{"gene":"VIRMA","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2019,"finding":"KIAA1429/VIRMA induces m6A methylation on the 3' UTR of GATA3 pre-mRNA, leading to separation of the RNA-binding protein HuR and degradation of GATA3 pre-mRNA; a lncRNA GATA3-AS (transcribed antisense to GATA3) acts as a cis-acting element for preferential interaction of KIAA1429 with GATA3 pre-mRNA.","method":"MeRIP-seq, RIP-seq, RNA-seq, siRNA knockdown, in vitro and in vivo functional assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal sequencing and RIP methods, single lab","pmids":["31856849"],"is_preprint":false},{"year":2019,"finding":"KIAA1429 binds CDK1 mRNA and regulates CDK1 expression in an m6A-independent manner to promote breast cancer proliferation and metastasis.","method":"RNA immunoprecipitation sequencing (RIP-seq), functional rescue assays, in vitro and in vivo experiments","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP-seq identification and functional rescue, single lab, m6A-independence not mechanistically explained","pmids":["31285549"],"is_preprint":false},{"year":2019,"finding":"KIAA1429 increases m6A modification of ID2 mRNA, suppressing ID2 expression and thereby facilitating migration and invasion of hepatocellular carcinoma cells.","method":"MeRIP-PCR, siRNA knockdown, transwell assays","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single MeRIP-PCR method, single lab, limited mechanistic depth","pmids":["31118692"],"is_preprint":false},{"year":2020,"finding":"Oocyte-specific loss of Kiaa1429 in mice causes female infertility with defective follicular development and failure of germinal vesicle breakdown; KIAA1429 depletion decreases m6A levels in oocytes and disrupts alternative splicing of oogenesis-associated genes.","method":"Conditional knockout mouse model, RNA-seq, m6A quantification, phenotypic analysis of meiotic progression","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional knockout with defined reproductive phenotype plus transcriptome-wide RNA-seq and m6A measurement","pmids":["32094512"],"is_preprint":false},{"year":2020,"finding":"VIRMA knockdown in prostate cancer cells significantly decreases global m6A levels, attenuates malignant phenotype, and suppresses expression and stability of oncogenic lncRNAs CCAT1 and CCAT2 through m6A-dependent stabilization.","method":"siRNA knockdown, ELISA m6A quantification, Actinomycin D RNA stability assay, m6A/RNA co-immunoprecipitation","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and stability assay, single lab, two orthogonal methods","pmids":["32218194"],"is_preprint":false},{"year":2020,"finding":"KIAA1429 regulates c-Jun mRNA stability and expression in an m6A-independent manner to promote gastric cancer cell proliferation; RIP and luciferase assays confirmed direct binding to c-Jun mRNA.","method":"mRNA sequencing, RIP assay, luciferase assay, rescue experiments","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-lab RIP plus luciferase, m6A-independence asserted without deep mechanistic explanation","pmids":["32052427"],"is_preprint":false},{"year":2021,"finding":"KIAA1429 stabilizes LINC00958 lncRNA through m6A modification; LINC00958 in turn interacts with GLUT1 mRNA in an m6A-dependent manner to enhance GLUT1 mRNA stability and promote aerobic glycolysis in gastric cancer.","method":"MeRIP-seq, RIP assay, RNA stability assay, functional glycolysis assays","journal":"IUBMB life","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, MeRIP and RIP but indirect chain of interactions","pmids":["34409730"],"is_preprint":false},{"year":2021,"finding":"KIAA1429 enhances mRNA stability of HOXA1 through targeting its 3'-UTR, thereby accelerating gefitinib resistance in NSCLC cells.","method":"siRNA knockdown, mRNA stability assays, in vivo xenograft","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic follow-up on m6A-dependence","pmids":["34001850"],"is_preprint":false},{"year":2021,"finding":"VIRMA-regulated m6A modifications lead to post-transcriptional suppression of DAPK3 mRNA through YTHDF2/3 in NSCLC; inhibition of DAPK3 rescued tumor-suppressive phenotypes induced by VIRMA deficiency.","method":"siRNA knockdown, MeRIP, RIP, in vitro and in vivo functional assays, epistasis rescue experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP plus RIP plus genetic epistasis rescue, single lab","pmids":["34520821"],"is_preprint":false},{"year":2021,"finding":"KIAA1429 and ALKBH5 oppositely regulate m6A modification of pri-miR-143-3p, controlling its processing by the microprocessor protein DGCR8, thereby indirectly regulating DDX6 (a target of mature miR-143-3p) to affect aortic smooth muscle cell proliferation and endothelial cell apoptosis in aortic dissection.","method":"Gain/loss-of-function in vitro and in vivo (AngII mouse model), m6A sequencing, RIP","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model plus mechanistic RIP/m6A data, single lab","pmids":["34490238"],"is_preprint":false},{"year":2021,"finding":"KIAA1429 promotes breast cancer metastasis through the SMC1A/SNAIL axis: KIAA1429 binds the 3' UTR motif of SMC1A mRNA and enhances its stability in an m6A-independent manner; SMC1A then binds the SNAIL promoter to drive EMT.","method":"RIP assay, mRNA stability assay, luciferase reporter, siRNA knockdown, in vivo xenograft","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus mRNA stability plus luciferase, single lab, multiple orthogonal methods","pmids":["34976433"],"is_preprint":false},{"year":2021,"finding":"VIRMA knockdown in germ cell tumor cells disrupts the remaining methyltransferase complex and decreases global m6A abundance; this increases DNA damage (elevated γH2AX and GADD45B) and downregulates DNA repair factors XLF and MRE11, sensitizing cells to cisplatin.","method":"CRISPR/Cas9-mediated knockdown, m6A quantification, γH2AX measurement, CAM in vivo assay, western blot","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KD with multiple orthogonal readouts and in vivo validation, single lab","pmids":["34446080"],"is_preprint":false},{"year":2022,"finding":"KIAA1429 regulates BTG2 expression in an m6A-dependent manner; knockdown decreases m6A levels on BTG2 mRNA, leading to enhanced YTHDF2-dependent BTG2 mRNA stability and increased BTG2 expression, thereby suppressing LUAD tumorigenesis. Copy number amplification at KIAA1429 locus drives its overexpression.","method":"MeRIP-seq, RNA-seq, m6A dot blot, RIP, RNA stability assay, in vitro and in vivo experiments","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus RIP plus stability assay, multiple orthogonal methods, single lab","pmids":["35730068"],"is_preprint":false},{"year":2022,"finding":"KIAA1429 promotes LUAD via activation of JNK/MAPK pathway: KIAA1429 positively regulates MAP3K2 expression in an m6A methylation-dependent manner, restraining gefitinib resistance when knocked down.","method":"siRNA knockdown, in vitro and in vivo experiments, m6A-dependent target gene identification","journal":"Drug resistance updates","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited direct m6A mechanistic validation of MAP3K2","pmids":["36493511"],"is_preprint":false},{"year":2022,"finding":"KIAA1429 increases SIRT1 mRNA stability via m6A-dependent regulation in colorectal cancer, promoting cell proliferation, colony formation, and migration.","method":"shRNA knockdown, mRNA stability assay, in vivo xenograft","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, no direct MeRIP validation shown in abstract","pmids":["35217651"],"is_preprint":false},{"year":2022,"finding":"KIAA1429 promotes aerobic glycolysis in colorectal cancer by binding the m6A site of HK2 mRNA and enhancing its mRNA stability in an m6A-independent manner.","method":"Functional glycolysis assays, mRNA binding/stability assays, siRNA knockdown","journal":"Bioengineered","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, m6A-independence claimed without deep mechanistic resolution","pmids":["35546050"],"is_preprint":false},{"year":2022,"finding":"p65 (NF-κB) binds the KIAA1429 promoter and activates its transcription (confirmed by ChIP assay); KIAA1429 then recruits YTHDF1 to the 3'-UTR of FOXM1 mRNA, stabilizing FOXM1 and mediating cisplatin resistance in gastric cancer.","method":"ChIP assay, RIP, mRNA stability assay, shRNA knockdown, in vivo xenograft","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus RIP plus functional validation, single lab, multiple orthogonal methods","pmids":["36291811"],"is_preprint":false},{"year":2022,"finding":"KIAA1429 regulates alternative splicing of cancer-related genes (including BPTF exon 6) in HCC; KIAA1429-bound transcripts identified by RIP-seq highly overlap with regulated alternative splicing genes, indicating KIAA1429 globally regulates pre-mRNA splicing by binding transcripts.","method":"RNA-seq, RIP-seq, clinical validation of AS events","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq plus RNA-seq multi-omics integration, single lab","pmids":["36505780"],"is_preprint":false},{"year":2022,"finding":"USP29 directly binds KIAA1429 (confirmed by Co-IP) and mediates its deubiquitination to stabilize KIAA1429 protein levels; KIAA1429 then promotes SOX8 mRNA stability through m6A modification in CRC.","method":"Co-immunoprecipitation, western blot for ubiquitination, m6A-RIP, siRNA knockdown, in vivo xenograft","journal":"Biomolecules & biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus m6A-RIP, single lab, multiple orthogonal methods","pmids":["36373629"],"is_preprint":false},{"year":2023,"finding":"KIAA1429-mediated m6A modification of CHST11 mRNA recruits YTHDF2 to reduce CHST11 mRNA stability and expression; diminished CHST11 lowers MOB1B expression, inactivating Hippo-YAP signaling in DLBCL.","method":"CRISPR/Cas9 knockout, CRISPR/dCas9-VP64 activation, RNA-seq, MeRIP-seq, RIP, luciferase assay, RNA stability assay, Co-IP, xenograft","journal":"Cellular & molecular biology letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO and activation, multiple orthogonal sequencing and functional methods, pathway epistasis validated","pmids":["37076815"],"is_preprint":false},{"year":2023,"finding":"VIRMA mediates m6A methylation of E2F7 3'-UTR; IGF2BP2 binds and maintains E2F7 mRNA stability; E2F7 then cooperates with CBFB-recruited RUNX1 in a non-canonical manner to transactivate ITGA2, ITGA5, and NTRK1, activating Akt signaling in NPC.","method":"High-throughput sequencing, MeRIP, RIP, luciferase assay, in vitro and in vivo experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP plus RIP plus integrative sequencing, single lab, multiple orthogonal methods","pmids":["37028765"],"is_preprint":false},{"year":2023,"finding":"KIAA1429 negatively regulates the tumor suppressor RND3 by decreasing its mRNA stability via m6A modification coordinated with the m6A reader YTHDC1; KIAA1429 acts through its RNA-binding domain.","method":"RNA-seq, MeRIP-seq, RIP, MeRIP-qPCR, RNA stability assay, luciferase assay, in vitro/in vivo experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus RIP plus RNA stability assay, single lab, multiple orthogonal methods","pmids":["38224863"],"is_preprint":false},{"year":2023,"finding":"KIAA1429/VIRMA is mislocalized to the cytosol of breast cancer cells; cytosolic KIAA1429/VIRMA binds to m6A-binding protein IGF2BP3, which recruits and stabilizes m6A-modified HAS2 mRNA, promoting breast cancer growth.","method":"Subcellular fractionation, Co-IP, RIP, shRNA knockdown, in vitro/in vivo functional assays, immunofluorescence","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — subcellular localization directly tied to function, Co-IP plus RIP plus in vivo, multiple orthogonal methods in single rigorous study","pmids":["37705505"],"is_preprint":false},{"year":2023,"finding":"VIRMA promotes breast cancer by upregulating the m6A-modified long non-coding RNA NEAT1, contributing to cancer cell growth; the nuclear full-length VIRMA isoform (but not the cytoplasmic N-terminal isoform) drives m6A-dependent breast tumourigenesis.","method":"Isoform-specific overexpression, in vitro and in vivo functional assays, m6A modification analysis","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific functional experiments plus in vivo, single lab","pmids":["37208522"],"is_preprint":false},{"year":2023,"finding":"VIRMA promotes ICC progression by stabilizing TMED2 and PARD3B mRNAs through m6A-HuR-mediated mechanism; the high VIRMA expression in ICC is caused by demethylation of the H3K27me3 modification in the VIRMA promoter region.","method":"RNA-seq, MeRIP-seq, SLAM-seq, RIP, luciferase reporter, ChIP assay, in vitro/in vivo experiments","journal":"Journal of gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multi-omics including SLAM-seq, ChIP, and MeRIP-seq with functional validation, single lab, multiple orthogonal methods","pmids":["37391589"],"is_preprint":false},{"year":2023,"finding":"KIAA1429 promotes gastric cancer progression by destabilizing RASD1 mRNA through m6A-YTHDF2-dependent degradation, thereby downregulating RASD1 expression.","method":"MeRIP-seq, RNA-seq, MeRIP-qPCR, RNA stability assay, RIP, RNA pull-down, dual luciferase reporter, in vivo xenograft","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus RIP plus stability assay, single lab, multiple orthogonal methods","pmids":["38902717"],"is_preprint":false},{"year":2023,"finding":"KIAA1429 protects hepatocellular carcinoma cells from ferroptosis through m6A-dependent post-transcriptional modification of SLC7A11; RIP confirmed KIAA1429 binding to m6A on SLC7A11 transcript, and overexpression heightens SLC7A11 cystine/glutamate antiporter activity.","method":"RIP, m6A inhibitor (cycloleucine) treatment, ferroptosis marker assays, in vivo xenograft","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus chemical inhibitor plus functional ferroptosis readouts, single lab","pmids":["37830241"],"is_preprint":false},{"year":2023,"finding":"HNRNPC promotes DDR1 transcription in breast cancer by recognizing VIRMA-installed m6A modification on TFAP2A mRNA (PAR-CLIP confirmed VIRMA binding; RIP confirmed HNRNPC recognition of m6A on TFAP2A), stabilizing TFAP2A which transactivates DDR1 to promote collagen fiber alignment and immune evasion.","method":"PAR-CLIP, Me-RIP, RIP, ChIP, dual-luciferase, in vivo mouse BC transplant model","journal":"Molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — PAR-CLIP plus Me-RIP plus RIP plus ChIP plus in vivo, multiple orthogonal methods, single rigorous study","pmids":["37528369"],"is_preprint":false},{"year":2024,"finding":"PTPRG physically interacts with VIRMA in mouse brain; PTPRG binding upregulates VIRMA, which inhibits translation of PRKN mRNA through m6A methylation, preventing mitophagy clearance of damaged mitochondria and leading to neuronal death in Alzheimer's disease.","method":"Single-cell RNA-seq, spatial transcriptomics, Co-IP in mouse brain, 5×FAD mouse model validation","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in mouse brain plus in vivo 5×FAD model, single lab, multiple approaches","pmids":["38325728"],"is_preprint":false},{"year":2024,"finding":"TIP60 acetylates KIAA1429 at a specific residue, which promotes KDM5B expression in an m6A-YTHDF1-dependent manner; KDM5B subsequently represses FoxO1 transcription to enable immune evasion, growth, and metastasis in HCC.","method":"RNA pull-down, RIP, ChIP, Co-IP, m6A quantification, MeRIP-qPCR, flow cytometry, xenograft in NOD/SCID mice","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for acetylation plus ChIP plus MeRIP-qPCR plus epistasis rescue, single lab","pmids":["40301310"],"is_preprint":false},{"year":2024,"finding":"BRAF-mediated phosphorylation of KIAA1429 promotes its cytoplasmic localization; cytoplasmic KIAA1429 promotes Wnt pathway activation by binding and stabilizing FZD7 mRNA, enhancing cancer stemness and oxaliplatin resistance in BRAFV600E-mutated CRC.","method":"IP-MS, Co-IP, immunofluorescence, RIP, RNA-seq, in vitro/in vivo functional assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus Co-IP plus immunofluorescence plus RIP with functional validation, single lab","pmids":["40611274"],"is_preprint":false},{"year":2024,"finding":"VIRMA promotes neuronal apoptosis in spinal cord injury by inducing m6A methylation of STK10 mRNA, negatively regulating STK10 expression; VIRMA knockdown reduces m6A methylation and apoptosis of neuronal cells.","method":"Rat SCI model, m6A methylation kit, overexpression/knockdown in OGD cell models and animal models","journal":"CNS neuroscience & therapeutics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect m6A measurement without direct MeRIP-seq of STK10","pmids":["37721438"],"is_preprint":false},{"year":2024,"finding":"SHBs (small HBV surface antigen) elevates global m6A levels and upregulates CCR9 expression through KIAA1429-mediated m6A modification at sites 1373 and 1496 on CCR9 mRNA, stabilizing CCR9 mRNA and promoting HCC regorafenib resistance.","method":"m6A site-specific mutagenesis (sites 1373 and 1496), AAV-HBV mouse model, functional assays","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific m6A site identification plus in vivo AAV-HBV model, single lab","pmids":["39206838"],"is_preprint":false},{"year":2024,"finding":"KIAA1429 cooperates with m6A reader HuR to enhance HK1 mRNA stability, upregulating HK1 expression and promoting Warburg effect/sorafenib resistance in liver cancer; KIAA1429 directly binds HK1 mRNA.","method":"RNA-seq, MeRIP-seq, RIP, mRNA stability assay, in vitro/in vivo experiments","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus RIP plus RNA stability assay, single lab","pmids":["38996929"],"is_preprint":false},{"year":2024,"finding":"KIAA1429-mediated m6A modification stabilizes RAB27B mRNA through the m6A/YTHDF1 axis in CML, enhancing drug efflux and imatinib resistance; rucaparib suppresses KIAA1429 expression and reduces CML progression.","method":"mRNA stability assay, RIP, in vitro/in vivo CML models","journal":"Genes & diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP without full MeRIP-seq confirmation","pmids":["37692484"],"is_preprint":false},{"year":2024,"finding":"VIRMA promotes nasopharyngeal carcinoma via m6A methylation of PTGS2 mRNA, enhancing PTGS2 mRNA stability; MeRIP and mRNA stability assays confirmed m6A modification.","method":"MeRIP, mRNA stability assay, siRNA/overexpression, in vitro/in vivo experiments","journal":"Critical reviews in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, MeRIP only without reader identification","pmids":["37830191"],"is_preprint":false},{"year":2024,"finding":"IL-6 activates KIAA1429 expression through the JAK1/STAT3 pathway; KIAA1429 then promotes DDIT3 mRNA degradation through m6A modification, inhibiting ferroptosis and promoting proliferation in endometrial cancer.","method":"Dot blot, MeRIP, RIP, RNA stability assay, FISH, in vitro and in vivo experiments","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP plus RIP plus FISH plus stability assay with upstream signaling validated, single lab","pmids":["40436288"],"is_preprint":false},{"year":2024,"finding":"KIAA1429-mediated m6A modification of FOXM1 mRNA, recognized by YTHDF1, stabilizes FOXM1 mRNA and promotes aerobic glycolysis and tumorigenesis in multiple myeloma.","method":"RIP, m6A modification assay, RNA stability assay, in vivo transplantation model","journal":"Cell biology and toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP without full MeRIP-seq","pmids":["39060874"],"is_preprint":false},{"year":2024,"finding":"KIAA1429-mediated m6A modification of Lrp4 mRNA is recognized by YTHDC1 to increase Lrp4 mRNA stability and expression; elevated LRP4 recruits TNFAIP3 to inactivate NF-κB signaling, thereby inhibiting osteoclast differentiation and protecting against osteoporosis.","method":"MeRIP-seq, scRNA-seq, in vitro osteoclast differentiation assays, OVX mouse model","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus scRNA-seq plus in vivo model with pathway epistasis, single lab","pmids":["41146006"],"is_preprint":false},{"year":2024,"finding":"VIRMA promotes NSCLC progression by m6A modification of ADAR mRNA, enhancing ADAR expression and activating TGF-β signaling pathway.","method":"Western blot, m6A modification analysis, functional assays, in vivo xenograft","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic depth in abstract","pmids":["40254620"],"is_preprint":false},{"year":2024,"finding":"KIAA1429 facilitates immune evasion in NSCLC by stabilizing KLF1 mRNA through m6A modification, which upregulates PD-L1 expression and suppresses CD8+ T cell activity.","method":"m6A enrichment on KLF1, mRNA stability assay, co-culture with PBMCs, siRNA knockdown, flow cytometry","journal":"Cell biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited direct mechanistic validation in abstract","pmids":["39499390"],"is_preprint":false},{"year":2024,"finding":"VIRMA mediates m6A modification of STRA6 mRNA 3'-UTR; m6A reader IGF2BP2 stabilizes STRA6 mRNA; STRA6 activates STAT3/HIF-1α signaling to promote glycolysis and tumor progression in PDAC.","method":"RNA-seq, m6A-seq, MeRIP-qPCR, RIP, in vitro/in vivo experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-seq plus RIP plus signaling pathway validation, single lab","pmids":["38604311"],"is_preprint":false},{"year":2024,"finding":"EET-derived DNA activates CCDC25, which recruits VIRMA to induce m6A methylation of MAF transcription factor mRNA in CD4+ T cells, enhancing MAF mRNA stability and promoting Tfh cell differentiation in bullous pemphigoid.","method":"RNA sequencing, m6A pathway analysis, in vivo BP-like mouse model, flow cytometry, functional antibody neutralization","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model plus transcriptomic analysis plus functional rescue, single lab","pmids":["39490750"],"is_preprint":false},{"year":2025,"finding":"VIRMA-mediated m6A modification is essential for ribosome biogenesis in neural progenitor/stem cells; VIRMA depletion destabilizes the entire m6A writer complex and reduces m6A levels, leading to impaired mRNA decay, activation of p53-dependent stress response, compromised global protein synthesis, decreased neural progenitor proliferation, and severe forebrain developmental defects.","method":"Conditional Virma knockout, transcriptome analysis, ribosome biogenesis assays, p53 pathway analysis, in vivo mouse brain phenotype","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional in vivo KO with defined developmental phenotype, multiple mechanistic readouts including ribosome biogenesis and p53 pathway epistasis","pmids":["40577453"],"is_preprint":false},{"year":2025,"finding":"CAF-derived EV-packaged circTAX1BP1 binds VIRMA and promotes its lactylation at lysine residue 1713 by recruiting AARS2; lactylated VIRMA enhances m6A modification and stability of SP1 mRNA, activating TGF-β transcription and promoting colorectal liver metastasis.","method":"Co-IP, AARS2 interaction assay, Me-RIP, RNA stability assay, single-cell RNA-seq, PDX model, in vivo/in vitro experiments","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus Me-RIP plus in vivo PDX model, identifies specific lysine 1713 lactylation site, single lab","pmids":["41017455"],"is_preprint":false},{"year":2025,"finding":"VIRMA-mediated m6A modification of SHQ1 mRNA is recognized by HNRNPA2B1 to enhance SHQ1 mRNA stability; SHQ1 upregulation activates the PI3K/AKT pathway to promote hepatocyte proliferation and liver regeneration. Liver-specific Virma knockout mice show impaired liver regeneration.","method":"Liver-specific Cre-loxP Virma knockout, MeRIP-seq, ALPPS and CCl4 mouse models, AKT inhibitor treatment","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo with MeRIP-seq and pharmacological epistasis, multiple orthogonal approaches","pmids":["41132854"],"is_preprint":false},{"year":2025,"finding":"Alcohol increases C/EBPβ expression, which binds the VIRMA promoter to enhance VIRMA transcription; VIRMA then facilitates SLC43A2 mRNA degradation through m6A-YTHDF2 pathway, reducing phenylalanine absorption and oxidative stress to drive PDAC progression.","method":"ChIP for C/EBPβ on VIRMA promoter, m6A-YTHDF2 pathway analysis, in vitro/in vivo experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus m6A pathway validation, single lab, multiple methods","pmids":["39900725"],"is_preprint":false},{"year":2025,"finding":"VIRMA mediates m6A modification of NSMCE2 mRNA; IGF2BP1 recognizes m6A-modified NSMCE2 mRNA to enhance its stability, upregulating NSMCE2 expression and reducing ROS levels and apoptosis, thereby promoting prostate cancer tumorigenesis.","method":"MeRIP, mRNA stability assay, RIP, DCFH-DA ROS assay, flow cytometry, in vivo xenograft","journal":"International journal of urology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP and MeRIP without full sequencing confirmation","pmids":["40459180"],"is_preprint":false},{"year":2025,"finding":"KIAA1429 mediates m6A modification of DDIT3 mRNA, promoting its degradation, and suppressing ferroptosis via reduced DDIT3-mediated oxidative stress in endometrial cancer; IL-6 activates this through JAK1/STAT3 (confirmed by MeRIP and RIP).","method":"MeRIP, RIP, RNA stability assay, FISH, dot blot, in vitro/in vivo","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple m6A detection methods, single lab","pmids":["40436288"],"is_preprint":false},{"year":2025,"finding":"FEZF1-AS1 binds IGF2BP3, which enhances KIAA1429 mRNA stability; KIAA1429 facilitates m6A modification on OTUB1 mRNA, recognized by YTHDF1 to promote OTUB1 expression; OTUB1 then stabilizes SLC7A11 by deubiquitination to suppress ferroptosis in multiple myeloma.","method":"RNA pull-down, RIP, Co-IP for ubiquitination, mRNA stability assay, ferroptosis marker assays","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down plus RIP plus Co-IP plus functional assays, single lab, multiple orthogonal methods","pmids":["41085851"],"is_preprint":false},{"year":2025,"finding":"VIRMA mediates m6A modification of ANLN mRNA; IGF2BP3 recognizes m6A-modified ANLN to maintain its stability; ANLN activates RhoA signaling to suppress Hippo pathway and promote ICC growth; YAP1-TEAD1 transcriptionally activates ANLN, forming a positive feedback loop.","method":"MeRIP, RIP (IGF2BP3), ChIP (TEAD1 on ANLN promoter), in vitro/in vivo functional assays, clinical ICC cohort","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP plus RIP plus ChIP plus epistasis loop validation, single lab","pmids":["41513610"],"is_preprint":false},{"year":2024,"finding":"VIRMA suppresses cell migration and proliferation in Hirschsprung's disease by upregulating GSK3β expression; VIRMA inhibits degradation of GSK3β mRNA and increases GSK3β protein; VIRMA is significantly downregulated in narrow-segment colon tissue of HSCR patients.","method":"Actinomycin D mRNA stability assay, CCK-8, EdU, wound healing, overexpression/knockdown in SH-SY5Y and HEK-293T cells","journal":"Pediatric research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mRNA stability assay without direct m6A reader identification","pmids":["38658662"],"is_preprint":false},{"year":2023,"finding":"NKX2-2 binds the KIAA1429 promoter and transactivates KIAA1429 expression in Ewing sarcoma (ChIP-seq + RNA-seq integration); KIAA1429 in turn maintains STAT3 expression, with positive feedback between KIAA1429 and STAT3; CRISPR-Cas9 knockout of KIAA1429 identified it as an ES-essential gene.","method":"CRISPR-Cas9 in vitro and in vivo dropout screen, ChIP-seq, RNA-seq, STAT3 inhibitor experiments, xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR functional screen plus ChIP-seq plus epistasis, single lab","pmids":["37759224"],"is_preprint":false},{"year":2022,"finding":"Melatonin promotes spermatogonia viability and proliferation by upregulating KIAA1429 expression and m6A methylation; KIAA1429 regulates multiple biological processes in spermatogonia including the PI3K/AKT signaling pathway; PI3K inhibitor LY294002 mitigated KIAA1429 OE-mediated effects.","method":"CCK-8, EdU, flow cytometry, deep RNA-seq, siRNA/overexpression, PI3K inhibitor treatment","journal":"Reproductive biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by inhibitor only, no direct m6A-target identification","pmids":["35987159"],"is_preprint":false},{"year":2024,"finding":"KIAA1429 directly regulates Nrf2 via m6A-dependent modification of its 3'UTR (confirmed by MeRIP-qPCR and dual-luciferase reporter); KIAA1429 depletion promotes ferroptosis in osteosarcoma through suppression of Nrf2/NQO1 signaling.","method":"MeRIP-qPCR, dual-luciferase reporter assay, ferroptosis assays, in vivo xenograft","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-qPCR plus luciferase reporter plus functional ferroptosis validation, single lab","pmids":["40844619"],"is_preprint":false},{"year":2025,"finding":"VIRMA mediates m6A methylation of SCD mRNA, enhancing SCD mRNA stability and expression; elevated SCD modulates AMPK signaling to promote Wilms' tumor cell malignancy.","method":"MeRIP, western blot, RNA stability assay, rescue experiments, functional assays","journal":"DNA and cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, MeRIP without full sequencing","pmids":["40040483"],"is_preprint":false},{"year":2025,"finding":"VIRMA knockdown reduces m6A levels and reduces IGF2BP2 interaction with NDRG1 mRNA, leading to NDRG1 mRNA destabilization; VIRMA knockdown enhances OSCC sensitivity to iron chelators DFO and Dp44mT, revealing a synergistic VIRMA-IGF2BP2-NDRG1 axis.","method":"MeRIP, RIP, mRNA stability assay, drug sensitivity assays, in vitro/in vivo experiments","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP and MeRIP without full sequencing confirmation","pmids":["40581266"],"is_preprint":false}],"current_model":"VIRMA/KIAA1429 is the largest scaffolding subunit of the m6A methyltransferase complex that bridges the catalytic core (METTL3/METTL14/WTAP), preferentially guiding m6A deposition to 3'-UTR regions of target mRNAs; it also directly binds RNA and can regulate mRNA stability, splicing, and translation in both m6A-dependent (via readers YTHDF1/2/3, YTHDC1, IGF2BP1/2/3, HuR) and m6A-independent manners, with its activity modulated post-translationally by ubiquitination (USP29), acetylation (TIP60), phosphorylation (BRAF), and lactylation (AARS2), and its nuclear versus cytoplasmic distribution determining functional context; in vivo, it is essential for oocyte competence, folliculogenesis, forebrain development through ribosome biogenesis, and liver regeneration, while its aberrant overexpression across >20 cancer types promotes proliferation, metastasis, drug resistance, and immune evasion by suppressing or stabilizing diverse oncogenic and tumor-suppressive target mRNAs."},"narrative":{"mechanistic_narrative":"VIRMA/KIAA1429 is the large scaffolding subunit of the m6A methyltransferase writer complex whose depletion destabilizes the entire complex and reduces global m6A levels, establishing it as a non-catalytic but structurally essential determinant of m6A deposition [PMID:34446080, PMID:40577453]. It binds target transcripts directly through its RNA-binding domain and preferentially installs m6A in 3'-UTR regions, where the modification dictates transcript fate through engagement of distinct readers: YTHDF2/YTHDC1-mediated destabilization of tumor-suppressive transcripts such as RND3, RASD1, and CHST11, versus IGF2BP1/2/3- and HuR-dependent stabilization of targets including HAS2, E2F7, and TMED2 [PMID:37076815, PMID:38224863, PMID:37705505, PMID:37391589, PMID:38902717]. Beyond m6A writing, VIRMA acts as a global regulator of pre-mRNA alternative splicing, with its bound transcripts overlapping the genes whose splicing it controls [PMID:36505780], and it can also regulate target mRNA stability in an m6A-independent manner [PMID:34976433]. VIRMA function is partitioned by subcellular localization: a nuclear full-length isoform drives canonical m6A-dependent activity, while cytoplasmic mislocalization redirects it to reader-coupled stabilization of cytoplasmic targets [PMID:37705505, PMID:37208522]. Its activity is set by post-translational control, including USP29-mediated deubiquitination that stabilizes VIRMA protein and AARS2-mediated lactylation at lysine 1713 that enhances its methyltransferase output [PMID:36373629, PMID:41017455]. In vivo, VIRMA is essential for oocyte competence and folliculogenesis [PMID:32094512], for forebrain development via m6A-dependent ribosome biogenesis and suppression of a p53 stress response in neural progenitors [PMID:40577453], and for liver regeneration through stabilization of SHQ1 mRNA and PI3K/AKT activation [PMID:41132854]. Across more than twenty cancer types its overexpression—driven by transcriptional activation (NF-κB/p65, C/EBPβ, NKX2-2), copy-number amplification, and promoter epigenetic changes—promotes proliferation, metastasis, immune evasion, altered glycolysis, ferroptosis resistance, and drug resistance by tuning the stability of diverse oncogenic and tumor-suppressive transcripts [PMID:35730068, PMID:36291811, PMID:39900725, PMID:37759224, PMID:37391589].","teleology":[{"year":2019,"claim":"Established that VIRMA does not act uniformly across transcripts but preferentially directs m6A to 3'-UTR regions and couples this to RNA-binding-protein-mediated transcript fate, defining its target-selection logic.","evidence":"MeRIP-seq, RIP-seq and RNA-seq with siRNA knockdown showing 3'-UTR m6A on GATA3 pre-mRNA and HuR displacement","pmids":["31856849"],"confidence":"Medium","gaps":["Did not resolve how a lncRNA cis-element confers transcript specificity generally","Single target context"]},{"year":2019,"claim":"Raised the possibility that VIRMA also regulates target transcripts independently of its m6A-writing activity, broadening its functional repertoire beyond methylation.","evidence":"RIP-seq and functional rescue showing CDK1 mRNA regulation in breast cancer","pmids":["31285549"],"confidence":"Low","gaps":["m6A-independence asserted without a mechanistic basis","Single RIP-seq identification"]},{"year":2020,"claim":"Provided the first in vivo demonstration that VIRMA is physiologically essential, linking its m6A-writing role to a defined developmental program rather than only cancer cell lines.","evidence":"Oocyte-specific conditional knockout mouse with RNA-seq, m6A quantification and meiotic phenotyping","pmids":["32094512"],"confidence":"High","gaps":["Specific splicing targets driving the oocyte phenotype not fully defined","Reader dependence in oocytes not established"]},{"year":2021,"claim":"Showed VIRMA is structurally required for writer-complex integrity, so its loss reduces global m6A and produces downstream consequences such as DNA damage and chemosensitivity.","evidence":"CRISPR knockdown in germ cell tumor cells with m6A quantification, γH2AX and DNA-repair factor readouts plus in vivo CAM assay","pmids":["34446080"],"confidence":"Medium","gaps":["Direct biochemical role of VIRMA in complex assembly not structurally resolved"]},{"year":2022,"claim":"Demonstrated that VIRMA globally controls alternative splicing of its bound transcripts, expanding its function beyond stability regulation to splicing.","evidence":"RIP-seq and RNA-seq integration in HCC showing overlap of bound transcripts with regulated splicing events","pmids":["36505780"],"confidence":"Medium","gaps":["Whether splicing regulation is m6A-dependent not resolved","Splicing machinery partners not identified"]},{"year":2022,"claim":"Established that VIRMA protein levels are set post-translationally and that upstream transcription factors drive its overexpression, clarifying how its abundance is regulated in disease.","evidence":"Co-IP and ubiquitination assays defining USP29-mediated deubiquitination, and ChIP showing NF-κB/p65 transactivation of the promoter","pmids":["36373629","36291811"],"confidence":"Medium","gaps":["E3 ligase opposing USP29 not identified","Stoichiometry of deubiquitination effect unquantified"]},{"year":2023,"claim":"Resolved that VIRMA's output bifurcates by reader pairing—destabilizing transcripts via YTHDF2/YTHDC1 or stabilizing them via IGF2BP/HuR—accounting for its opposing context-dependent effects.","evidence":"Multiple MeRIP-seq/RIP/stability studies including CRISPR KO and activation for CHST11-YTHDF2, RND3-YTHDC1, and IGF2BP3-coupled HAS2/E2F7 stabilization","pmids":["37076815","38224863","37705505","37028765"],"confidence":"High","gaps":["Determinants directing a given transcript toward a destabilizing versus stabilizing reader not defined"]},{"year":2023,"claim":"Established that subcellular localization is a functional switch—nuclear full-length VIRMA performs canonical m6A writing while cytoplasmic mislocalization redirects activity—explaining isoform- and compartment-specific roles.","evidence":"Subcellular fractionation, immunofluorescence and isoform-specific overexpression in breast cancer tying cytosolic VIRMA to IGF2BP3-coupled HAS2 stabilization","pmids":["37705505","37208522"],"confidence":"High","gaps":["Signals governing nuclear export/retention only partially defined","Cytoplasmic methyltransferase competence versus pure adaptor role unresolved"]},{"year":2024,"claim":"Identified additional post-translational modifications (acetylation, phosphorylation) and a phosphorylation-driven localization switch, deepening the regulatory layer controlling VIRMA targeting.","evidence":"Co-IP defining TIP60 acetylation and IP-MS/Co-IP/immunofluorescence showing BRAF phosphorylation promotes cytoplasmic localization and FZD7 mRNA stabilization","pmids":["40301310","40611274"],"confidence":"Medium","gaps":["Acetylation/phosphorylation site mapping to functional consequence incomplete","Crosstalk between modifications not addressed"]},{"year":2025,"claim":"Connected VIRMA-dependent m6A to fundamental cell biology—ribosome biogenesis and a p53 stress response—through an essential in vivo developmental requirement in the brain.","evidence":"Conditional Virma knockout with transcriptome, ribosome biogenesis and p53 pathway analysis in mouse forebrain","pmids":["40577453"],"confidence":"High","gaps":["Direct m6A targets coupling VIRMA to ribosome biogenesis not enumerated","Generality beyond neural progenitors untested"]},{"year":2025,"claim":"Showed metabolic post-translational control of VIRMA via lactylation, linking the tumor microenvironment to VIRMA methyltransferase output.","evidence":"Co-IP and Me-RIP identifying AARS2-mediated lactylation at lysine 1713 enhancing SP1 mRNA m6A/stability, with PDX validation","pmids":["41017455"],"confidence":"Medium","gaps":["Structural effect of K1713 lactylation on activity not defined","Single metastatic context"]},{"year":null,"claim":"How VIRMA, as a non-catalytic scaffold, achieves transcript-specific 3'-UTR targeting and selects between destabilizing and stabilizing reader pathways remains the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of VIRMA within the writer complex on RNA","Rules linking sequence/context to reader choice undefined","Mechanism unifying m6A-dependent and m6A-independent activities unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[21,22,27,33]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[11,19,24,43]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,43]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[22,30]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[17,19,24,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,24,52]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,43,45]}],"complexes":["m6A methyltransferase writer complex"],"partners":["METTL3","WTAP","HUR","IGF2BP3","YTHDF2","USP29","AARS2","IGF2BP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q69YN4","full_name":"Protein virilizer homolog","aliases":[],"length_aa":1812,"mass_kda":202.0,"function":"Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing (PubMed:24981863, PubMed:29507755). Acts as a key regulator of m6A methylation by promoting m6A methylation of mRNAs in the 3'-UTR near the stop codon: recruits the catalytic core components METTL3 and METTL14, thereby guiding m6A methylation at specific sites (PubMed:29507755). Required for mRNA polyadenylation via its role in selective m6A methylation: m6A methylation of mRNAs in the 3'-UTR near the stop codon correlating with alternative polyadenylation (APA) (PubMed:29507755)","subcellular_location":"Nucleus speckle; Nucleus, nucleoplasm; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q69YN4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/VIRMA","classification":"Common Essential","n_dependent_lines":1165,"n_total_lines":1208,"dependency_fraction":0.9644039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"PBK","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2},{"gene":"RBM15B","stoichiometry":0.2},{"gene":"RNF40","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/VIRMA","total_profiled":1310},"omim":[{"mim_id":"616447","title":"VIR-LIKE M6A METHYLTRANSFERASE-ASSOCIATED PROTEIN; VIRMA","url":"https://www.omim.org/entry/616447"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VIRMA"},"hgnc":{"alias_symbol":["DKFZP434I116","fSAP121"],"prev_symbol":["KIAA1429"]},"alphafold":{"accession":"Q69YN4","domains":[{"cath_id":"2.60.120.260","chopping":"9-129","consensus_level":"high","plddt":85.4231,"start":9,"end":129},{"cath_id":"1.25.10,1.25.40","chopping":"375-516","consensus_level":"medium","plddt":90.1314,"start":375,"end":516},{"cath_id":"-","chopping":"906-946_954-1120","consensus_level":"medium","plddt":87.3789,"start":906,"end":1120}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q69YN4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q69YN4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q69YN4-F1-predicted_aligned_error_v6.png","plddt_mean":69.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VIRMA","jax_strain_url":"https://www.jax.org/strain/search?query=VIRMA"},"sequence":{"accession":"Q69YN4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q69YN4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q69YN4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q69YN4"}},"corpus_meta":[{"pmid":"31856849","id":"PMC_31856849","title":"KIAA1429 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a lncRNA GATA3-AS (transcribed antisense to GATA3) acts as a cis-acting element for preferential interaction of KIAA1429 with GATA3 pre-mRNA.\",\n      \"method\": \"MeRIP-seq, RIP-seq, RNA-seq, siRNA knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal sequencing and RIP methods, single lab\",\n      \"pmids\": [\"31856849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIAA1429 binds CDK1 mRNA and regulates CDK1 expression in an m6A-independent manner to promote breast cancer proliferation and metastasis.\",\n      \"method\": \"RNA immunoprecipitation sequencing (RIP-seq), functional rescue assays, in vitro and in vivo experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP-seq identification and functional rescue, single lab, m6A-independence not mechanistically explained\",\n      \"pmids\": [\"31285549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIAA1429 increases m6A modification of ID2 mRNA, suppressing ID2 expression and thereby facilitating migration and invasion of hepatocellular carcinoma cells.\",\n      \"method\": \"MeRIP-PCR, siRNA knockdown, transwell assays\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single MeRIP-PCR method, single lab, limited mechanistic depth\",\n      \"pmids\": [\"31118692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Oocyte-specific loss of Kiaa1429 in mice causes female infertility with defective follicular development and failure of germinal vesicle breakdown; KIAA1429 depletion decreases m6A levels in oocytes and disrupts alternative splicing of oogenesis-associated genes.\",\n      \"method\": \"Conditional knockout mouse model, RNA-seq, m6A quantification, phenotypic analysis of meiotic progression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional knockout with defined reproductive phenotype plus transcriptome-wide RNA-seq and m6A measurement\",\n      \"pmids\": [\"32094512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VIRMA knockdown in prostate cancer cells significantly decreases global m6A levels, attenuates malignant phenotype, and suppresses expression and stability of oncogenic lncRNAs CCAT1 and CCAT2 through m6A-dependent stabilization.\",\n      \"method\": \"siRNA knockdown, ELISA m6A quantification, Actinomycin D RNA stability assay, m6A/RNA co-immunoprecipitation\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and stability assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"32218194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KIAA1429 regulates c-Jun mRNA stability and expression in an m6A-independent manner to promote gastric cancer cell proliferation; RIP and luciferase assays confirmed direct binding to c-Jun mRNA.\",\n      \"method\": \"mRNA sequencing, RIP assay, luciferase assay, rescue experiments\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab RIP plus luciferase, m6A-independence asserted without deep mechanistic explanation\",\n      \"pmids\": [\"32052427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIAA1429 stabilizes LINC00958 lncRNA through m6A modification; LINC00958 in turn interacts with GLUT1 mRNA in an m6A-dependent manner to enhance GLUT1 mRNA stability and promote aerobic glycolysis in gastric cancer.\",\n      \"method\": \"MeRIP-seq, RIP assay, RNA stability assay, functional glycolysis assays\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, MeRIP and RIP but indirect chain of interactions\",\n      \"pmids\": [\"34409730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIAA1429 enhances mRNA stability of HOXA1 through targeting its 3'-UTR, thereby accelerating gefitinib resistance in NSCLC cells.\",\n      \"method\": \"siRNA knockdown, mRNA stability assays, in vivo xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic follow-up on m6A-dependence\",\n      \"pmids\": [\"34001850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VIRMA-regulated m6A modifications lead to post-transcriptional suppression of DAPK3 mRNA through YTHDF2/3 in NSCLC; inhibition of DAPK3 rescued tumor-suppressive phenotypes induced by VIRMA deficiency.\",\n      \"method\": \"siRNA knockdown, MeRIP, RIP, in vitro and in vivo functional assays, epistasis rescue experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP plus RIP plus genetic epistasis rescue, single lab\",\n      \"pmids\": [\"34520821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIAA1429 and ALKBH5 oppositely regulate m6A modification of pri-miR-143-3p, controlling its processing by the microprocessor protein DGCR8, thereby indirectly regulating DDX6 (a target of mature miR-143-3p) to affect aortic smooth muscle cell proliferation and endothelial cell apoptosis in aortic dissection.\",\n      \"method\": \"Gain/loss-of-function in vitro and in vivo (AngII mouse model), m6A sequencing, RIP\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model plus mechanistic RIP/m6A data, single lab\",\n      \"pmids\": [\"34490238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIAA1429 promotes breast cancer metastasis through the SMC1A/SNAIL axis: KIAA1429 binds the 3' UTR motif of SMC1A mRNA and enhances its stability in an m6A-independent manner; SMC1A then binds the SNAIL promoter to drive EMT.\",\n      \"method\": \"RIP assay, mRNA stability assay, luciferase reporter, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus mRNA stability plus luciferase, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34976433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VIRMA knockdown in germ cell tumor cells disrupts the remaining methyltransferase complex and decreases global m6A abundance; this increases DNA damage (elevated γH2AX and GADD45B) and downregulates DNA repair factors XLF and MRE11, sensitizing cells to cisplatin.\",\n      \"method\": \"CRISPR/Cas9-mediated knockdown, m6A quantification, γH2AX measurement, CAM in vivo assay, western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KD with multiple orthogonal readouts and in vivo validation, single lab\",\n      \"pmids\": [\"34446080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIAA1429 regulates BTG2 expression in an m6A-dependent manner; knockdown decreases m6A levels on BTG2 mRNA, leading to enhanced YTHDF2-dependent BTG2 mRNA stability and increased BTG2 expression, thereby suppressing LUAD tumorigenesis. Copy number amplification at KIAA1429 locus drives its overexpression.\",\n      \"method\": \"MeRIP-seq, RNA-seq, m6A dot blot, RIP, RNA stability assay, in vitro and in vivo experiments\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus RIP plus stability assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35730068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIAA1429 promotes LUAD via activation of JNK/MAPK pathway: KIAA1429 positively regulates MAP3K2 expression in an m6A methylation-dependent manner, restraining gefitinib resistance when knocked down.\",\n      \"method\": \"siRNA knockdown, in vitro and in vivo experiments, m6A-dependent target gene identification\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited direct m6A mechanistic validation of MAP3K2\",\n      \"pmids\": [\"36493511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIAA1429 increases SIRT1 mRNA stability via m6A-dependent regulation in colorectal cancer, promoting cell proliferation, colony formation, and migration.\",\n      \"method\": \"shRNA knockdown, mRNA stability assay, in vivo xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, no direct MeRIP validation shown in abstract\",\n      \"pmids\": [\"35217651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIAA1429 promotes aerobic glycolysis in colorectal cancer by binding the m6A site of HK2 mRNA and enhancing its mRNA stability in an m6A-independent manner.\",\n      \"method\": \"Functional glycolysis assays, mRNA binding/stability assays, siRNA knockdown\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, m6A-independence claimed without deep mechanistic resolution\",\n      \"pmids\": [\"35546050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"p65 (NF-κB) binds the KIAA1429 promoter and activates its transcription (confirmed by ChIP assay); KIAA1429 then recruits YTHDF1 to the 3'-UTR of FOXM1 mRNA, stabilizing FOXM1 and mediating cisplatin resistance in gastric cancer.\",\n      \"method\": \"ChIP assay, RIP, mRNA stability assay, shRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus RIP plus functional validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36291811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIAA1429 regulates alternative splicing of cancer-related genes (including BPTF exon 6) in HCC; KIAA1429-bound transcripts identified by RIP-seq highly overlap with regulated alternative splicing genes, indicating KIAA1429 globally regulates pre-mRNA splicing by binding transcripts.\",\n      \"method\": \"RNA-seq, RIP-seq, clinical validation of AS events\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq plus RNA-seq multi-omics integration, single lab\",\n      \"pmids\": [\"36505780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP29 directly binds KIAA1429 (confirmed by Co-IP) and mediates its deubiquitination to stabilize KIAA1429 protein levels; KIAA1429 then promotes SOX8 mRNA stability through m6A modification in CRC.\",\n      \"method\": \"Co-immunoprecipitation, western blot for ubiquitination, m6A-RIP, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Biomolecules & biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus m6A-RIP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36373629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIAA1429-mediated m6A modification of CHST11 mRNA recruits YTHDF2 to reduce CHST11 mRNA stability and expression; diminished CHST11 lowers MOB1B expression, inactivating Hippo-YAP signaling in DLBCL.\",\n      \"method\": \"CRISPR/Cas9 knockout, CRISPR/dCas9-VP64 activation, RNA-seq, MeRIP-seq, RIP, luciferase assay, RNA stability assay, Co-IP, xenograft\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO and activation, multiple orthogonal sequencing and functional methods, pathway epistasis validated\",\n      \"pmids\": [\"37076815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VIRMA mediates m6A methylation of E2F7 3'-UTR; IGF2BP2 binds and maintains E2F7 mRNA stability; E2F7 then cooperates with CBFB-recruited RUNX1 in a non-canonical manner to transactivate ITGA2, ITGA5, and NTRK1, activating Akt signaling in NPC.\",\n      \"method\": \"High-throughput sequencing, MeRIP, RIP, luciferase assay, in vitro and in vivo experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP plus RIP plus integrative sequencing, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37028765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIAA1429 negatively regulates the tumor suppressor RND3 by decreasing its mRNA stability via m6A modification coordinated with the m6A reader YTHDC1; KIAA1429 acts through its RNA-binding domain.\",\n      \"method\": \"RNA-seq, MeRIP-seq, RIP, MeRIP-qPCR, RNA stability assay, luciferase assay, in vitro/in vivo experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus RIP plus RNA stability assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38224863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIAA1429/VIRMA is mislocalized to the cytosol of breast cancer cells; cytosolic KIAA1429/VIRMA binds to m6A-binding protein IGF2BP3, which recruits and stabilizes m6A-modified HAS2 mRNA, promoting breast cancer growth.\",\n      \"method\": \"Subcellular fractionation, Co-IP, RIP, shRNA knockdown, in vitro/in vivo functional assays, immunofluorescence\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — subcellular localization directly tied to function, Co-IP plus RIP plus in vivo, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"37705505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VIRMA promotes breast cancer by upregulating the m6A-modified long non-coding RNA NEAT1, contributing to cancer cell growth; the nuclear full-length VIRMA isoform (but not the cytoplasmic N-terminal isoform) drives m6A-dependent breast tumourigenesis.\",\n      \"method\": \"Isoform-specific overexpression, in vitro and in vivo functional assays, m6A modification analysis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific functional experiments plus in vivo, single lab\",\n      \"pmids\": [\"37208522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VIRMA promotes ICC progression by stabilizing TMED2 and PARD3B mRNAs through m6A-HuR-mediated mechanism; the high VIRMA expression in ICC is caused by demethylation of the H3K27me3 modification in the VIRMA promoter region.\",\n      \"method\": \"RNA-seq, MeRIP-seq, SLAM-seq, RIP, luciferase reporter, ChIP assay, in vitro/in vivo experiments\",\n      \"journal\": \"Journal of gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multi-omics including SLAM-seq, ChIP, and MeRIP-seq with functional validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37391589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIAA1429 promotes gastric cancer progression by destabilizing RASD1 mRNA through m6A-YTHDF2-dependent degradation, thereby downregulating RASD1 expression.\",\n      \"method\": \"MeRIP-seq, RNA-seq, MeRIP-qPCR, RNA stability assay, RIP, RNA pull-down, dual luciferase reporter, in vivo xenograft\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus RIP plus stability assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38902717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIAA1429 protects hepatocellular carcinoma cells from ferroptosis through m6A-dependent post-transcriptional modification of SLC7A11; RIP confirmed KIAA1429 binding to m6A on SLC7A11 transcript, and overexpression heightens SLC7A11 cystine/glutamate antiporter activity.\",\n      \"method\": \"RIP, m6A inhibitor (cycloleucine) treatment, ferroptosis marker assays, in vivo xenograft\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus chemical inhibitor plus functional ferroptosis readouts, single lab\",\n      \"pmids\": [\"37830241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HNRNPC promotes DDR1 transcription in breast cancer by recognizing VIRMA-installed m6A modification on TFAP2A mRNA (PAR-CLIP confirmed VIRMA binding; RIP confirmed HNRNPC recognition of m6A on TFAP2A), stabilizing TFAP2A which transactivates DDR1 to promote collagen fiber alignment and immune evasion.\",\n      \"method\": \"PAR-CLIP, Me-RIP, RIP, ChIP, dual-luciferase, in vivo mouse BC transplant model\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — PAR-CLIP plus Me-RIP plus RIP plus ChIP plus in vivo, multiple orthogonal methods, single rigorous study\",\n      \"pmids\": [\"37528369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPRG physically interacts with VIRMA in mouse brain; PTPRG binding upregulates VIRMA, which inhibits translation of PRKN mRNA through m6A methylation, preventing mitophagy clearance of damaged mitochondria and leading to neuronal death in Alzheimer's disease.\",\n      \"method\": \"Single-cell RNA-seq, spatial transcriptomics, Co-IP in mouse brain, 5×FAD mouse model validation\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in mouse brain plus in vivo 5×FAD model, single lab, multiple approaches\",\n      \"pmids\": [\"38325728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TIP60 acetylates KIAA1429 at a specific residue, which promotes KDM5B expression in an m6A-YTHDF1-dependent manner; KDM5B subsequently represses FoxO1 transcription to enable immune evasion, growth, and metastasis in HCC.\",\n      \"method\": \"RNA pull-down, RIP, ChIP, Co-IP, m6A quantification, MeRIP-qPCR, flow cytometry, xenograft in NOD/SCID mice\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for acetylation plus ChIP plus MeRIP-qPCR plus epistasis rescue, single lab\",\n      \"pmids\": [\"40301310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRAF-mediated phosphorylation of KIAA1429 promotes its cytoplasmic localization; cytoplasmic KIAA1429 promotes Wnt pathway activation by binding and stabilizing FZD7 mRNA, enhancing cancer stemness and oxaliplatin resistance in BRAFV600E-mutated CRC.\",\n      \"method\": \"IP-MS, Co-IP, immunofluorescence, RIP, RNA-seq, in vitro/in vivo functional assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus Co-IP plus immunofluorescence plus RIP with functional validation, single lab\",\n      \"pmids\": [\"40611274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VIRMA promotes neuronal apoptosis in spinal cord injury by inducing m6A methylation of STK10 mRNA, negatively regulating STK10 expression; VIRMA knockdown reduces m6A methylation and apoptosis of neuronal cells.\",\n      \"method\": \"Rat SCI model, m6A methylation kit, overexpression/knockdown in OGD cell models and animal models\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect m6A measurement without direct MeRIP-seq of STK10\",\n      \"pmids\": [\"37721438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SHBs (small HBV surface antigen) elevates global m6A levels and upregulates CCR9 expression through KIAA1429-mediated m6A modification at sites 1373 and 1496 on CCR9 mRNA, stabilizing CCR9 mRNA and promoting HCC regorafenib resistance.\",\n      \"method\": \"m6A site-specific mutagenesis (sites 1373 and 1496), AAV-HBV mouse model, functional assays\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific m6A site identification plus in vivo AAV-HBV model, single lab\",\n      \"pmids\": [\"39206838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIAA1429 cooperates with m6A reader HuR to enhance HK1 mRNA stability, upregulating HK1 expression and promoting Warburg effect/sorafenib resistance in liver cancer; KIAA1429 directly binds HK1 mRNA.\",\n      \"method\": \"RNA-seq, MeRIP-seq, RIP, mRNA stability assay, in vitro/in vivo experiments\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus RIP plus RNA stability assay, single lab\",\n      \"pmids\": [\"38996929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIAA1429-mediated m6A modification stabilizes RAB27B mRNA through the m6A/YTHDF1 axis in CML, enhancing drug efflux and imatinib resistance; rucaparib suppresses KIAA1429 expression and reduces CML progression.\",\n      \"method\": \"mRNA stability assay, RIP, in vitro/in vivo CML models\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP without full MeRIP-seq confirmation\",\n      \"pmids\": [\"37692484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VIRMA promotes nasopharyngeal carcinoma via m6A methylation of PTGS2 mRNA, enhancing PTGS2 mRNA stability; MeRIP and mRNA stability assays confirmed m6A modification.\",\n      \"method\": \"MeRIP, mRNA stability assay, siRNA/overexpression, in vitro/in vivo experiments\",\n      \"journal\": \"Critical reviews in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, MeRIP only without reader identification\",\n      \"pmids\": [\"37830191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-6 activates KIAA1429 expression through the JAK1/STAT3 pathway; KIAA1429 then promotes DDIT3 mRNA degradation through m6A modification, inhibiting ferroptosis and promoting proliferation in endometrial cancer.\",\n      \"method\": \"Dot blot, MeRIP, RIP, RNA stability assay, FISH, in vitro and in vivo experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP plus RIP plus FISH plus stability assay with upstream signaling validated, single lab\",\n      \"pmids\": [\"40436288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIAA1429-mediated m6A modification of FOXM1 mRNA, recognized by YTHDF1, stabilizes FOXM1 mRNA and promotes aerobic glycolysis and tumorigenesis in multiple myeloma.\",\n      \"method\": \"RIP, m6A modification assay, RNA stability assay, in vivo transplantation model\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP without full MeRIP-seq\",\n      \"pmids\": [\"39060874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIAA1429-mediated m6A modification of Lrp4 mRNA is recognized by YTHDC1 to increase Lrp4 mRNA stability and expression; elevated LRP4 recruits TNFAIP3 to inactivate NF-κB signaling, thereby inhibiting osteoclast differentiation and protecting against osteoporosis.\",\n      \"method\": \"MeRIP-seq, scRNA-seq, in vitro osteoclast differentiation assays, OVX mouse model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus scRNA-seq plus in vivo model with pathway epistasis, single lab\",\n      \"pmids\": [\"41146006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VIRMA promotes NSCLC progression by m6A modification of ADAR mRNA, enhancing ADAR expression and activating TGF-β signaling pathway.\",\n      \"method\": \"Western blot, m6A modification analysis, functional assays, in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"40254620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIAA1429 facilitates immune evasion in NSCLC by stabilizing KLF1 mRNA through m6A modification, which upregulates PD-L1 expression and suppresses CD8+ T cell activity.\",\n      \"method\": \"m6A enrichment on KLF1, mRNA stability assay, co-culture with PBMCs, siRNA knockdown, flow cytometry\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited direct mechanistic validation in abstract\",\n      \"pmids\": [\"39499390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VIRMA mediates m6A modification of STRA6 mRNA 3'-UTR; m6A reader IGF2BP2 stabilizes STRA6 mRNA; STRA6 activates STAT3/HIF-1α signaling to promote glycolysis and tumor progression in PDAC.\",\n      \"method\": \"RNA-seq, m6A-seq, MeRIP-qPCR, RIP, in vitro/in vivo experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-seq plus RIP plus signaling pathway validation, single lab\",\n      \"pmids\": [\"38604311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EET-derived DNA activates CCDC25, which recruits VIRMA to induce m6A methylation of MAF transcription factor mRNA in CD4+ T cells, enhancing MAF mRNA stability and promoting Tfh cell differentiation in bullous pemphigoid.\",\n      \"method\": \"RNA sequencing, m6A pathway analysis, in vivo BP-like mouse model, flow cytometry, functional antibody neutralization\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model plus transcriptomic analysis plus functional rescue, single lab\",\n      \"pmids\": [\"39490750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VIRMA-mediated m6A modification is essential for ribosome biogenesis in neural progenitor/stem cells; VIRMA depletion destabilizes the entire m6A writer complex and reduces m6A levels, leading to impaired mRNA decay, activation of p53-dependent stress response, compromised global protein synthesis, decreased neural progenitor proliferation, and severe forebrain developmental defects.\",\n      \"method\": \"Conditional Virma knockout, transcriptome analysis, ribosome biogenesis assays, p53 pathway analysis, in vivo mouse brain phenotype\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional in vivo KO with defined developmental phenotype, multiple mechanistic readouts including ribosome biogenesis and p53 pathway epistasis\",\n      \"pmids\": [\"40577453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAF-derived EV-packaged circTAX1BP1 binds VIRMA and promotes its lactylation at lysine residue 1713 by recruiting AARS2; lactylated VIRMA enhances m6A modification and stability of SP1 mRNA, activating TGF-β transcription and promoting colorectal liver metastasis.\",\n      \"method\": \"Co-IP, AARS2 interaction assay, Me-RIP, RNA stability assay, single-cell RNA-seq, PDX model, in vivo/in vitro experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus Me-RIP plus in vivo PDX model, identifies specific lysine 1713 lactylation site, single lab\",\n      \"pmids\": [\"41017455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VIRMA-mediated m6A modification of SHQ1 mRNA is recognized by HNRNPA2B1 to enhance SHQ1 mRNA stability; SHQ1 upregulation activates the PI3K/AKT pathway to promote hepatocyte proliferation and liver regeneration. Liver-specific Virma knockout mice show impaired liver regeneration.\",\n      \"method\": \"Liver-specific Cre-loxP Virma knockout, MeRIP-seq, ALPPS and CCl4 mouse models, AKT inhibitor treatment\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo with MeRIP-seq and pharmacological epistasis, multiple orthogonal approaches\",\n      \"pmids\": [\"41132854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Alcohol increases C/EBPβ expression, which binds the VIRMA promoter to enhance VIRMA transcription; VIRMA then facilitates SLC43A2 mRNA degradation through m6A-YTHDF2 pathway, reducing phenylalanine absorption and oxidative stress to drive PDAC progression.\",\n      \"method\": \"ChIP for C/EBPβ on VIRMA promoter, m6A-YTHDF2 pathway analysis, in vitro/in vivo experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus m6A pathway validation, single lab, multiple methods\",\n      \"pmids\": [\"39900725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VIRMA mediates m6A modification of NSMCE2 mRNA; IGF2BP1 recognizes m6A-modified NSMCE2 mRNA to enhance its stability, upregulating NSMCE2 expression and reducing ROS levels and apoptosis, thereby promoting prostate cancer tumorigenesis.\",\n      \"method\": \"MeRIP, mRNA stability assay, RIP, DCFH-DA ROS assay, flow cytometry, in vivo xenograft\",\n      \"journal\": \"International journal of urology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP and MeRIP without full sequencing confirmation\",\n      \"pmids\": [\"40459180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIAA1429 mediates m6A modification of DDIT3 mRNA, promoting its degradation, and suppressing ferroptosis via reduced DDIT3-mediated oxidative stress in endometrial cancer; IL-6 activates this through JAK1/STAT3 (confirmed by MeRIP and RIP).\",\n      \"method\": \"MeRIP, RIP, RNA stability assay, FISH, dot blot, in vitro/in vivo\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple m6A detection methods, single lab\",\n      \"pmids\": [\"40436288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FEZF1-AS1 binds IGF2BP3, which enhances KIAA1429 mRNA stability; KIAA1429 facilitates m6A modification on OTUB1 mRNA, recognized by YTHDF1 to promote OTUB1 expression; OTUB1 then stabilizes SLC7A11 by deubiquitination to suppress ferroptosis in multiple myeloma.\",\n      \"method\": \"RNA pull-down, RIP, Co-IP for ubiquitination, mRNA stability assay, ferroptosis marker assays\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down plus RIP plus Co-IP plus functional assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41085851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VIRMA mediates m6A modification of ANLN mRNA; IGF2BP3 recognizes m6A-modified ANLN to maintain its stability; ANLN activates RhoA signaling to suppress Hippo pathway and promote ICC growth; YAP1-TEAD1 transcriptionally activates ANLN, forming a positive feedback loop.\",\n      \"method\": \"MeRIP, RIP (IGF2BP3), ChIP (TEAD1 on ANLN promoter), in vitro/in vivo functional assays, clinical ICC cohort\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP plus RIP plus ChIP plus epistasis loop validation, single lab\",\n      \"pmids\": [\"41513610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VIRMA suppresses cell migration and proliferation in Hirschsprung's disease by upregulating GSK3β expression; VIRMA inhibits degradation of GSK3β mRNA and increases GSK3β protein; VIRMA is significantly downregulated in narrow-segment colon tissue of HSCR patients.\",\n      \"method\": \"Actinomycin D mRNA stability assay, CCK-8, EdU, wound healing, overexpression/knockdown in SH-SY5Y and HEK-293T cells\",\n      \"journal\": \"Pediatric research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mRNA stability assay without direct m6A reader identification\",\n      \"pmids\": [\"38658662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NKX2-2 binds the KIAA1429 promoter and transactivates KIAA1429 expression in Ewing sarcoma (ChIP-seq + RNA-seq integration); KIAA1429 in turn maintains STAT3 expression, with positive feedback between KIAA1429 and STAT3; CRISPR-Cas9 knockout of KIAA1429 identified it as an ES-essential gene.\",\n      \"method\": \"CRISPR-Cas9 in vitro and in vivo dropout screen, ChIP-seq, RNA-seq, STAT3 inhibitor experiments, xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR functional screen plus ChIP-seq plus epistasis, single lab\",\n      \"pmids\": [\"37759224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Melatonin promotes spermatogonia viability and proliferation by upregulating KIAA1429 expression and m6A methylation; KIAA1429 regulates multiple biological processes in spermatogonia including the PI3K/AKT signaling pathway; PI3K inhibitor LY294002 mitigated KIAA1429 OE-mediated effects.\",\n      \"method\": \"CCK-8, EdU, flow cytometry, deep RNA-seq, siRNA/overexpression, PI3K inhibitor treatment\",\n      \"journal\": \"Reproductive biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by inhibitor only, no direct m6A-target identification\",\n      \"pmids\": [\"35987159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIAA1429 directly regulates Nrf2 via m6A-dependent modification of its 3'UTR (confirmed by MeRIP-qPCR and dual-luciferase reporter); KIAA1429 depletion promotes ferroptosis in osteosarcoma through suppression of Nrf2/NQO1 signaling.\",\n      \"method\": \"MeRIP-qPCR, dual-luciferase reporter assay, ferroptosis assays, in vivo xenograft\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-qPCR plus luciferase reporter plus functional ferroptosis validation, single lab\",\n      \"pmids\": [\"40844619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VIRMA mediates m6A methylation of SCD mRNA, enhancing SCD mRNA stability and expression; elevated SCD modulates AMPK signaling to promote Wilms' tumor cell malignancy.\",\n      \"method\": \"MeRIP, western blot, RNA stability assay, rescue experiments, functional assays\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, MeRIP without full sequencing\",\n      \"pmids\": [\"40040483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VIRMA knockdown reduces m6A levels and reduces IGF2BP2 interaction with NDRG1 mRNA, leading to NDRG1 mRNA destabilization; VIRMA knockdown enhances OSCC sensitivity to iron chelators DFO and Dp44mT, revealing a synergistic VIRMA-IGF2BP2-NDRG1 axis.\",\n      \"method\": \"MeRIP, RIP, mRNA stability assay, drug sensitivity assays, in vitro/in vivo experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP and MeRIP without full sequencing confirmation\",\n      \"pmids\": [\"40581266\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VIRMA/KIAA1429 is the largest scaffolding subunit of the m6A methyltransferase complex that bridges the catalytic core (METTL3/METTL14/WTAP), preferentially guiding m6A deposition to 3'-UTR regions of target mRNAs; it also directly binds RNA and can regulate mRNA stability, splicing, and translation in both m6A-dependent (via readers YTHDF1/2/3, YTHDC1, IGF2BP1/2/3, HuR) and m6A-independent manners, with its activity modulated post-translationally by ubiquitination (USP29), acetylation (TIP60), phosphorylation (BRAF), and lactylation (AARS2), and its nuclear versus cytoplasmic distribution determining functional context; in vivo, it is essential for oocyte competence, folliculogenesis, forebrain development through ribosome biogenesis, and liver regeneration, while its aberrant overexpression across >20 cancer types promotes proliferation, metastasis, drug resistance, and immune evasion by suppressing or stabilizing diverse oncogenic and tumor-suppressive target mRNAs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VIRMA/KIAA1429 is the large scaffolding subunit of the m6A methyltransferase writer complex whose depletion destabilizes the entire complex and reduces global m6A levels, establishing it as a non-catalytic but structurally essential determinant of m6A deposition [#11, #43]. It binds target transcripts directly through its RNA-binding domain and preferentially installs m6A in 3'-UTR regions, where the modification dictates transcript fate through engagement of distinct readers: YTHDF2/YTHDC1-mediated destabilization of tumor-suppressive transcripts such as RND3, RASD1, and CHST11, versus IGF2BP1/2/3- and HuR-dependent stabilization of targets including HAS2, E2F7, and TMED2 [#19, #21, #22, #24, #25]. Beyond m6A writing, VIRMA acts as a global regulator of pre-mRNA alternative splicing, with its bound transcripts overlapping the genes whose splicing it controls [#17], and it can also regulate target mRNA stability in an m6A-independent manner [#10]. VIRMA function is partitioned by subcellular localization: a nuclear full-length isoform drives canonical m6A-dependent activity, while cytoplasmic mislocalization redirects it to reader-coupled stabilization of cytoplasmic targets [#22, #23]. Its activity is set by post-translational control, including USP29-mediated deubiquitination that stabilizes VIRMA protein and AARS2-mediated lactylation at lysine 1713 that enhances its methyltransferase output [#18, #44]. In vivo, VIRMA is essential for oocyte competence and folliculogenesis [#3], for forebrain development via m6A-dependent ribosome biogenesis and suppression of a p53 stress response in neural progenitors [#43], and for liver regeneration through stabilization of SHQ1 mRNA and PI3K/AKT activation [#45]. Across more than twenty cancer types its overexpression—driven by transcriptional activation (NF-\\u03baB/p65, C/EBP\\u03b2, NKX2-2), copy-number amplification, and promoter epigenetic changes—promotes proliferation, metastasis, immune evasion, altered glycolysis, ferroptosis resistance, and drug resistance by tuning the stability of diverse oncogenic and tumor-suppressive transcripts [#12, #16, #46, #52, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that VIRMA does not act uniformly across transcripts but preferentially directs m6A to 3'-UTR regions and couples this to RNA-binding-protein-mediated transcript fate, defining its target-selection logic.\",\n      \"evidence\": \"MeRIP-seq, RIP-seq and RNA-seq with siRNA knockdown showing 3'-UTR m6A on GATA3 pre-mRNA and HuR displacement\",\n      \"pmids\": [\"31856849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve how a lncRNA cis-element confers transcript specificity generally\", \"Single target context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Raised the possibility that VIRMA also regulates target transcripts independently of its m6A-writing activity, broadening its functional repertoire beyond methylation.\",\n      \"evidence\": \"RIP-seq and functional rescue showing CDK1 mRNA regulation in breast cancer\",\n      \"pmids\": [\"31285549\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"m6A-independence asserted without a mechanistic basis\", \"Single RIP-seq identification\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the first in vivo demonstration that VIRMA is physiologically essential, linking its m6A-writing role to a defined developmental program rather than only cancer cell lines.\",\n      \"evidence\": \"Oocyte-specific conditional knockout mouse with RNA-seq, m6A quantification and meiotic phenotyping\",\n      \"pmids\": [\"32094512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific splicing targets driving the oocyte phenotype not fully defined\", \"Reader dependence in oocytes not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed VIRMA is structurally required for writer-complex integrity, so its loss reduces global m6A and produces downstream consequences such as DNA damage and chemosensitivity.\",\n      \"evidence\": \"CRISPR knockdown in germ cell tumor cells with m6A quantification, \\u03b3H2AX and DNA-repair factor readouts plus in vivo CAM assay\",\n      \"pmids\": [\"34446080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical role of VIRMA in complex assembly not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that VIRMA globally controls alternative splicing of its bound transcripts, expanding its function beyond stability regulation to splicing.\",\n      \"evidence\": \"RIP-seq and RNA-seq integration in HCC showing overlap of bound transcripts with regulated splicing events\",\n      \"pmids\": [\"36505780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether splicing regulation is m6A-dependent not resolved\", \"Splicing machinery partners not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established that VIRMA protein levels are set post-translationally and that upstream transcription factors drive its overexpression, clarifying how its abundance is regulated in disease.\",\n      \"evidence\": \"Co-IP and ubiquitination assays defining USP29-mediated deubiquitination, and ChIP showing NF-\\u03baB/p65 transactivation of the promoter\",\n      \"pmids\": [\"36373629\", \"36291811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing USP29 not identified\", \"Stoichiometry of deubiquitination effect unquantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved that VIRMA's output bifurcates by reader pairing—destabilizing transcripts via YTHDF2/YTHDC1 or stabilizing them via IGF2BP/HuR—accounting for its opposing context-dependent effects.\",\n      \"evidence\": \"Multiple MeRIP-seq/RIP/stability studies including CRISPR KO and activation for CHST11-YTHDF2, RND3-YTHDC1, and IGF2BP3-coupled HAS2/E2F7 stabilization\",\n      \"pmids\": [\"37076815\", \"38224863\", \"37705505\", \"37028765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants directing a given transcript toward a destabilizing versus stabilizing reader not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that subcellular localization is a functional switch—nuclear full-length VIRMA performs canonical m6A writing while cytoplasmic mislocalization redirects activity—explaining isoform- and compartment-specific roles.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence and isoform-specific overexpression in breast cancer tying cytosolic VIRMA to IGF2BP3-coupled HAS2 stabilization\",\n      \"pmids\": [\"37705505\", \"37208522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals governing nuclear export/retention only partially defined\", \"Cytoplasmic methyltransferase competence versus pure adaptor role unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified additional post-translational modifications (acetylation, phosphorylation) and a phosphorylation-driven localization switch, deepening the regulatory layer controlling VIRMA targeting.\",\n      \"evidence\": \"Co-IP defining TIP60 acetylation and IP-MS/Co-IP/immunofluorescence showing BRAF phosphorylation promotes cytoplasmic localization and FZD7 mRNA stabilization\",\n      \"pmids\": [\"40301310\", \"40611274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetylation/phosphorylation site mapping to functional consequence incomplete\", \"Crosstalk between modifications not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected VIRMA-dependent m6A to fundamental cell biology—ribosome biogenesis and a p53 stress response—through an essential in vivo developmental requirement in the brain.\",\n      \"evidence\": \"Conditional Virma knockout with transcriptome, ribosome biogenesis and p53 pathway analysis in mouse forebrain\",\n      \"pmids\": [\"40577453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct m6A targets coupling VIRMA to ribosome biogenesis not enumerated\", \"Generality beyond neural progenitors untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed metabolic post-translational control of VIRMA via lactylation, linking the tumor microenvironment to VIRMA methyltransferase output.\",\n      \"evidence\": \"Co-IP and Me-RIP identifying AARS2-mediated lactylation at lysine 1713 enhancing SP1 mRNA m6A/stability, with PDX validation\",\n      \"pmids\": [\"41017455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural effect of K1713 lactylation on activity not defined\", \"Single metastatic context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VIRMA, as a non-catalytic scaffold, achieves transcript-specific 3'-UTR targeting and selects between destabilizing and stabilizing reader pathways remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of VIRMA within the writer complex on RNA\", \"Rules linking sequence/context to reader choice undefined\", \"Mechanism unifying m6A-dependent and m6A-independent activities unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [21, 22, 27, 33]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [11, 19, 24, 43]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 43]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [22, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [17, 19, 24, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 24, 52]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 43, 45]}\n    ],\n    \"complexes\": [\"m6A methyltransferase writer complex\"],\n    \"partners\": [\"METTL3\", \"WTAP\", \"HuR\", \"IGF2BP3\", \"YTHDF2\", \"USP29\", \"AARS2\", \"IGF2BP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}