"Uncovered an m6A-independent chromatin function, showing METTL14 directly reads H3K27me3/bivalent domains and recruits histone-modifying machinery.","evidence":"ChIP-seq, reciprocal Co-IP with KDM6B/KDM5B/PRC2, and enzymatic-inactive mutant rescue in Mettl14-KO mESCs","pmids":["37030005","37314930"],"confidence":"High","gaps":["Structural basis of METTL14-H3K27me3 recognition unknown","Relationship between chromatin role and canonical m6A writing not integrated"]},{"year":2023,"claim":"Defined how METTL14 protein abundance—and thus global m6A—is controlled, identifying competitive ubiquitination and arginine methylation.","evidence":"Site-directed mutagenesis of ubiquitination lysines, Co-IP, ubiquitination and arginine-methylation assays with STUB1, METTL3, PRMT1, and PRMT3","pmids":["36597993","37269817","37973560"],"confidence":"Medium","gaps":["Signals controlling STUB1 vs METTL3 competition in vivo unknown","Interplay among the multiple PTMs not jointly tested"]},{"year":2024,"claim":"Connected a kinase-dependent PTM to assembly, showing p38-mediated Thr72 phosphorylation promotes METTL14 phase separation and METTL3 interaction, and that a pathogen disrupts this axis.","evidence":"Phospho-site mutagenesis, LLPS assays, MeRIP/RIP, and mouse infection model with M. tuberculosis EsxB","pmids":["38548762"],"confidence":"Medium","gaps":["Physiological triggers of p38-METTL14 phosphorylation outside infection unclear","Quantitative contribution of LLPS to bulk m6A deposition unmeasured"]},{"year":2024,"claim":"Explained how a cancer mutation corrupts substrate selection, linking R298P to noncanonical GGAU methylation resistant to ALKBH5 erasure.","evidence":"In vitro methylation on GGAU substrates, MeRIP-seq, structural modeling, and transgenic mouse","pmids":["37355987","39705353"],"confidence":"High","gaps":["Full transcriptome-wide consequences of GGAU methylation not catalogued","Therapeutic exploitability of the mutant selectivity untested"]},{"year":null,"claim":"It remains unresolved how METTL14 integrates its dual roles—m6A writing versus chromatin/histone regulation—and what determines reader selection and opposing stabilizing/destabilizing outcomes on individual targets.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking the chromatin and methyltransferase functions","Rules governing which reader engages a given m6A-modified transcript undefined","Endogenous physiological signals coordinating the PTM network unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,29]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2,3,49]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[6,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,7,30]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[2]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[30]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,30]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,24]}],"complexes":["METTL3-METTL14 m6A methyltransferase complex","PRC2 (recruited)","CRL4 E3 ubiquitin ligase (adapter)"],"partners":["METTL3","WTAP","STUB1","KDM6B","KDM5B","PRMT1","PRMT3","YTHDF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HCE5","full_name":"N(6)-adenosine-methyltransferase non-catalytic subunit METTL14","aliases":["Methyltransferase-like protein 14","hMETTL14"],"length_aa":456,"mass_kda":52.1,"function":"The METTL3-METTL14 heterodimer forms a N6-methyltransferase complex that methylates adenosine residues at the N(6) position of some mRNAs and regulates the circadian clock, differentiation of embryonic stem cells and cortical neurogenesis (PubMed:24316715, PubMed:24407421, PubMed:25719671, PubMed:27281194, PubMed:27373337, PubMed:29348140). In the heterodimer formed with METTL3, METTL14 constitutes the RNA-binding scaffold that recognizes the substrate rather than the catalytic core (PubMed:27281194, PubMed:27373337, PubMed:27627798, PubMed:29348140). N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in mRNA stability and processing (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A acts as a key regulator of mRNA stability by promoting mRNA destabilization and degradation (By similarity). In embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity). M6A regulates spermatogonial differentiation and meiosis and is essential for male fertility and spermatogenesis (By similarity). M6A also regulates cortical neurogenesis: m6A methylation of transcripts related to transcription factors, neural stem cells, the cell cycle and neuronal differentiation during brain development promotes their destabilization and decay, promoting differentiation of radial glial cells (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9HCE5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/METTL14","classification":"Common Essential","n_dependent_lines":965,"n_total_lines":1208,"dependency_fraction":0.7988410596026491},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/METTL14","total_profiled":1310},"omim":[{"mim_id":"617283","title":"YTH DOMAIN-CONTAINING PROTEIN 1; YTHDC1","url":"https://www.omim.org/entry/617283"},{"mim_id":"616504","title":"METHYLTRANSFERASE 14, N6-ADENOSINE-METHYLTRANSFERASE SUBUNIT; METTL14","url":"https://www.omim.org/entry/616504"},{"mim_id":"616447","title":"VIR-LIKE M6A METHYLTRANSFERASE-ASSOCIATED PROTEIN; VIRMA","url":"https://www.omim.org/entry/616447"},{"mim_id":"612472","title":"METHYLTRANSFERASE 3, N6-ADENOSINE-METHYLTRANSFERASE COMPLEX CATALYTIC SUBUNIT; METTL3","url":"https://www.omim.org/entry/612472"},{"mim_id":"609373","title":"LYSINE DEMETHYLASE 3B; KDM3B","url":"https://www.omim.org/entry/609373"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/METTL14"},"hgnc":{"alias_symbol":["KIAA1627"],"prev_symbol":[]},"alphafold":{"accession":"Q9HCE5","domains":[{"cath_id":"3.40.50.150","chopping":"146-393","consensus_level":"high","plddt":95.8321,"start":146,"end":393}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCE5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCE5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCE5-F1-predicted_aligned_error_v6.png","plddt_mean":79.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=METTL14","jax_strain_url":"https://www.jax.org/strain/search?query=METTL14"},"sequence":{"accession":"Q9HCE5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCE5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCE5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCE5"}},"corpus_meta":[{"pmid":"24316715","id":"PMC_24316715","title":"A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation.","date":"2013","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/24316715","citation_count":2772,"is_preprint":false},{"pmid":"27281194","id":"PMC_27281194","title":"Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27281194","citation_count":996,"is_preprint":false},{"pmid":"29290617","id":"PMC_29290617","title":"METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification.","date":"2017","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/29290617","citation_count":827,"is_preprint":false},{"pmid":"32111213","id":"PMC_32111213","title":"METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST.","date":"2020","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32111213","citation_count":443,"is_preprint":false},{"pmid":"28914256","id":"PMC_28914256","title":"Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis.","date":"2017","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28914256","citation_count":414,"is_preprint":false},{"pmid":"29348140","id":"PMC_29348140","title":"Interactions, localization, and phosphorylation of the m6A generating METTL3-METTL14-WTAP complex.","date":"2018","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29348140","citation_count":383,"is_preprint":false},{"pmid":"32552762","id":"PMC_32552762","title":"METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer.","date":"2020","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32552762","citation_count":328,"is_preprint":false},{"pmid":"34019807","id":"PMC_34019807","title":"The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth.","date":"2021","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/34019807","citation_count":233,"is_preprint":false},{"pmid":"32802173","id":"PMC_32802173","title":"METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32802173","citation_count":230,"is_preprint":false},{"pmid":"33414476","id":"PMC_33414476","title":"METTL14-regulated PI3K/Akt signaling pathway via PTEN affects HDAC5-mediated epithelial-mesenchymal transition of renal tubular cells in diabetic kidney disease.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33414476","citation_count":174,"is_preprint":false},{"pmid":"32576970","id":"PMC_32576970","title":"LNC942 promoting METTL14-mediated m6A methylation in 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reprogramming via ICP0-mediated suppression of METTL14 potentiates oncolytic activity in glioma.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39325621","citation_count":13,"is_preprint":false},{"pmid":"37972448","id":"PMC_37972448","title":"CircMETTL14(11)S upregulated METTL14 and induced CXCR4 to aggravate endothelial inflammation and atherosclerosis.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37972448","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56849,"output_tokens":14090,"usd":0.190948,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":25507,"output_tokens":4195,"usd":0.116205,"stage2_stop_reason":"end_turn"},"total_usd":0.307153,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"METTL14 forms a stable heterodimer core complex with METTL3 that together catalyzes N6-methyladenosine (m6A) deposition on mammalian nuclear RNAs; WTAP interacts with this complex and affects methylation activity.\",\n      \"method\": \"Biochemical co-purification, in vitro methylation assay, Co-IP\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — foundational discovery using in vitro assays and pulldown; independently replicated across many subsequent studies\",\n      \"pmids\": [\"24316715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structures of the METTL3-METTL14 heterodimer (MTase domains) in ligand-free, SAM-bound, and SAH-bound states revealed that METTL3 is the catalytic core (SAM binds only in METTL3 pocket) while METTL14 serves as an RNA-binding platform; they interact via an extensive hydrogen-bonding network forming a positively charged RNA-binding groove.\",\n      \"method\": \"X-ray crystallography (1.61–1.9 Å resolution) combined with biochemical mutational analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structures in three states plus biochemical validation; landmark study\",\n      \"pmids\": [\"27281194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The C-terminal RGG repeats of METTL14 are required for RNA substrate binding and for METTL3/METTL14 methyltransferase activity; monomeric METTL3 is soluble but inactive alone, and the catalytic center of METTL14 is degenerate and inactive alone. WTAP is required for nuclear speckle localization of METTL3/METTL14. Phosphorylation sites on endogenous METTL3 and METTL14 were identified.\",\n      \"method\": \"Recombinant protein binding-surface mapping, in vitro methylation assay, nuclear localization signal identification, phosphorylation site mapping, immunofluorescence\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical methods (in vitro reconstitution, mutagenesis of RGG repeats, localization) in a single focused study\",\n      \"pmids\": [\"29348140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 binds RNA G-quadruplex (rG4) structures via its C-terminal RGG repeats, and the METTL3/METTL14 heterodimer selectively methylates adenosines proximal to rG4 sequences, suggesting a mechanism for direct recruitment of the complex to specific methylation sites.\",\n      \"method\": \"In vitro RNA-binding assay, selective methylation assay with rG4-containing substrates\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro biochemical assay, single laboratory study\",\n      \"pmids\": [\"34908152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The MettL3-METTL14 complex is active in vitro on double-stranded DNA containing cyclopyrymidine dimers, abasic sites, or mismatches; N6-methyladenine in DNA decreases misincorporation of 8-oxoG opposite N6mA and inhibits N6mA excision by the adenine DNA glycosylase MYH from the template strand.\",\n      \"method\": \"In vitro methyltransferase assay on dsDNA substrates, structural analysis of YTHDC1 with gapped duplex DNA\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro biochemical reconstitution but single study, no in vivo confirmation of DNA methylation activity\",\n      \"pmids\": [\"34086966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNA binding to the METTL3-METTL14 complex largely restricts N6-deoxyadenosine methylation of DNA in vitro; the complex preferentially catalyzes m6dA in single-stranded DNA despite weaker binding to DNA, and binds structured RNAs with high affinity but methylates RNA adenosine less efficiently than ssDNA adenosine.\",\n      \"method\": \"Systematic in vitro methylation activity and binding affinity assays on panels of RNA/DNA oligonucleotides\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro biochemistry, single study\",\n      \"pmids\": [\"35060905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL14, but not METTL3, directly binds H3K27me3 chromatin marks and recruits KDM6B (H3K27me3 demethylase) to induce H3K27me3 demethylation independently of METTL3 and of m6A methyltransferase activity; depletion of METTL14 leads to globally increased H3K27me3 and suppressed gene transcription in mouse embryonic stem cells.\",\n      \"method\": \"ChIP-seq, nascent RNA synthesis assay, KDM6B co-IP/pulldown, Mettl14-KO mESCs, enzymatic-inactive METTL14 mutant rescue\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, and functional KO with multiple orthogonal readouts in single study demonstrating m6A-independent chromatin function\",\n      \"pmids\": [\"37030005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL14 specifically binds bivalent chromatin domains (H3K27me3 + H3K4me3) independently of METTL3 or m6A, enhances H3K27me3 by recruiting PRC2, and reduces H3K4me3 by recruiting KDM5B; Mettl14 knockout in mESCs decreases H3K27me3 and increases H3K4me3 at bivalent genes, increasing their transcription.\",\n      \"method\": \"ChIP-seq, Co-IP, Mettl14-KO mESCs, transcriptional analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with PRC2/KDM5B, ChIP-seq in KO cells, consistent with independent parallel study (PMID 37030005)\",\n      \"pmids\": [\"37314930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STUB1 (E3 ubiquitin ligase) directly interacts with METTL14 and ubiquitinates it at lysine residues K148, K156, and K162, promoting its proteasomal degradation and decreasing global m6A levels; METTL3 competes with STUB1 for METTL14 binding (via METTL3 residues 450–454 and 464–480) to stabilize METTL14 and maintain m6A homeostasis.\",\n      \"method\": \"Co-IP, ubiquitination assay, site-directed mutagenesis of K148/K156/K162, domain-mapping of METTL3 interaction surface\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-specific mutagenesis of ubiquitination sites combined with reciprocal Co-IP and functional rescue; single laboratory but multiple orthogonal methods\",\n      \"pmids\": [\"36597993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT1 asymmetrically methylates arginine residues at the C-terminus of METTL14; the m6A reader SPF30 recognizes this arginine methylation; PRMT1-mediated arginine methylation on METTL14 is required for its m6A catalytic function and promotes cell proliferation.\",\n      \"method\": \"Co-IP, arginine methylation assay, functional rescue with PRMT1 inhibitor MS023\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP and functional inhibitor experiment; single laboratory, limited mutagenesis detail in abstract\",\n      \"pmids\": [\"37269817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRMT3 interacts with METTL14 and mediates its arginine methylation; PRMT3 inhibition leads to METTL14 overexpression, which promotes m6A modification of GPX4 mRNA via YTHDF2-dependent mechanism reducing GPX4 mRNA stability and increasing ferroptosis.\",\n      \"method\": \"Co-IP, arginine methylation assay, MeRIP, functional rescue experiments in endometrial carcinoma cells\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP demonstrating PRMT3-METTL14 interaction and downstream m6A mechanistic assay; single laboratory\",\n      \"pmids\": [\"37973560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The HSV-1 immediate-early protein ICP0 interacts with METTL14 within ND10 nuclear bodies and acts as an E3 ubiquitin ligase, ubiquitinating METTL14 at lysine 156 and 162, leading to its proteasomal degradation and decreased global m6A levels; METTL14 stabilizes ISG15 mRNA via IGF2BP3 to promote antiviral immunity.\",\n      \"method\": \"Co-IP, ubiquitination assay with site-specific mutants (K156/K162), RIP assay for IGF2BP3-ISG15 interaction, functional rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, site-specific ubiquitination mutagenesis, and RIP; single laboratory\",\n      \"pmids\": [\"39325621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EBV latent oncoprotein EBNA3C activates METTL14 transcription and directly interacts with METTL14 protein to promote its stability; METTL14 knockdown decreases expression of latent EBV transcripts, demonstrating that EBV hijacks METTL14-mediated m6A modification to stabilize viral transcripts.\",\n      \"method\": \"Co-IP (EBNA3C-METTL14), transcriptional activation assay, METTL14 knockdown with viral transcript quantification, xenograft tumor model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP and functional KD with in vivo xenograft; single laboratory\",\n      \"pmids\": [\"31226160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UVB irradiation downregulates METTL14 protein through NBR1-dependent selective autophagy; METTL14 promotes global genome nucleotide excision repair (GGR) by increasing m6A methylation and translation of DDB2 mRNA, an effect dependent on its methyltransferase activity (enzymatically inactive mutant fails to rescue); YTHDF1 (m6A reader promoting translation) also binds DDB2 transcript and is required for normal DDB2 levels.\",\n      \"method\": \"METTL14 KD/OE with enzymatically inactive mutant, m6A MeRIP of DDB2 mRNA, YTHDF1 RIP, GGR repair assay, mouse skin-specific heterozygous KO\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic-inactive mutant rescue, MeRIP, RIP, and mouse in vivo KO with defined phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"34452996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mycobacterium tuberculosis secreted antigen EsxB interacts with p38 MAPK and disrupts TAB1-mediated autophosphorylation of p38, thereby inhibiting p38-mediated phosphorylation of METTL14 at Thr72; loss of pThr72 impairs liquid-liquid phase separation (LLPS) of METTL14 and its interaction with METTL3, preventing m6A modification of Nox2 mRNA and its stabilization by IGF2BP1.\",\n      \"method\": \"Co-IP (EsxB-p38, p38-METTL14), phosphorylation assay at Thr72, METTL14 LLPS assay, MeRIP of Nox2 mRNA, RIP (IGF2BP1), site-directed mutation of phosphorylation site, mouse infection model\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple mechanistic experiments including phospho-site mutagenesis and LLPS assay; single laboratory\",\n      \"pmids\": [\"38548762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NF-κB directly transactivates the METTL14 gene (and METTL3) upon LPS challenge in Kupffer cells, increasing global m6A; METTL14-dependent m6A on the 5′UTR of TGF-β1 mRNA promotes cap-independent translation of TGF-β1; this mechanism is abolished in myeloid lineage cell-specific Mettl14-KO mice.\",\n      \"method\": \"ChIP-PCR (NF-κB on METTL14 promoter), dual-luciferase reporter with m6A site mutations in TGF-β1 5′UTR, m6A-seq, METTL14-deficient KCs and myeloid-specific KO mice\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validation of NF-κB binding, m6A site mutagenesis in reporter, and KO mouse confirmation; multiple orthogonal methods\",\n      \"pmids\": [\"33992834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Germ cell-specific inactivation of Mettl14 (with Vasa-Cre) depletes spermatogonial stem cells and causes loss of m6A; this dysregulates translation of transcripts required for SSC proliferation/differentiation. Combined deletion of Mettl3 and Mettl14 in advanced germ cells (Stra8-GFPCre) disrupts spermiogenesis and impairs translation of haploid-specific genes.\",\n      \"method\": \"Conditional Mettl14-KO mice, ribosome profiling/translation assay, m6A sequencing across spermatogenic cell stages\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with translational readout; replicated across multiple Cre lines; multiple spermatogenic stages analyzed\",\n      \"pmids\": [\"28914256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"METTL14 regulates m6A modification of MYB and MYC mRNAs in AML cells; the transcription factor SPI1 negatively regulates METTL14 protein expression, defining a SPI1-METTL14-MYB/MYC signaling axis in myelopoiesis.\",\n      \"method\": \"MeRIP of MYB/MYC mRNAs upon METTL14 silencing, RNA-seq, ChIP for SPI1, gain/loss-of-function in AML cells and mouse models\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MeRIP and ChIP with functional KD/KO; single laboratory\",\n      \"pmids\": [\"29290617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"METTL14 promotes m6A methylation of lncRNA XIST, enabling recognition by YTHDF2 and mediating XIST degradation; knockdown of METTL14 reduces m6A on XIST, increases XIST expression, and enhances CRC proliferation and invasion.\",\n      \"method\": \"Me-RIP, RNA pulldown, RIP, rescue experiment with YTHDF2\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP and RIP validation; single laboratory\",\n      \"pmids\": [\"32111213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"METTL14-mediated m6A modification of SOX4 mRNA promotes its degradation via YTHDF2; KDM5C-mediated demethylation of H3K4me3 at the METTL14 promoter inhibits METTL14 transcription in CRC.\",\n      \"method\": \"MeRIP-Seq, RIP, ChIP (KDM5C on METTL14 promoter), YTHDF2 functional rescue\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MeRIP, RIP, ChIP; single laboratory\",\n      \"pmids\": [\"32552762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mettl14 promotes m6A modification of Notch1 mRNA, reducing its stability; Mettl14 knockout increases Notch1 mRNA stability and promotes bladder tumor-initiating cell self-renewal.\",\n      \"method\": \"RNA stability assay, Me-RIP of Notch1 mRNA, gain/loss-of-function in bladder TICs\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP and RNA stability assay; single laboratory\",\n      \"pmids\": [\"31760940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL14 directly binds FOXO1 mRNA via RIP assay, increases its m6A modification, and enhances FOXO1 translation through YTHDF1 recognition; METTL14 also interacts with FOXO1 protein to act on VCAM-1 and ICAM-1 promoters to promote their transcription in endothelial cells; METTL14 knockout in mice reduces atherosclerotic plaque formation.\",\n      \"method\": \"MeRIP-seq, RIP (METTL14-FOXO1 mRNA), Co-IP (METTL14-FOXO1 protein), luciferase reporter, METTL14-KO mouse atherosclerosis model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — RIP, MeRIP, Co-IP, and KO mouse; single laboratory\",\n      \"pmids\": [\"32802173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 mediates m6A modification of Myd88 mRNA to regulate its stability, promoting NF-κB/IL-6 inflammatory signaling in macrophages; Mettl14 knockout reduces macrophage inflammation and atherosclerosis in mice.\",\n      \"method\": \"MeRIP (Myd88 mRNA stability), Mettl14-KD THP-1 cells, Mettl14-KO mice with atherosclerosis model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP and in vivo KO; single laboratory\",\n      \"pmids\": [\"35598196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL14 overexpression (but not an MTase-inactive mutant) blocks exercise-induced physiological cardiac hypertrophy; cardiac-specific METTL14 knockdown attenuates ischemia-reperfusion injury; METTL14 silencing suppresses Phlpp2 mRNA m6A modifications and activates Akt-S473 signaling to regulate cardiomyocyte growth and apoptosis.\",\n      \"method\": \"Wild-type vs. MTase-inactive mutant METTL14 OE, cardiac-specific KD, MeRIP of Phlpp2 mRNA, Akt-S473 phosphorylation assay, in vivo exercise and IR models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatically inactive mutant distinguishes m6A-dependent mechanism; in vivo cardiac-specific KD with defined signaling readout; multiple orthogonal methods\",\n      \"pmids\": [\"36351918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of METTL14 in tumor-associated macrophages decreases m6A abundance on Ebi3 mRNA and increases Ebi3 transcript and EBI3 cytokine subunit levels, which drives CD8+ T cell dysfunctional differentiation; neutralization of EBI3 reinvigorates dysfunctional CD8+ T cells.\",\n      \"method\": \"Macrophage-specific METTL14-KO mice, MeRIP of Ebi3 mRNA, EBI3 neutralization rescue, flow cytometry of CD8+ T cell states\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — macrophage-specific KO with MeRIP of specific target and functional rescue by neutralization; rigorous mechanistic dissection\",\n      \"pmids\": [\"34019807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL14 knockdown in podocytes upregulates Sirt1 by relieving m6A-dependent Sirt1 mRNA degradation; podocyte-specific METTL14-KO mice show improved glomerular function with activated autophagy and reduced apoptosis; MeRIP-qPCR and dual-luciferase assay confirmed METTL14 promotes Sirt1 mRNA m6A modification and degradation.\",\n      \"method\": \"Podocyte-specific Mettl14-KO mice, MeRIP-qPCR, dual-luciferase reporter, gain/loss-of-function in cultured podocytes\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MeRIP, luciferase, and in vivo KO; single laboratory\",\n      \"pmids\": [\"34580283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mettl14 loss in liver-specific KO mice disrupts liver regeneration and causes G1 cell-cycle arrest; key ER stress response transcripts (Hsp90b1, Erp29, Stt3a, P4hb, Lman1) are m6A-hypomethylated and their levels decrease, resulting in unresolved ER stress and hepatocyte death; Mettl3 loss does not reproduce this phenotype.\",\n      \"method\": \"Hepatocyte-specific Mettl14-KO and Mettl3-KO mice, m6A-seq of regenerating liver, biochemical ER stress markers\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo conditional KO with m6A-seq; single laboratory; comparison with Mettl3 KO strengthens specificity\",\n      \"pmids\": [\"33848642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14-mediated m6A modification of GluN2A (GRIN2A) mRNA stabilizes it via IGF2BP2 recognition, enhancing NMDAR activity in DRG neurons; overexpression of METTL14 upregulates m6A and facilitates pain hypersensitivity; DBP transcription factor drives METTL14 upregulation in CINP.\",\n      \"method\": \"Gain/loss-of-function in DRG neurons, m6A dot blot, MeRIP of GluN2A mRNA, IGF2BP2 RIP, behavioral pain assays, human DRG validation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MeRIP and RIP with in vivo and in vitro functional assays; single laboratory\",\n      \"pmids\": [\"38319733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The cancer-associated METTL14 R298P mutation reduces m6A modification at canonical DRACH motifs and induces m6A at aberrant GGAU motifs; aberrant GGAU-context m6A is recognized normally by YTH readers but demethylated less efficiently by ALKBH5; one consequence is hypermethylation of c-MET mRNA at canonical sites near aberrant sites, destabilizing c-MET mRNA and reducing c-Myc expression.\",\n      \"method\": \"MeRIP-seq of WT vs. R298P cell lines, in vitro methyltransferase assay on GGAU substrates, structural modeling, mRNA stability assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro biochemistry plus MeRIP-seq; single laboratory\",\n      \"pmids\": [\"37355987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biochemical and structural data show that the METTL14 R298P cancer mutation shifts substrate selectivity toward noncanonical GGAU motifs in vitro and in vivo, and GGAU-context m6A is demethylated less efficiently by ALKBH5 than canonical sites; structural analysis provides a model for cognate RNA sequence selection by METTL3-METTL14.\",\n      \"method\": \"Biochemical in vitro methylation assay, MeRIP-seq, structural analysis, transgenic mouse model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution combined with structural data, MeRIP-seq, and transgenic mouse; multiple orthogonal approaches\",\n      \"pmids\": [\"39705353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3/METTL14 complex acts as an essential adapter for CRL4 E3 ubiquitin ligase to target SUV39H1/H2 histone methyltransferases for polyubiquitination and proteasomal degradation, preventing H3K9me3 accumulation in nucleoli and maintaining nucleolar integrity and LLPS in human embryonic stem cells.\",\n      \"method\": \"Co-IP (METTL3/METTL14 with CRL4 and SUV39H1/H2), ubiquitination assay, METTL3/METTL14 KO hESCs, nucleolar LLPS analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assay with KO phenotype; single laboratory\",\n      \"pmids\": [\"39169036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 promotes m6A modification of TNFAIP3 mRNA (a NF-κB pathway suppressor) and regulates TNFAIP3 mRNA stability and protein translocation in coding-sequence context; METTL14 knockdown reduces TNFAIP3, increases IL-6 and IL-17, and worsens joint inflammation in CAIA mice.\",\n      \"method\": \"MeRIP-seq, RIP assay, METTL14 KD in PBMCs and CAIA mouse model\",\n      \"journal\": \"Arthritis & rheumatology (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP-seq and RIP with in vivo KD; single laboratory\",\n      \"pmids\": [\"37327357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 promotes m6A modification of LASP1 mRNA, increasing LASP1 mRNA stability and protein expression; LASP1 activates the SRC/AKT signaling axis to promote fibroblast-like synoviocyte migration, invasion, and inflammation in rheumatoid arthritis.\",\n      \"method\": \"MeRIP, RIP, mRNA stability assay, METTL14 shRNA in vitro and RA rat model\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP and RIP with in vivo model; single laboratory\",\n      \"pmids\": [\"36878846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14 mediates m6A modification of FTH1 mRNA, reducing its stability and expression via YTHDF2-dependent degradation, thereby promoting sorafenib-induced ferroptosis in cervical cancer cells; this operates through the PI3K/Akt signaling pathway.\",\n      \"method\": \"MeRIP, luciferase reporter, mRNA stability assay (qRT-PCR), in vivo xenograft\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP and luciferase reporter with in vivo xenograft; single laboratory\",\n      \"pmids\": [\"38738555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL14 mediates m6A modification of FOXO3a mRNA, stabilizing it and increasing FOXO3a expression; loss of METTL14 reduces FOXO3a, impairing autophagic flux and increasing inflammation in T cells from ankylosing spondylitis patients.\",\n      \"method\": \"MeRIP, RNA stability assay, gain/loss-of-function in T cells\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single MeRIP and stability assay; single laboratory\",\n      \"pmids\": [\"37935312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 mediates m6A modification on Lnc-LSG1, enabling binding by YTHDC1 (m6A reader) which blocks Lnc-LSG1 interaction with ESRP2 protein; without m6A, Lnc-LSG1 binds ESRP2 and promotes its ubiquitination-dependent degradation, facilitating ccRCC metastasis.\",\n      \"method\": \"MeRIP-seq, RIP, ESRP2 ubiquitination assay, rescue experiments in ccRCC cells\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP-seq and RIP with functional rescue; single laboratory\",\n      \"pmids\": [\"35036065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14 overexpression in adipocytes decreases m6A on Adrb2, Adrb3, Atgl, and Cgi-58 transcripts; Mettl14 adipocyte-specific KO decreases m6A on these transcripts, increasing their protein levels and thereby enhancing β-adrenergic signaling and lipolysis; mice with adipocyte-specific Mettl14 deletion are resistant to HFD-induced obesity, insulin resistance, and NAFLD.\",\n      \"method\": \"Adipocyte-specific Mettl14-KO mice (HFD model), MeRIP of specific transcripts, lipolysis assays, metabolic phenotyping\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo conditional KO with MeRIP and metabolic readouts; single laboratory\",\n      \"pmids\": [\"37526326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mettl14 loss in retinal rod cells causes ectopic accumulation of outer segment proteins in the inner segment and progressive degeneration; Mettl14 loss in cone cells causes mislocalization of cone opsin proteins and cone cell death; mechanistically, m6A depletion reduces expression of phototransduction- and cilium-associated genes, impairing ciliogenesis and OS protein synthesis/transport.\",\n      \"method\": \"Retina-specific Mettl14-KO mouse models (Rho-Cre and HRGP-Cre), MeRIP-seq, transcriptomic analysis, immunofluorescence for protein localization\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — cell-type-specific KO with MeRIP-seq; single laboratory\",\n      \"pmids\": [\"35698136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Beta-cell-specific Mettl14 KO mice develop glucose intolerance, decreased glucose-stimulated insulin secretion, increased beta-cell death, and reduced beta-cell mass; HFD-fed KO mice also show decreased beta-cell proliferation, AKT hyperactivation (insulin sensitivity) and altered lipid metabolism.\",\n      \"method\": \"Conditional Mettl14-KO mice (RIP-Cre), glucose tolerance tests, GSIS assays, islet RNA-seq, histology\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional KO with defined metabolic phenotype; single laboratory\",\n      \"pmids\": [\"31029827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL14 regulates m6A modification and maturation of pri-miR-17 by reducing YTHDC2 recognition of the GGACC binding site, thereby inhibiting pri-miR-17 mRNA decay; this increases pri-miR-17 and mature miR-17-5p levels, which targets Mitofusin 2 (MFN2) to decrease mitochondrial fusion and promote 5-FU resistance.\",\n      \"method\": \"MeRIP (pri-miR-17), YTHDC2 RIP, MFN2 3'UTR reporter assay, mitochondrial morphology analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP and RIP mechanistic assays; single laboratory\",\n      \"pmids\": [\"36810285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL14 transcriptional activation by wild-type p53 suppresses colorectal tumor growth by promoting m6A-YTHDF2-dependent processing of pri-miR-6769b and pri-miR-499a into mature miRNAs, which repress SLC2A3 and PGAM1 to restrain aerobic glycolysis; enzymatic activity of METTL14 is required for this effect.\",\n      \"method\": \"ChIP (p53 on METTL14 promoter), MeRIP of pri-miRNAs, YTHDF2 rescue, intestinal epithelial cell-specific METTL14-KO mouse models (AOM/DSS and AOM)\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP, MeRIP, and in vivo KO; single laboratory\",\n      \"pmids\": [\"36794620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The CLK1 kinase phosphorylates SRSF5 at Ser250, which inhibits METTL14 exon 10 skipping; aberrant METTL14 exon10 skipping (when CLK1-SRSF5 axis is disrupted) enhances m6A modification levels and promotes pancreatic cancer metastasis.\",\n      \"method\": \"Phosphorylation mass spec (SRSF5-Ser250), RNA-seq (alternative splicing), RIP, RNA pulldown, CLIP-qPCR\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — phospho-mass spec, RIP/pulldown; single laboratory\",\n      \"pmids\": [\"33849617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 increases m6A modification of UCHL5 mRNA and promotes its expression via YTHDF1 recognition; UCHL5 deubiquitinates NLRP3 to enhance its protein stability, activating NLRP3 inflammasome and promoting VSMC phenotypic switching in atherosclerosis.\",\n      \"method\": \"MeRIP, RIP, Co-IP (UCHL5-NLRP3), ubiquitination assay, dual-luciferase reporter\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP, RIP, Co-IP and ubiquitination; single laboratory\",\n      \"pmids\": [\"37044315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 promotes m6A modification of NLRP3 transcripts; IGF2BP2 (m6A reader) recognizes and stabilizes METTL14-methylated NLRP3 mRNA, activating NLRP3 inflammasome in macrophages during acute lung injury.\",\n      \"method\": \"MeRIP, RIP (IGF2BP2-NLRP3), METTL14 KD in macrophages, ALI mouse model with IGF2BP2 KD\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP and RIP with in vivo model; single laboratory\",\n      \"pmids\": [\"38218935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL14 enhances m6A modification and expression of KAT3B mRNA; KAT3B (a histone acetyltransferase) increases STING expression via H3K27ac on the STING promoter; this METTL14-KAT3B-STING axis promotes M1 microglia/macrophage polarization and NLRP3 inflammasome activation after ischemic stroke.\",\n      \"method\": \"MeRIP (KAT3B mRNA), ChIP (H3K27ac on STING promoter), METTL14 KD in MCAO rat model and OGD/R cells\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP and ChIP with in vivo KD; single laboratory\",\n      \"pmids\": [\"37541353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 increases m6A modification of SMAD1 mRNA; IGF2BP1 acts as the m6A reader stabilizing SMAD1 mRNA; METTL14 knockdown reduces SMAD1 m6A and stability, suppressing osteogenic differentiation of BMSCs and reducing bone mass in OVX mice.\",\n      \"method\": \"Me-RIP, RIP (IGF2BP1-SMAD1), luciferase reporter, METTL14 KD in BMSCs, OVX mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Me-RIP, RIP, luciferase; single laboratory\",\n      \"pmids\": [\"36319624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of Mettl14 in the uterus causes infertility due to implantation failure; Mettl14-deficient uteri show aberrant upregulation of ERα signaling and ERα phosphorylation, abnormal innate immune pathway activation with macrophage/dendritic cell infiltration; MeRIP-seq shows decreased m6A peaks on innate immune response genes.\",\n      \"method\": \"Uterine-specific Mettl14-KO mice, MeRIP-seq, immunofluorescence for immune cell infiltration, ERα signaling assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional KO with MeRIP-seq; single laboratory\",\n      \"pmids\": [\"37440278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX41 promotes YTHDC1 recruitment to R-loops by facilitating METTL3-YTHDC1 binding; DDX41 KO/KI leads to increased m6A-methylated R-loops and impaired YTHDC1-dependent R-loop resolution, contributing to genomic instability in MDS.\",\n      \"method\": \"Co-IP (DDX41-METTL3-METTL14 complex), DDX41-KO and KI (R525H, Y259C) cell lines, m6A R-loop quantification\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP and KO/KI cell lines; single laboratory\",\n      \"pmids\": [\"38514771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14 mediates m6A modification of MN1 mRNA in the CDS region; this is recognized by IGF2BP2, which prevents MN1 mRNA degradation and promotes its translation; elevated MN1 contributes to osteosarcoma progression and ATRA resistance.\",\n      \"method\": \"MeRIP-seq, RNA-seq, RNA pulldown, RIP (IGF2BP2), RNA stability and polysome analysis\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MeRIP-seq combined with polysome profiling and RIP; single laboratory\",\n      \"pmids\": [\"35810559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LNC942 (LINC00942) directly recruits METTL14 protein by harboring a specific recognition sequence (+176–+265), thereby increasing METTL14-mediated m6A methylation and stabilizing CXCR4 and CYP1B1 mRNAs in breast cancer cells.\",\n      \"method\": \"RNA pulldown, RIP, m6A quantification, RNA stability assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — RNA pulldown and RIP; single laboratory\",\n      \"pmids\": [\"32576970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14-mediated m6A modification of ITGB4 3′UTR promotes ITGB4 mRNA degradation via YTHDF2 recognition, reducing ITGB4 expression and inhibiting EMT and PI3K/AKT signaling in ccRCC.\",\n      \"method\": \"MeRIP, RIP (YTHDF2-ITGB4), luciferase reporter, METTL14 KD/OE in vitro and in vivo\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP, RIP, luciferase; single laboratory\",\n      \"pmids\": [\"35305660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 increases m6A modification of α-klotho mRNA and downregulates α-klotho expression; overexpression of METTL14 aggravates renal injury in diabetic nephropathy mice; α-klotho supplementation partially rescues METTL14-driven injury.\",\n      \"method\": \"MeRIP (α-klotho mRNA), in vitro HRGECs and db/db mouse model, α-klotho rescue\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MeRIP without detailed mechanistic validation; single laboratory\",\n      \"pmids\": [\"34503454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14 decreases GLS2 translation efficiency via YTHDF1 in hepatocytes in an m6A-dependent manner; hepatocyte-specific Mettl14 depletion aggravates MAFLD by creating an oxidative stress microenvironment that recruits Cx3cr1+Ccr2+ monocyte-derived macrophages, which activate hepatic stellate cells via CX3CR1/MyD88/NF-κB/S100A4 signaling.\",\n      \"method\": \"Hepatocyte-specific Mettl14-KO and OE mice, MeRIP (GLS2), YTHDF1 RIP, in vivo and in vitro mechanistic studies\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo KO/OE with MeRIP and YTHDF1 RIP; single laboratory\",\n      \"pmids\": [\"38627387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 promotes m6A modification of circORC5, reducing its abundance; reduced circORC5 decreases sponging of miR-30c-2-3p, reducing AKT1S1 and EIF4B expression to suppress gastric cancer progression.\",\n      \"method\": \"m6A-circRNA epitranscriptomic microarray, Me-RIP of circORC5, luciferase (circORC5-miR-30c-2-3p sponge), RIP\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Me-RIP and luciferase; single laboratory\",\n      \"pmids\": [\"35164771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL14 promotes m6A modification of Mettl14-mediated α-synuclein (SNCA) mRNA; this reduces α-syn mRNA stability; YTHDF2 recognizes m6A-modified α-syn mRNA, facilitating its degradation; overexpression of Mettl14 in PD cell models significantly increases m6A on α-syn CDS and weakens its stability.\",\n      \"method\": \"RIP (METTL14-α-syn mRNA), m6A modification analysis, RNA stability assay, YTHDF2 recognition assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — RIP and stability assay; single laboratory\",\n      \"pmids\": [\"37309980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 promotes m6A modification of MALAT1 lncRNA, increasing its nuclear stability and expression; MALAT1 sponges miR-224-5p to promote KDM2A expression and OSCC cell proliferation.\",\n      \"method\": \"MeRIP (MALAT1), m6A level quantification, subcellular fractionation, RNA stability assay, in vivo xenograft\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MeRIP and subcellular fractionation; single laboratory\",\n      \"pmids\": [\"35467063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 promotes m6A modification of METTL14-mediated NIXLRP3 transcript stabilization via IGF2BP2 in cardiomyocytes; in diabetic cardiomyopathy METTL14 decreases m6A of TINCR lncRNA; YTHDF2 recognizes m6A-modified TINCR and mediates its degradation; lower TINCR reduces NLRP3 mRNA stability, suppressing pyroptosis.\",\n      \"method\": \"RIP (YTHDF2-TINCR), MeRIP (TINCR m6A), RNA pulldown, NLRP3 mRNA stability assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — MeRIP, RIP, and stability assay; single laboratory\",\n      \"pmids\": [\"35013106\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"METTL14 is an RNA-binding scaffold subunit that heterodimerizes with the catalytic METTL3 to form the core m6A methyltransferase complex (with WTAP as a localization/activity co-factor), where METTL14's positively charged surface recognizes RNA substrates—including via RGG-repeat-dependent G-quadruplex binding—while METTL3 carries out catalysis using SAM; beyond m6A writing, METTL14 independently binds H3K27me3 chromatin and recruits KDM6B/KDM5B and PRC2 to regulate bivalent domain histone marks, and its stability is controlled by competitive ubiquitination (STUB1 at K148/K156/K162) versus METTL3-dependent protection, as well as by arginine methylation (PRMT1/PRMT3) and phosphorylation (p38 at Thr72); through m6A deposition, METTL14 controls mRNA stability, translation, and miRNA maturation of a broad set of target transcripts (including MYB, MYC, DDB2, TGF-β1, Phlpp2, GluN2A, and many others) in a context- and cell-type-specific manner, with downstream consequences for hematopoiesis, spermatogenesis, cardiac homeostasis, immune function, DNA repair, and tumorigenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"METTL14 is the RNA-binding scaffold subunit of the mammalian N6-methyladenosine (m6A) writer, forming a stable heterodimer with the catalytic METTL3 that deposits m6A on nuclear RNAs, with WTAP modulating activity and localization [#0]. Crystal structures resolved the division of labor: SAM binds only METTL3's pocket while METTL14's degenerate catalytic center and extensive interface with METTL3 build a positively charged groove that engages RNA [#1]; the complex is inactive when either subunit is monomeric, and METTL14's C-terminal RGG repeats are required for substrate binding and methyltransferase activity, including recognition of RNA G-quadruplex structures that can recruit the complex to specific sites [#2, #3]. Through m6A deposition, METTL14 governs the stability, translation, and processing of a broad target set—stabilizing or destabilizing transcripts through m6A readers (YTHDF1/2, IGF2BP1/2/3, YTHDC1) to control DDB2-dependent nucleotide excision repair [#13], TGF-\\u03b21 cap-independent translation [#15], and pri-miRNA maturation [#39, #40]—with cell-type-specific consequences for spermatogenesis [#16], cardiac homeostasis [#23], macrophage-driven immunity and CD8+ T-cell function [#24], and tumorigenesis [#17]. Beyond catalysis, METTL14 carries m6A-independent activities: it directly binds H3K27me3 and bivalent chromatin and recruits KDM6B, KDM5B, and PRC2 to set histone marks and gene transcription [#6, #7]. METTL14 protein levels are set by competitive ubiquitination—STUB1 ubiquitinates K148/K156/K162 to drive degradation while METTL3 binding protects it [#8]—and by arginine methylation (PRMT1, PRMT3) and p38-mediated Thr72 phosphorylation that promotes its phase separation and METTL3 association [#9, #10, #14]. A cancer-associated R298P mutation shifts substrate selectivity from canonical DRACH motifs toward aberrant GGAU sites that are demethylated poorly by ALKBH5 [#28, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that m6A on mammalian mRNA is written by a defined protein complex rather than a single enzyme, identifying METTL14 as a core partner of METTL3.\",\n      \"evidence\": \"Biochemical co-purification, in vitro methylation, and Co-IP defining a METTL3-METTL14 heterodimer with WTAP\",\n      \"pmids\": [\"24316715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which subunit is catalytic\", \"Substrate sequence/structural determinants not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the structural basis of the writer, showing METTL3 is the catalytic SAM-binding subunit and METTL14 an RNA-binding platform.\",\n      \"evidence\": \"X-ray crystallography of the MTase domains in ligand-free, SAM- and SAH-bound states with mutational validation\",\n      \"pmids\": [\"27281194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not include the disordered C-terminal RGG region\", \"How the complex selects specific adenosines in vivo unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined METTL14's RGG repeats as the RNA-substrate-binding element required for activity and pinned WTAP to nuclear speckle localization, clarifying the functional roles of each subunit.\",\n      \"evidence\": \"Recombinant binding-surface mapping, in vitro methylation, NLS identification, and immunofluorescence\",\n      \"pmids\": [\"29348140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific RNA features the RGG region recognizes not yet defined\", \"Functional role of mapped phosphorylation sites unestablished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tested whether the writer acts on DNA, showing in vitro activity on dsDNA and ssDNA but with RNA binding restricting DNA methylation.\",\n      \"evidence\": \"In vitro methyltransferase and binding-affinity assays on RNA/DNA oligonucleotide panels\",\n      \"pmids\": [\"34086966\", \"35060905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo confirmation of physiological DNA methylation\", \"Biological relevance of m6dA activity unestablished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Addressed how the complex finds specific sites, showing RGG-dependent binding to RNA G-quadruplexes directs methylation of proximal adenosines.\",\n      \"evidence\": \"In vitro RNA-binding and selective methylation assays on rG4-containing substrates\",\n      \"pmids\": [\"34908152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-laboratory in vitro study without in vivo validation\", \"Generality of rG4-directed targeting across the transcriptome unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated in vivo physiological requirements for METTL14-dependent m6A in germ cell biology and myeloid m6A target control, moving from biochemistry to function.\",\n      \"evidence\": \"Conditional Mettl14-KO mice with ribosome profiling and m6A-seq; MeRIP/ChIP in AML cells defining a SPI1-METTL14-MYB/MYC axis\",\n      \"pmids\": [\"28914256\", \"29290617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct targets driving phenotypes only partially mapped\", \"Reader specificity for individual transcripts not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that METTL14-deposited m6A directs reader-dependent fate decisions across diverse tissues, establishing it as a context-specific post-transcriptional regulator.\",\n      \"evidence\": \"Enzymatic-inactive mutant rescue, MeRIP, reader RIP and tissue-specific KO mice across DNA repair (DDB2/YTHDF1), TGF-\\u03b21 translation, and tumor-macrophage immunity (Ebi3)\",\n      \"pmids\": [\"34452996\", \"33992834\", \"34019807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of reader selection (YTHDF1 vs YTHDF2 vs IGF2BPs) per transcript unclear\", \"Why the same writer stabilizes some targets and destabilizes others not mechanistically unified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered an m6A-independent chromatin function, showing METTL14 directly reads H3K27me3/bivalent domains and recruits histone-modifying machinery.\",\n      \"evidence\": \"ChIP-seq, reciprocal Co-IP with KDM6B/KDM5B/PRC2, and enzymatic-inactive mutant rescue in Mettl14-KO mESCs\",\n      \"pmids\": [\"37030005\", \"37314930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of METTL14-H3K27me3 recognition unknown\", \"Relationship between chromatin role and canonical m6A writing not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined how METTL14 protein abundance—and thus global m6A—is controlled, identifying competitive ubiquitination and arginine methylation.\",\n      \"evidence\": \"Site-directed mutagenesis of ubiquitination lysines, Co-IP, ubiquitination and arginine-methylation assays with STUB1, METTL3, PRMT1, and PRMT3\",\n      \"pmids\": [\"36597993\", \"37269817\", \"37973560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals controlling STUB1 vs METTL3 competition in vivo unknown\", \"Interplay among the multiple PTMs not jointly tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected a kinase-dependent PTM to assembly, showing p38-mediated Thr72 phosphorylation promotes METTL14 phase separation and METTL3 interaction, and that a pathogen disrupts this axis.\",\n      \"evidence\": \"Phospho-site mutagenesis, LLPS assays, MeRIP/RIP, and mouse infection model with M. tuberculosis EsxB\",\n      \"pmids\": [\"38548762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological triggers of p38-METTL14 phosphorylation outside infection unclear\", \"Quantitative contribution of LLPS to bulk m6A deposition unmeasured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Explained how a cancer mutation corrupts substrate selection, linking R298P to noncanonical GGAU methylation resistant to ALKBH5 erasure.\",\n      \"evidence\": \"In vitro methylation on GGAU substrates, MeRIP-seq, structural modeling, and transgenic mouse\",\n      \"pmids\": [\"37355987\", \"39705353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full transcriptome-wide consequences of GGAU methylation not catalogued\", \"Therapeutic exploitability of the mutant selectivity untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how METTL14 integrates its dual roles—m6A writing versus chromatin/histone regulation—and what determines reader selection and opposing stabilizing/destabilizing outcomes on individual targets.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking the chromatin and methyltransferase functions\", \"Rules governing which reader engages a given m6A-modified transcript undefined\", \"Endogenous physiological signals coordinating the PTM network unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 29]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2, 3, 49]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 7, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 30]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 24]}\n    ],\n    \"complexes\": [\n      \"METTL3-METTL14 m6A methyltransferase complex\",\n      \"PRC2 (recruited)\",\n      \"CRL4 E3 ubiquitin ligase (adapter)\"\n    ],\n    \"partners\": [\n      \"METTL3\",\n      \"WTAP\",\n      \"STUB1\",\n      \"KDM6B\",\n      \"KDM5B\",\n      \"PRMT1\",\n      \"PRMT3\",\n      \"YTHDF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}