{"gene":"RBM47","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2014,"finding":"RBM47 binds broadly to mRNAs, most prominently in introns and 3'UTRs (HITS-CLIP), and alters splicing and abundance of a subset of target mRNAs, including stabilizing DKK1 mRNA to inhibit tumor progression.","method":"Transcriptome-wide HITS-CLIP, mRNA stability assays, loss-of-function in cell line models","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — HITS-CLIP with functional validation, replicated across multiple models, highly cited foundational paper","pmids":["24898756"],"is_preprint":false},{"year":2014,"finding":"RBM47 physically interacts with APOBEC1 and A1CF, can substitute for A1CF, and is necessary and sufficient for APOBEC1-mediated C-to-U RNA editing in vitro; editing is impaired in Rbm47-deficient mice.","method":"Co-immunoprecipitation, in vitro RNA editing reconstitution, Rbm47 knockout mouse model","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution plus genetic knockout, replicated in subsequent studies","pmids":["24916387"],"is_preprint":false},{"year":2018,"finding":"A1CF and RBM47 function independently yet interact in a tissue-specific manner to regulate APOBEC1-dependent C-to-U RNA editing; intestine-specific Rbm47 knockout virtually eliminates apoB RNA editing, while liver-specific knockout reduces editing in a subset of targets; double knockout of A1cf and Rbm47 eliminates apoB editing and abrogates most other targets.","method":"Tissue-specific conditional knockout mice, RNA editing quantification in liver and intestine","journal":"RNA","confidence":"High","confidence_rationale":"Tier 2 — multiple conditional knockout models with quantitative editing assays, orthogonal to prior in vitro work","pmids":["30309881"],"is_preprint":false},{"year":2019,"finding":"RBM47 promotes inclusion of exon 20 of TJP1 pre-mRNA by recognizing a (U)GCAUG motif in the downstream intronic region; the first RRM domain of RBM47 is critical for this alternative splicing regulation; TJP1 isoform lacking exon 20 enhances actin stress fiber assembly and promotes cell migration during EMT.","method":"Minigene splicing assays, RRM domain mutagenesis, wound healing assay, isoform-specific functional rescue","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — sequence element mapping, domain mutagenesis, and functional isoform validation in one study","pmids":["31358901"],"is_preprint":false},{"year":2019,"finding":"RBM47 regulates p53 at the transcriptional level by controlling p53 promoter activity; RBM47 knockdown reduces p53 mRNA and protein levels, consequently reducing p21 expression and shifting irradiated cells from senescence to cell death.","method":"siRNA knockdown, p53 promoter-luciferase reporter assay, Flag-RBM47 overexpression","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 — promoter activity assay with knockdown and overexpression, single lab","pmids":["31511650"],"is_preprint":false},{"year":2019,"finding":"APOBEC1 cofactors A1CF and RBM47 show differential RNA editing activity on APOB and other target RNAs; the minimal domain requirement of RBM47 for editing activity was determined; human vs. mouse RBM47 show clear differences in editing selectivity.","method":"HEK293T cell reconstitution with APOBEC1 + cofactor, fluorescence-based eGFP localization editing assay, domain deletion analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — cell-based reconstitution with domain mapping, quantitative editing assay","pmids":["30844405"],"is_preprint":false},{"year":2018,"finding":"RBM47 promotes IL-10 mRNA stability in B cells by binding to AU-rich elements in the 3'UTR of Il10 mRNA, thereby elevating IL-10 production and enhancing regulatory B cell immunosuppressive function.","method":"mRNA microarray, RNA immunoprecipitation (RIP), mRNA stability assay, overexpression in primary B cells","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — RIP plus mRNA stability assay with functional readout, single lab","pmids":["29844590"],"is_preprint":false},{"year":2020,"finding":"RBM47 binds AXIN1 mRNA and stabilizes it, thereby enhancing suppression of Wnt/β-catenin signaling and inhibiting NSCLC cell proliferation, migration, and invasion.","method":"RNA immunoprecipitation, mRNA stability assay, lentiviral knockdown, in vitro and in vivo functional assays","journal":"Surgical oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP with functional validation, single lab","pmids":["32891348"],"is_preprint":false},{"year":2021,"finding":"RBM47 binds to the 3'UTR of IFNAR1 mRNA, increases its stability, and retards IFNAR1 protein degradation, thereby amplifying type I interferon downstream signaling and conferring broad-spectrum antiviral activity.","method":"RNA immunoprecipitation, mRNA stability assay, multiple virus infection models in vitro and in vivo, ISRE reporter assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — RIP, mRNA stability, in vivo viral models, multiple orthogonal methods","pmids":["34160127"],"is_preprint":false},{"year":2021,"finding":"RBM47 binds to the promoter of BCAT1 and regulates its transcription; RBM47 also binds hnRNPM and cooperatively regulates alternative splicing of multiple pre-mRNAs in nasopharyngeal carcinoma cells.","method":"ChIP, transcriptome analysis, Co-immunoprecipitation with hnRNPM, functional rescue experiments","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and Co-IP with functional rescue, single lab","pmids":["34274258"],"is_preprint":false},{"year":2022,"finding":"RBM47 directly binds and stabilizes lncRNA SNHG5; SNHG5 in turn inhibits ubiquitination and degradation of FOXO3 by recruiting USP21, promoting FOXO3 nuclear translocation that activates ATG3/ATG5 to induce autophagy; FOXO3 feeds back to activate RBM47 transcription, forming a loop.","method":"RIP, co-immunoprecipitation, ubiquitination assay, nuclear fractionation, in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple biochemical assays but complex multi-component pathway from single lab","pmids":["35338124"],"is_preprint":false},{"year":2022,"finding":"RBM47 stabilizes UPF1 mRNA by binding to its 3'UTR and also promotes UPF1 transcription as a transcription factor, thereby upregulating NMD activity and suppressing HCC progression.","method":"RNA immunoprecipitation, mRNA stability assay, promoter activity assay, xenograft tumor model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP and promoter assay, single lab","pmids":["35831298"],"is_preprint":false},{"year":2022,"finding":"RBM47 binds PTEN mRNA and stabilizes it; miR-181c/d-5p directly targets RBM47 mRNA to suppress its expression, thereby reducing PTEN stability and activating PI3K/AKT signaling in colorectal cancer.","method":"RNA pulldown, luciferase reporter assay, RIP, mRNA stability assay with actinomycin D, rescue experiments","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple binding assays, single lab","pmids":["36321407"],"is_preprint":false},{"year":2013,"finding":"RBM47 specifically binds RNA but not single-stranded DNA; knockdown of rbm47 in zebrafish causes headless/small-head phenotypes rescued by wnt8a morpholino, placing rbm47 upstream of Wnt8a signaling in head development.","method":"RNA binding assay, morpholino knockdown in zebrafish, genetic rescue with wnt8a morpholino, microarray gene expression analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in zebrafish ortholog with functional rescue, consistent with mammalian gene context","pmids":["24038582"],"is_preprint":false},{"year":2016,"finding":"Rbm47 function is required in the embryo proper (not the visceral endoderm) for viability and growth; conditional inactivation using Cre/FLP-mediated approaches demonstrates tissue-specific requirement.","method":"Conditional knockout/restoration using FlEx gene-trap cassette with Cre and FLP recombinases in mice","journal":"Genesis","confidence":"Medium","confidence_rationale":"Tier 2 — conditional genetic approach with tissue-specific rescue, single lab","pmids":["26789794"],"is_preprint":false},{"year":2020,"finding":"Zebrafish RBM47 interacts with MAVS and promotes its lysosome-dependent degradation, changing MAVS cellular localization from cytoplasm to lysosome region, thereby suppressing downstream MITA and IRF3/7 activation and inhibiting IFN production.","method":"Co-immunoprecipitation, subcellular fractionation/localization, lysosome inhibitor assays, reporter assays for IFN pathway components","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with localization and pathway assays; zebrafish ortholog, context consistent with mammalian gene","pmids":["32859727"],"is_preprint":false},{"year":2013,"finding":"RBM47 binds Nanog mRNA in mouse embryonic stem cells (but not Sox2 or Oct4 mRNA), as demonstrated by RNA-binding protein immunoprecipitation after overexpression of HA-tagged Rbm47.","method":"RIP followed by RT-PCR in mouse ESCs overexpressing HA-Rbm47","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP/RIP experiment, no functional follow-up","pmids":["23649762"],"is_preprint":false},{"year":2023,"finding":"RBM47 undergoes ISGylation at lysine 329, dependent on prior S309 phosphorylation (induced by epinephrine); K329R knockin mice with defective RBM47-ISGylation show impaired immune activation and increased susceptibility to lung injury; RBM47-ISGylation regulates TSC22D3 mRNA expression.","method":"K329R knockin mouse model, site-specific nanobody-targeted E3 ligase ISGylation in human cells, cytokine/immune phenotyping","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — knockin mouse with site-specific PTM validation and functional consequence, single lab","pmids":["38036512"],"is_preprint":false},{"year":2024,"finding":"Deubiquitinase OTUD4 directly interacts with RBM47 and promotes RBM47 protein stability via deubiquitination; stabilized RBM47 in turn regulates ATF3 mRNA stability, promoting ATF3-mediated ferroptosis in ccRCC.","method":"Co-immunoprecipitation, ubiquitination assay, mRNA stability assay, rescue experiments in vitro and in vivo","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with deubiquitination assay and mRNA stability, single lab","pmids":["38553613"],"is_preprint":false},{"year":2023,"finding":"RBM47 binds to flanking introns of circFNDC3B to facilitate its biogenesis (back-splicing), resulting in reduced FNDC3B linear mRNA; the resulting circFNDC3B competitively inhibits IGF2BP1 binding to FNDC3B mRNA, further destabilizing it.","method":"RIP assay, RNA stability analysis, RNA-FISH, immunofluorescence, functional assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP and stability assays, single lab","pmids":["38129874"],"is_preprint":false},{"year":2023,"finding":"RBM47 stabilizes FBXO2 mRNA, promoting STAT3 phosphorylation in chondrocytes and advancing osteoarthritis; RBM47 knockdown alleviates IL-1β-induced inflammation, apoptosis, and ECM degradation.","method":"RIP, mRNA stability assay, STAT3 phosphorylation western blot, rescue experiments with FBXO2/STAT3 overexpression","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP and mRNA stability with pathway rescue, single lab","pmids":["38070024"],"is_preprint":false},{"year":2025,"finding":"RBM47 directly binds to the 3'UTR of ITGAV mRNA via AU-rich elements and promotes its degradation; miR-122 suppresses RBM47 expression, thereby elevating ITGAV levels, which activates latent TGF-β and promotes HCC metastasis.","method":"RIP, mRNA stability assay with AU-rich element mapping, luciferase reporter, functional rescue in vitro and in vivo","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP with element mapping and rescue experiments, single lab","pmids":["40638600"],"is_preprint":false},{"year":2025,"finding":"RBM47 destabilizes PD-L1 mRNA via 3'UTR binding, reducing PD-L1 expression and thereby enhancing T-cell proliferation and cytotoxicity against NSCLC cancer stem cells; m6A modification by METTL3/YTHDF1 decreases RBM47 expression.","method":"m6A methylated RIP-PCR, RIP, functional T-cell co-culture assay, in vitro and in vivo CSC assays","journal":"Journal of thoracic disease","confidence":"Low","confidence_rationale":"Tier 3 — RIP assay with functional readout, limited mechanistic detail, single lab","pmids":["41376900"],"is_preprint":false},{"year":2025,"finding":"RBM47 (via its RRM2 domain) binds to the 3'UTR of cGAS mRNA and enhances its stability, thereby activating the cGAS-STING pathway; RUNX1 directly binds the Rbm47 promoter and drives its transcription, placing RUNX1 upstream of RBM47 in this pathway.","method":"RIP (RRM2 domain interaction), ChIP (RUNX1 on Rbm47 promoter), mRNA stability assay, cGAS inhibitor rescue, mouse POCD model","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — domain-specific RIP, ChIP, and in vivo genetic model with inhibitor rescue","pmids":["41407921"],"is_preprint":false},{"year":2025,"finding":"RBM47 regulates tissue-specific alternative splicing of SEC31A (a COPII component), and inclusion of an uncharacterized exon in SEC31A increases lipid transport; RBM47 was identified as the trans-acting splicing regulator by correlation of splicing with RBP expression across tissues and then validated experimentally.","method":"RNA-seq across human tissues, correlation analysis, experimental validation of RBM47-mediated SEC31A splicing, lipid transport functional assay","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 — in silico identification with experimental splicing validation and functional lipid transport readout, single lab","pmids":["40436629"],"is_preprint":false},{"year":2026,"finding":"RBM47 directly binds to the 3'UTR of GSDMA mRNA and stabilizes it; GSDMA is necessary for RBM47-induced mesenchymal-to-epithelial transition (MET), suppression of migration/invasion, pyroptosis induction, and chemosensitization to Oxaliplatin in CRC cells.","method":"RNA-Seq, RIP, mRNA stability assay, GSDMA knockdown rescue experiments, functional migration/invasion/pyroptosis assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — RIP with mRNA stability, genetic rescue defining pathway position, single lab","pmids":["41681975"],"is_preprint":false},{"year":2026,"finding":"RBM47 binds to AU-rich elements in ENC1 mRNA and enhances ENC1 stability, thereby curbing NRF2 synthesis and nuclear translocation in macrophages during atherosclerosis, promoting oxidative stress.","method":"RIP, mRNA stability assay, AAV-mediated in vivo knockdown, NRF2 inhibitor rescue in vitro","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP with in vivo AAV and rescue assays, single lab","pmids":["41962778"],"is_preprint":false},{"year":2024,"finding":"RBM47 stabilizes PDIA6 mRNA by binding to its 3'UTR, maintaining PDIA6 expression to promote pancreatic cancer cell proliferation and immune evasion from NK cells.","method":"RIP, luciferase reporter assay, mRNA stability assay, rescue experiments, metabolomics","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 — RIP with functional rescue, single lab, limited mechanistic depth","pmids":["39741300"],"is_preprint":false},{"year":2025,"finding":"HDAC2 promotes RBM47 expression through H3K27 deacetylation; RBM47 in turn increases NONO expression in medulloblastoma cells, defining a HDAC2/RBM47/NONO oncogenic axis.","method":"ChIP-qPCR, luciferase reporter assay, qRT-PCR, western blot, lentiviral RNAi","journal":"Translational oncology","confidence":"Low","confidence_rationale":"Tier 3 — ChIP and reporter assay linking HDAC2 to RBM47, but RBM47-NONO mechanism not fully characterized","pmids":["41027284"],"is_preprint":false},{"year":2023,"finding":"Intestine-specific Rbm47 knockout mice exhibit increased intestinal proliferation, abnormal villus morphology, upregulation of antioxidant and Wnt signaling pathways, and protection against colitis-associated cancer but increased spontaneous polyposis with age; RBM47 regulates alternative splicing of TJP1 mRNA in human colorectal cancer.","method":"Intestine-specific conditional knockout mouse (Rbm47-IKO), intestinal organoids, ApcMin/+ crosses, radiation/chemical injury models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic mouse models with defined phenotypic readouts across several orthogonal assays","pmids":["37014710"],"is_preprint":false},{"year":2021,"finding":"RBM47 inhibits K562 cell proliferation and cell cycle progression by binding HMGA2 mRNA and promoting its degradation, reducing HMGA2 protein expression.","method":"RIP, mRNA stability assay, CCK-8, flow cytometry, lentiviral overexpression/knockdown","journal":"Zhongguo shi yan xue ye xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 — single RIP with stability assay, single lab","pmids":["34105460"],"is_preprint":false},{"year":2024,"finding":"In glioblastoma, RBM47 stabilizes mRNAs of inflammatory genes and activates the NF-κB pathway; NF-κB acts as a transcription factor that in turn enhances RBM47 transcription, forming a positive feedback loop that promotes M2 macrophage polarization in the tumor microenvironment.","method":"RNA-immunoprecipitation (RIP), ChIP, RNA sequencing, immunofluorescence, western blot","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP and ChIP supporting feedback loop, single lab","pmids":["38518642"],"is_preprint":false},{"year":2023,"finding":"RBM47 interferes with the interaction between lncRNA HOXB-AS1 and p53 protein by directly binding HOXB-AS1, freeing p53 to enter the nucleus and activating p53 signaling in renal cell carcinoma; RBM47 expression is regulated by CBP/P300-mediated H3K27ac.","method":"RIP, Co-immunoprecipitation, nuclear fractionation, chromatin modification assay, functional assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 — RIP and Co-IP linking RBM47 to lncRNA-p53 axis, single lab","pmids":["37660095"],"is_preprint":false}],"current_model":"RBM47 is a multi-functional RNA-binding protein with three RRM domains that acts primarily as an RNA chaperone: it binds intronic and 3'UTR sequences of diverse mRNA targets to regulate their splicing, stability, and abundance, serves as an essential cofactor (substituting for A1CF) in the APOBEC1-mediated C-to-U RNA editing complex, undergoes ISGylation at K329 (primed by S309 phosphorylation) to regulate immune gene expression, can function as a transcription factor at select gene promoters, and suppresses cancer progression in most epithelial contexts by stabilizing tumor-suppressor mRNAs (e.g., DKK1, AXIN1, IFNAR1, GSDMA) and promoting epithelial splicing programs (e.g., TJP1 exon 20 inclusion)."},"narrative":{"teleology":[{"year":2013,"claim":"Early work established that RBM47 is a bona fide RNA-binding protein (not DNA-binding) and placed it genetically upstream of Wnt signaling in head development, providing the first functional framework for the gene.","evidence":"Zebrafish morpholino knockdown with wnt8a epistasis rescue and RNA-binding specificity assay","pmids":["24038582"],"confidence":"Medium","gaps":["Mechanism by which RBM47 restrains Wnt8a signaling was not determined","Direct RNA targets in zebrafish not identified"]},{"year":2014,"claim":"Transcriptome-wide binding maps revealed that RBM47 binds broadly to mRNA introns and 3′UTRs and regulates both splicing and mRNA stability, with DKK1 mRNA stabilization identified as a tumor-suppressive mechanism — establishing RBM47 as a multi-modal post-transcriptional regulator.","evidence":"HITS-CLIP in mammalian cell lines with mRNA stability assays and loss-of-function cancer models","pmids":["24898756"],"confidence":"High","gaps":["Precise cis-elements for stability regulation not mapped","In vivo tumor suppression not validated with genetic models at this point"]},{"year":2014,"claim":"Concurrent biochemical work demonstrated that RBM47 physically associates with APOBEC1 and can substitute for A1CF as a cofactor for C-to-U RNA editing, revealing a second major molecular activity distinct from mRNA stabilization.","evidence":"Co-immunoprecipitation, in vitro RNA editing reconstitution, Rbm47 knockout mouse","pmids":["24916387"],"confidence":"High","gaps":["Structural basis of RBM47–APOBEC1 interaction unknown","Relative contribution of A1CF vs RBM47 in different tissues not yet resolved"]},{"year":2018,"claim":"Tissue-specific conditional knockouts resolved the relative contributions of A1CF and RBM47 to RNA editing: RBM47 is the dominant editing cofactor in the intestine whereas liver editing depends on both cofactors, and double knockout eliminates nearly all APOBEC1-dependent editing.","evidence":"Intestine- and liver-specific conditional knockout mice with quantitative RNA editing assays","pmids":["30309881"],"confidence":"High","gaps":["Molecular basis for tissue-specific cofactor selectivity not determined","Non-apoB editing targets not fully characterized"]},{"year":2019,"claim":"The cis-regulatory logic of RBM47-dependent splicing was decoded: RBM47's first RRM domain recognizes a (U)GCAUG motif in flanking introns to promote TJP1 exon 20 inclusion, linking RBM47 loss to EMT-promoting isoform switching.","evidence":"Minigene splicing assays, RRM domain mutagenesis, isoform-specific functional rescue","pmids":["31358901"],"confidence":"High","gaps":["Whether GCAUG motif governs all RBM47-regulated splicing events is unknown","Contribution of RRM2/RRM3 to splicing specificity not defined"]},{"year":2019,"claim":"Domain-mapping studies determined the minimal RBM47 regions required for APOBEC1-dependent editing and revealed species-specific differences in editing selectivity between human and mouse RBM47.","evidence":"HEK293T reconstitution with domain deletions and fluorescence-based editing assay","pmids":["30844405"],"confidence":"High","gaps":["Structural basis for species-specific selectivity not resolved","Whether domain requirements differ for editing versus mRNA stability functions is untested"]},{"year":2019,"claim":"An unexpected transcription-factor-like activity was reported: RBM47 controls p53 promoter activity, adding a DNA-level regulatory mode to its repertoire, though this was at odds with earlier evidence of RNA-only binding.","evidence":"siRNA knockdown and p53 promoter-luciferase reporter assay","pmids":["31511650"],"confidence":"Medium","gaps":["Direct DNA binding by RBM47 at the p53 promoter was not demonstrated","Transcription factor activity not reconciled with earlier finding that RBM47 does not bind DNA"]},{"year":2020,"claim":"RBM47's mRNA stabilization function was extended to the Wnt pathway negative regulator AXIN1 in NSCLC, providing a second mechanism (alongside DKK1) by which RBM47 suppresses Wnt/β-catenin signaling.","evidence":"RIP, mRNA stability assay, lentiviral knockdown with in vitro and in vivo tumor assays","pmids":["32891348"],"confidence":"Medium","gaps":["Specific 3′UTR elements mediating AXIN1 stabilization not mapped","Relative importance of DKK1 vs AXIN1 stabilization in Wnt suppression not tested"]},{"year":2021,"claim":"RBM47 was shown to amplify type I interferon signaling by stabilizing IFNAR1 mRNA and retarding IFNAR1 protein degradation, establishing a role in antiviral innate immunity beyond its RNA editing and splicing functions.","evidence":"RIP, mRNA stability assay, multiple in vitro and in vivo virus infection models, ISRE reporter assay","pmids":["34160127"],"confidence":"High","gaps":["Mechanism of IFNAR1 protein stabilization (whether direct or indirect) not fully resolved","Relationship between IFNAR1 stabilization and APOBEC1 editing activity unclear"]},{"year":2023,"claim":"Intestine-specific Rbm47 knockout mice revealed that RBM47 restrains intestinal stem cell proliferation and Wnt signaling in vivo; paradoxically, loss protects against colitis-associated cancer but promotes spontaneous polyposis, demonstrating context-dependent tumor modulation.","evidence":"Intestine-specific conditional knockout mice, organoids, ApcMin/+ crosses, radiation and chemical injury models","pmids":["37014710"],"confidence":"High","gaps":["Molecular targets responsible for the paradoxical polyposis phenotype not identified","Whether splicing or stability targets drive the proliferative phenotype not separated"]},{"year":2023,"claim":"A new post-translational regulatory layer was uncovered: RBM47 undergoes ISGylation at K329 (dependent on S309 phosphorylation), and K329R knockin mice show impaired immune activation, linking a specific PTM to RBM47's immune-regulatory output.","evidence":"K329R knockin mouse model, site-specific nanobody-targeted E3 ligase ISGylation, immune phenotyping","pmids":["38036512"],"confidence":"Medium","gaps":["How ISGylation alters RBM47 RNA-binding or protein interactions is unknown","Kinase responsible for S309 phosphorylation not identified beyond epinephrine stimulus"]},{"year":2024,"claim":"RBM47 protein stability was shown to be regulated by OTUD4-mediated deubiquitination, revealing that RBM47's tumor-suppressive output is itself controlled at the protein turnover level.","evidence":"Co-immunoprecipitation, ubiquitination assay, mRNA stability assay, in vivo rescue in ccRCC","pmids":["38553613"],"confidence":"Medium","gaps":["E3 ubiquitin ligase targeting RBM47 for degradation not identified","Whether OTUD4 regulation is tissue-specific is unknown"]},{"year":2025,"claim":"RBM47 was identified as a tissue-specific splicing regulator of SEC31A, a COPII coat component, linking RBM47's splicing activity to lipid transport and vesicular trafficking — extending its function beyond cancer and immunity.","evidence":"Cross-tissue RNA-seq correlation analysis with experimental splicing validation and lipid transport assay","pmids":["40436629"],"confidence":"Medium","gaps":["Cis-elements in SEC31A pre-mRNA recognized by RBM47 not mapped","Physiological consequence of SEC31A mis-splicing in Rbm47-null animals not tested"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for RBM47's dual role in RNA editing versus mRNA stabilization, whether the reported transcription factor activity represents direct DNA binding, and the full spectrum of tissue-specific splicing programs controlled by RBM47 in vivo.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of RBM47 alone or in complex with APOBEC1","Direct DNA-binding activity contradicts earlier RNA-specificity data and has not been reconciled","Genome-wide splicing maps in Rbm47-knockout tissues not yet generated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,3,6,7,8,13,16,19,21,23,24,25,26]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,9,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,9,32]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,15]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,3,5,24]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,8,17,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,12,13,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,9,11]}],"complexes":["APOBEC1 editosome"],"partners":["APOBEC1","A1CF","HNRNPM","OTUD4","MAVS","RUNX1"],"other_free_text":[]},"mechanistic_narrative":"RBM47 is a three-RRM-domain RNA-binding protein that broadly regulates mRNA fate — splicing, stability, and editing — across epithelial, immune, and neural tissues. It binds predominantly to intronic and 3′UTR sequences of target mRNAs via GCAUG and AU-rich motifs, stabilizing transcripts such as DKK1, AXIN1, IFNAR1, and GSDMA to restrain Wnt/β-catenin signaling and promote epithelial identity, while also directing alternative splicing events including TJP1 exon 20 inclusion and SEC31A tissue-specific exon usage [PMID:24898756, PMID:31358901, PMID:40436629, PMID:41681975]. RBM47 serves as an essential cofactor of the APOBEC1 C-to-U RNA editing complex, where it can substitute for A1CF; intestine-specific Rbm47 knockout virtually eliminates apoB mRNA editing [PMID:24916387, PMID:30309881]. RBM47 undergoes ISGylation at K329, primed by S309 phosphorylation, to regulate immune gene expression, and its protein stability is itself controlled by OTUD4-mediated deubiquitination and m6A-dependent mRNA regulation [PMID:38036512, PMID:38553613]."},"prefetch_data":{"uniprot":{"accession":"A0AV96","full_name":"RNA-binding protein 47","aliases":["RNA-binding motif protein 47"],"length_aa":593,"mass_kda":64.1,"function":"Single-stranded RNA-binding protein that functions in a variety of RNA processes, including alternative splicing, RNA stabilization, and RNA editing (PubMed:24038582, PubMed:24916387, PubMed:27050523, PubMed:30844405, PubMed:31358901, PubMed:34160127). Functions as an enzyme-substrate adapter for the cytidine deaminase APOBEC1. With APOBEC1 forms an mRNA editing complex involved into cytidine to uridine editing of a variety of mRNA molecules (PubMed:24038582, PubMed:24916387, PubMed:30844405). Through the binding of their 3'UTR, also stabilizes a variety of mRNAs and regulates the expression of genes such as the interferon alpha/beta receptor and interleukin-10 (PubMed:34160127). Also involved in the alternative splicing of several genes including TJP1. Binds the pre-mRNA (U)GCAUG consensus sequences in downstream intronic regions of alternative exons, regulating their exclusion and inclusion into mRNAs (PubMed:27050523, PubMed:31358901). Independently of its RNA-binding activity, could negatively regulate MAVS by promoting its lysosomal degradation (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/A0AV96/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM47","classification":"Not Classified","n_dependent_lines":30,"n_total_lines":1208,"dependency_fraction":0.024834437086092714},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RBM47","total_profiled":1310},"omim":[{"mim_id":"619104","title":"RNA-BINDING MOTIF PROTEIN 47; RBM47","url":"https://www.omim.org/entry/619104"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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regulating RBM47 splicing in breast cancer.","date":"2026","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41690343","citation_count":0,"is_preprint":false},{"pmid":"41376900","id":"PMC_41376900","title":"Pseudomonas putida KT2440-induced RBM47 regulates non-small cell lung cancer stem cell properties and T cell-mediated antitumor activity.","date":"2025","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/41376900","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23558,"output_tokens":6803,"usd":0.08636},"stage2":{"model":"claude-opus-4-6","input_tokens":10543,"output_tokens":3299,"usd":0.202785},"total_usd":0.289145,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"RBM47 binds broadly to mRNAs, most prominently in introns and 3'UTRs (HITS-CLIP), and alters splicing and abundance of a subset of target mRNAs, including stabilizing DKK1 mRNA to inhibit tumor progression.\",\n      \"method\": \"Transcriptome-wide HITS-CLIP, mRNA stability assays, loss-of-function in cell line models\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — HITS-CLIP with functional validation, replicated across multiple models, highly cited foundational paper\",\n      \"pmids\": [\"24898756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RBM47 physically interacts with APOBEC1 and A1CF, can substitute for A1CF, and is necessary and sufficient for APOBEC1-mediated C-to-U RNA editing in vitro; editing is impaired in Rbm47-deficient mice.\",\n      \"method\": \"Co-immunoprecipitation, in vitro RNA editing reconstitution, Rbm47 knockout mouse model\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution plus genetic knockout, replicated in subsequent studies\",\n      \"pmids\": [\"24916387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A1CF and RBM47 function independently yet interact in a tissue-specific manner to regulate APOBEC1-dependent C-to-U RNA editing; intestine-specific Rbm47 knockout virtually eliminates apoB RNA editing, while liver-specific knockout reduces editing in a subset of targets; double knockout of A1cf and Rbm47 eliminates apoB editing and abrogates most other targets.\",\n      \"method\": \"Tissue-specific conditional knockout mice, RNA editing quantification in liver and intestine\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple conditional knockout models with quantitative editing assays, orthogonal to prior in vitro work\",\n      \"pmids\": [\"30309881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RBM47 promotes inclusion of exon 20 of TJP1 pre-mRNA by recognizing a (U)GCAUG motif in the downstream intronic region; the first RRM domain of RBM47 is critical for this alternative splicing regulation; TJP1 isoform lacking exon 20 enhances actin stress fiber assembly and promotes cell migration during EMT.\",\n      \"method\": \"Minigene splicing assays, RRM domain mutagenesis, wound healing assay, isoform-specific functional rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — sequence element mapping, domain mutagenesis, and functional isoform validation in one study\",\n      \"pmids\": [\"31358901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RBM47 regulates p53 at the transcriptional level by controlling p53 promoter activity; RBM47 knockdown reduces p53 mRNA and protein levels, consequently reducing p21 expression and shifting irradiated cells from senescence to cell death.\",\n      \"method\": \"siRNA knockdown, p53 promoter-luciferase reporter assay, Flag-RBM47 overexpression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter activity assay with knockdown and overexpression, single lab\",\n      \"pmids\": [\"31511650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"APOBEC1 cofactors A1CF and RBM47 show differential RNA editing activity on APOB and other target RNAs; the minimal domain requirement of RBM47 for editing activity was determined; human vs. mouse RBM47 show clear differences in editing selectivity.\",\n      \"method\": \"HEK293T cell reconstitution with APOBEC1 + cofactor, fluorescence-based eGFP localization editing assay, domain deletion analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cell-based reconstitution with domain mapping, quantitative editing assay\",\n      \"pmids\": [\"30844405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBM47 promotes IL-10 mRNA stability in B cells by binding to AU-rich elements in the 3'UTR of Il10 mRNA, thereby elevating IL-10 production and enhancing regulatory B cell immunosuppressive function.\",\n      \"method\": \"mRNA microarray, RNA immunoprecipitation (RIP), mRNA stability assay, overexpression in primary B cells\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP plus mRNA stability assay with functional readout, single lab\",\n      \"pmids\": [\"29844590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RBM47 binds AXIN1 mRNA and stabilizes it, thereby enhancing suppression of Wnt/β-catenin signaling and inhibiting NSCLC cell proliferation, migration, and invasion.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, lentiviral knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"Surgical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP with functional validation, single lab\",\n      \"pmids\": [\"32891348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM47 binds to the 3'UTR of IFNAR1 mRNA, increases its stability, and retards IFNAR1 protein degradation, thereby amplifying type I interferon downstream signaling and conferring broad-spectrum antiviral activity.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, multiple virus infection models in vitro and in vivo, ISRE reporter assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP, mRNA stability, in vivo viral models, multiple orthogonal methods\",\n      \"pmids\": [\"34160127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM47 binds to the promoter of BCAT1 and regulates its transcription; RBM47 also binds hnRNPM and cooperatively regulates alternative splicing of multiple pre-mRNAs in nasopharyngeal carcinoma cells.\",\n      \"method\": \"ChIP, transcriptome analysis, Co-immunoprecipitation with hnRNPM, functional rescue experiments\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and Co-IP with functional rescue, single lab\",\n      \"pmids\": [\"34274258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM47 directly binds and stabilizes lncRNA SNHG5; SNHG5 in turn inhibits ubiquitination and degradation of FOXO3 by recruiting USP21, promoting FOXO3 nuclear translocation that activates ATG3/ATG5 to induce autophagy; FOXO3 feeds back to activate RBM47 transcription, forming a loop.\",\n      \"method\": \"RIP, co-immunoprecipitation, ubiquitination assay, nuclear fractionation, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple biochemical assays but complex multi-component pathway from single lab\",\n      \"pmids\": [\"35338124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM47 stabilizes UPF1 mRNA by binding to its 3'UTR and also promotes UPF1 transcription as a transcription factor, thereby upregulating NMD activity and suppressing HCC progression.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, promoter activity assay, xenograft tumor model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP and promoter assay, single lab\",\n      \"pmids\": [\"35831298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM47 binds PTEN mRNA and stabilizes it; miR-181c/d-5p directly targets RBM47 mRNA to suppress its expression, thereby reducing PTEN stability and activating PI3K/AKT signaling in colorectal cancer.\",\n      \"method\": \"RNA pulldown, luciferase reporter assay, RIP, mRNA stability assay with actinomycin D, rescue experiments\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple binding assays, single lab\",\n      \"pmids\": [\"36321407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBM47 specifically binds RNA but not single-stranded DNA; knockdown of rbm47 in zebrafish causes headless/small-head phenotypes rescued by wnt8a morpholino, placing rbm47 upstream of Wnt8a signaling in head development.\",\n      \"method\": \"RNA binding assay, morpholino knockdown in zebrafish, genetic rescue with wnt8a morpholino, microarray gene expression analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in zebrafish ortholog with functional rescue, consistent with mammalian gene context\",\n      \"pmids\": [\"24038582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rbm47 function is required in the embryo proper (not the visceral endoderm) for viability and growth; conditional inactivation using Cre/FLP-mediated approaches demonstrates tissue-specific requirement.\",\n      \"method\": \"Conditional knockout/restoration using FlEx gene-trap cassette with Cre and FLP recombinases in mice\",\n      \"journal\": \"Genesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional genetic approach with tissue-specific rescue, single lab\",\n      \"pmids\": [\"26789794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Zebrafish RBM47 interacts with MAVS and promotes its lysosome-dependent degradation, changing MAVS cellular localization from cytoplasm to lysosome region, thereby suppressing downstream MITA and IRF3/7 activation and inhibiting IFN production.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/localization, lysosome inhibitor assays, reporter assays for IFN pathway components\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with localization and pathway assays; zebrafish ortholog, context consistent with mammalian gene\",\n      \"pmids\": [\"32859727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBM47 binds Nanog mRNA in mouse embryonic stem cells (but not Sox2 or Oct4 mRNA), as demonstrated by RNA-binding protein immunoprecipitation after overexpression of HA-tagged Rbm47.\",\n      \"method\": \"RIP followed by RT-PCR in mouse ESCs overexpressing HA-Rbm47\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/RIP experiment, no functional follow-up\",\n      \"pmids\": [\"23649762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM47 undergoes ISGylation at lysine 329, dependent on prior S309 phosphorylation (induced by epinephrine); K329R knockin mice with defective RBM47-ISGylation show impaired immune activation and increased susceptibility to lung injury; RBM47-ISGylation regulates TSC22D3 mRNA expression.\",\n      \"method\": \"K329R knockin mouse model, site-specific nanobody-targeted E3 ligase ISGylation in human cells, cytokine/immune phenotyping\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockin mouse with site-specific PTM validation and functional consequence, single lab\",\n      \"pmids\": [\"38036512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Deubiquitinase OTUD4 directly interacts with RBM47 and promotes RBM47 protein stability via deubiquitination; stabilized RBM47 in turn regulates ATF3 mRNA stability, promoting ATF3-mediated ferroptosis in ccRCC.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, mRNA stability assay, rescue experiments in vitro and in vivo\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with deubiquitination assay and mRNA stability, single lab\",\n      \"pmids\": [\"38553613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM47 binds to flanking introns of circFNDC3B to facilitate its biogenesis (back-splicing), resulting in reduced FNDC3B linear mRNA; the resulting circFNDC3B competitively inhibits IGF2BP1 binding to FNDC3B mRNA, further destabilizing it.\",\n      \"method\": \"RIP assay, RNA stability analysis, RNA-FISH, immunofluorescence, functional assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP and stability assays, single lab\",\n      \"pmids\": [\"38129874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM47 stabilizes FBXO2 mRNA, promoting STAT3 phosphorylation in chondrocytes and advancing osteoarthritis; RBM47 knockdown alleviates IL-1β-induced inflammation, apoptosis, and ECM degradation.\",\n      \"method\": \"RIP, mRNA stability assay, STAT3 phosphorylation western blot, rescue experiments with FBXO2/STAT3 overexpression\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP and mRNA stability with pathway rescue, single lab\",\n      \"pmids\": [\"38070024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM47 directly binds to the 3'UTR of ITGAV mRNA via AU-rich elements and promotes its degradation; miR-122 suppresses RBM47 expression, thereby elevating ITGAV levels, which activates latent TGF-β and promotes HCC metastasis.\",\n      \"method\": \"RIP, mRNA stability assay with AU-rich element mapping, luciferase reporter, functional rescue in vitro and in vivo\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP with element mapping and rescue experiments, single lab\",\n      \"pmids\": [\"40638600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM47 destabilizes PD-L1 mRNA via 3'UTR binding, reducing PD-L1 expression and thereby enhancing T-cell proliferation and cytotoxicity against NSCLC cancer stem cells; m6A modification by METTL3/YTHDF1 decreases RBM47 expression.\",\n      \"method\": \"m6A methylated RIP-PCR, RIP, functional T-cell co-culture assay, in vitro and in vivo CSC assays\",\n      \"journal\": \"Journal of thoracic disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — RIP assay with functional readout, limited mechanistic detail, single lab\",\n      \"pmids\": [\"41376900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM47 (via its RRM2 domain) binds to the 3'UTR of cGAS mRNA and enhances its stability, thereby activating the cGAS-STING pathway; RUNX1 directly binds the Rbm47 promoter and drives its transcription, placing RUNX1 upstream of RBM47 in this pathway.\",\n      \"method\": \"RIP (RRM2 domain interaction), ChIP (RUNX1 on Rbm47 promoter), mRNA stability assay, cGAS inhibitor rescue, mouse POCD model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific RIP, ChIP, and in vivo genetic model with inhibitor rescue\",\n      \"pmids\": [\"41407921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM47 regulates tissue-specific alternative splicing of SEC31A (a COPII component), and inclusion of an uncharacterized exon in SEC31A increases lipid transport; RBM47 was identified as the trans-acting splicing regulator by correlation of splicing with RBP expression across tissues and then validated experimentally.\",\n      \"method\": \"RNA-seq across human tissues, correlation analysis, experimental validation of RBM47-mediated SEC31A splicing, lipid transport functional assay\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in silico identification with experimental splicing validation and functional lipid transport readout, single lab\",\n      \"pmids\": [\"40436629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM47 directly binds to the 3'UTR of GSDMA mRNA and stabilizes it; GSDMA is necessary for RBM47-induced mesenchymal-to-epithelial transition (MET), suppression of migration/invasion, pyroptosis induction, and chemosensitization to Oxaliplatin in CRC cells.\",\n      \"method\": \"RNA-Seq, RIP, mRNA stability assay, GSDMA knockdown rescue experiments, functional migration/invasion/pyroptosis assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP with mRNA stability, genetic rescue defining pathway position, single lab\",\n      \"pmids\": [\"41681975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM47 binds to AU-rich elements in ENC1 mRNA and enhances ENC1 stability, thereby curbing NRF2 synthesis and nuclear translocation in macrophages during atherosclerosis, promoting oxidative stress.\",\n      \"method\": \"RIP, mRNA stability assay, AAV-mediated in vivo knockdown, NRF2 inhibitor rescue in vitro\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP with in vivo AAV and rescue assays, single lab\",\n      \"pmids\": [\"41962778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM47 stabilizes PDIA6 mRNA by binding to its 3'UTR, maintaining PDIA6 expression to promote pancreatic cancer cell proliferation and immune evasion from NK cells.\",\n      \"method\": \"RIP, luciferase reporter assay, mRNA stability assay, rescue experiments, metabolomics\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — RIP with functional rescue, single lab, limited mechanistic depth\",\n      \"pmids\": [\"39741300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC2 promotes RBM47 expression through H3K27 deacetylation; RBM47 in turn increases NONO expression in medulloblastoma cells, defining a HDAC2/RBM47/NONO oncogenic axis.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, qRT-PCR, western blot, lentiviral RNAi\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ChIP and reporter assay linking HDAC2 to RBM47, but RBM47-NONO mechanism not fully characterized\",\n      \"pmids\": [\"41027284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intestine-specific Rbm47 knockout mice exhibit increased intestinal proliferation, abnormal villus morphology, upregulation of antioxidant and Wnt signaling pathways, and protection against colitis-associated cancer but increased spontaneous polyposis with age; RBM47 regulates alternative splicing of TJP1 mRNA in human colorectal cancer.\",\n      \"method\": \"Intestine-specific conditional knockout mouse (Rbm47-IKO), intestinal organoids, ApcMin/+ crosses, radiation/chemical injury models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic mouse models with defined phenotypic readouts across several orthogonal assays\",\n      \"pmids\": [\"37014710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM47 inhibits K562 cell proliferation and cell cycle progression by binding HMGA2 mRNA and promoting its degradation, reducing HMGA2 protein expression.\",\n      \"method\": \"RIP, mRNA stability assay, CCK-8, flow cytometry, lentiviral overexpression/knockdown\",\n      \"journal\": \"Zhongguo shi yan xue ye xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single RIP with stability assay, single lab\",\n      \"pmids\": [\"34105460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In glioblastoma, RBM47 stabilizes mRNAs of inflammatory genes and activates the NF-κB pathway; NF-κB acts as a transcription factor that in turn enhances RBM47 transcription, forming a positive feedback loop that promotes M2 macrophage polarization in the tumor microenvironment.\",\n      \"method\": \"RNA-immunoprecipitation (RIP), ChIP, RNA sequencing, immunofluorescence, western blot\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP and ChIP supporting feedback loop, single lab\",\n      \"pmids\": [\"38518642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM47 interferes with the interaction between lncRNA HOXB-AS1 and p53 protein by directly binding HOXB-AS1, freeing p53 to enter the nucleus and activating p53 signaling in renal cell carcinoma; RBM47 expression is regulated by CBP/P300-mediated H3K27ac.\",\n      \"method\": \"RIP, Co-immunoprecipitation, nuclear fractionation, chromatin modification assay, functional assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RIP and Co-IP linking RBM47 to lncRNA-p53 axis, single lab\",\n      \"pmids\": [\"37660095\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM47 is a multi-functional RNA-binding protein with three RRM domains that acts primarily as an RNA chaperone: it binds intronic and 3'UTR sequences of diverse mRNA targets to regulate their splicing, stability, and abundance, serves as an essential cofactor (substituting for A1CF) in the APOBEC1-mediated C-to-U RNA editing complex, undergoes ISGylation at K329 (primed by S309 phosphorylation) to regulate immune gene expression, can function as a transcription factor at select gene promoters, and suppresses cancer progression in most epithelial contexts by stabilizing tumor-suppressor mRNAs (e.g., DKK1, AXIN1, IFNAR1, GSDMA) and promoting epithelial splicing programs (e.g., TJP1 exon 20 inclusion).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RBM47 is a three-RRM-domain RNA-binding protein that broadly regulates mRNA fate — splicing, stability, and editing — across epithelial, immune, and neural tissues. It binds predominantly to intronic and 3′UTR sequences of target mRNAs via GCAUG and AU-rich motifs, stabilizing transcripts such as DKK1, AXIN1, IFNAR1, and GSDMA to restrain Wnt/β-catenin signaling and promote epithelial identity, while also directing alternative splicing events including TJP1 exon 20 inclusion and SEC31A tissue-specific exon usage [PMID:24898756, PMID:31358901, PMID:40436629, PMID:41681975]. RBM47 serves as an essential cofactor of the APOBEC1 C-to-U RNA editing complex, where it can substitute for A1CF; intestine-specific Rbm47 knockout virtually eliminates apoB mRNA editing [PMID:24916387, PMID:30309881]. RBM47 undergoes ISGylation at K329, primed by S309 phosphorylation, to regulate immune gene expression, and its protein stability is itself controlled by OTUD4-mediated deubiquitination and m6A-dependent mRNA regulation [PMID:38036512, PMID:38553613].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Early work established that RBM47 is a bona fide RNA-binding protein (not DNA-binding) and placed it genetically upstream of Wnt signaling in head development, providing the first functional framework for the gene.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with wnt8a epistasis rescue and RNA-binding specificity assay\",\n      \"pmids\": [\"24038582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which RBM47 restrains Wnt8a signaling was not determined\", \"Direct RNA targets in zebrafish not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Transcriptome-wide binding maps revealed that RBM47 binds broadly to mRNA introns and 3′UTRs and regulates both splicing and mRNA stability, with DKK1 mRNA stabilization identified as a tumor-suppressive mechanism — establishing RBM47 as a multi-modal post-transcriptional regulator.\",\n      \"evidence\": \"HITS-CLIP in mammalian cell lines with mRNA stability assays and loss-of-function cancer models\",\n      \"pmids\": [\"24898756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise cis-elements for stability regulation not mapped\", \"In vivo tumor suppression not validated with genetic models at this point\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Concurrent biochemical work demonstrated that RBM47 physically associates with APOBEC1 and can substitute for A1CF as a cofactor for C-to-U RNA editing, revealing a second major molecular activity distinct from mRNA stabilization.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro RNA editing reconstitution, Rbm47 knockout mouse\",\n      \"pmids\": [\"24916387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RBM47–APOBEC1 interaction unknown\", \"Relative contribution of A1CF vs RBM47 in different tissues not yet resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tissue-specific conditional knockouts resolved the relative contributions of A1CF and RBM47 to RNA editing: RBM47 is the dominant editing cofactor in the intestine whereas liver editing depends on both cofactors, and double knockout eliminates nearly all APOBEC1-dependent editing.\",\n      \"evidence\": \"Intestine- and liver-specific conditional knockout mice with quantitative RNA editing assays\",\n      \"pmids\": [\"30309881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for tissue-specific cofactor selectivity not determined\", \"Non-apoB editing targets not fully characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The cis-regulatory logic of RBM47-dependent splicing was decoded: RBM47's first RRM domain recognizes a (U)GCAUG motif in flanking introns to promote TJP1 exon 20 inclusion, linking RBM47 loss to EMT-promoting isoform switching.\",\n      \"evidence\": \"Minigene splicing assays, RRM domain mutagenesis, isoform-specific functional rescue\",\n      \"pmids\": [\"31358901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GCAUG motif governs all RBM47-regulated splicing events is unknown\", \"Contribution of RRM2/RRM3 to splicing specificity not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Domain-mapping studies determined the minimal RBM47 regions required for APOBEC1-dependent editing and revealed species-specific differences in editing selectivity between human and mouse RBM47.\",\n      \"evidence\": \"HEK293T reconstitution with domain deletions and fluorescence-based editing assay\",\n      \"pmids\": [\"30844405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for species-specific selectivity not resolved\", \"Whether domain requirements differ for editing versus mRNA stability functions is untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"An unexpected transcription-factor-like activity was reported: RBM47 controls p53 promoter activity, adding a DNA-level regulatory mode to its repertoire, though this was at odds with earlier evidence of RNA-only binding.\",\n      \"evidence\": \"siRNA knockdown and p53 promoter-luciferase reporter assay\",\n      \"pmids\": [\"31511650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA binding by RBM47 at the p53 promoter was not demonstrated\", \"Transcription factor activity not reconciled with earlier finding that RBM47 does not bind DNA\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"RBM47's mRNA stabilization function was extended to the Wnt pathway negative regulator AXIN1 in NSCLC, providing a second mechanism (alongside DKK1) by which RBM47 suppresses Wnt/β-catenin signaling.\",\n      \"evidence\": \"RIP, mRNA stability assay, lentiviral knockdown with in vitro and in vivo tumor assays\",\n      \"pmids\": [\"32891348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific 3′UTR elements mediating AXIN1 stabilization not mapped\", \"Relative importance of DKK1 vs AXIN1 stabilization in Wnt suppression not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"RBM47 was shown to amplify type I interferon signaling by stabilizing IFNAR1 mRNA and retarding IFNAR1 protein degradation, establishing a role in antiviral innate immunity beyond its RNA editing and splicing functions.\",\n      \"evidence\": \"RIP, mRNA stability assay, multiple in vitro and in vivo virus infection models, ISRE reporter assay\",\n      \"pmids\": [\"34160127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IFNAR1 protein stabilization (whether direct or indirect) not fully resolved\", \"Relationship between IFNAR1 stabilization and APOBEC1 editing activity unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Intestine-specific Rbm47 knockout mice revealed that RBM47 restrains intestinal stem cell proliferation and Wnt signaling in vivo; paradoxically, loss protects against colitis-associated cancer but promotes spontaneous polyposis, demonstrating context-dependent tumor modulation.\",\n      \"evidence\": \"Intestine-specific conditional knockout mice, organoids, ApcMin/+ crosses, radiation and chemical injury models\",\n      \"pmids\": [\"37014710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets responsible for the paradoxical polyposis phenotype not identified\", \"Whether splicing or stability targets drive the proliferative phenotype not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A new post-translational regulatory layer was uncovered: RBM47 undergoes ISGylation at K329 (dependent on S309 phosphorylation), and K329R knockin mice show impaired immune activation, linking a specific PTM to RBM47's immune-regulatory output.\",\n      \"evidence\": \"K329R knockin mouse model, site-specific nanobody-targeted E3 ligase ISGylation, immune phenotyping\",\n      \"pmids\": [\"38036512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ISGylation alters RBM47 RNA-binding or protein interactions is unknown\", \"Kinase responsible for S309 phosphorylation not identified beyond epinephrine stimulus\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"RBM47 protein stability was shown to be regulated by OTUD4-mediated deubiquitination, revealing that RBM47's tumor-suppressive output is itself controlled at the protein turnover level.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, mRNA stability assay, in vivo rescue in ccRCC\",\n      \"pmids\": [\"38553613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ubiquitin ligase targeting RBM47 for degradation not identified\", \"Whether OTUD4 regulation is tissue-specific is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"RBM47 was identified as a tissue-specific splicing regulator of SEC31A, a COPII coat component, linking RBM47's splicing activity to lipid transport and vesicular trafficking — extending its function beyond cancer and immunity.\",\n      \"evidence\": \"Cross-tissue RNA-seq correlation analysis with experimental splicing validation and lipid transport assay\",\n      \"pmids\": [\"40436629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cis-elements in SEC31A pre-mRNA recognized by RBM47 not mapped\", \"Physiological consequence of SEC31A mis-splicing in Rbm47-null animals not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for RBM47's dual role in RNA editing versus mRNA stabilization, whether the reported transcription factor activity represents direct DNA binding, and the full spectrum of tissue-specific splicing programs controlled by RBM47 in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of RBM47 alone or in complex with APOBEC1\", \"Direct DNA-binding activity contradicts earlier RNA-specificity data and has not been reconciled\", \"Genome-wide splicing maps in Rbm47-knockout tissues not yet generated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 3, 6, 7, 8, 13, 16, 19, 21, 23, 24, 25, 26]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 9, 32]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008953854\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 24]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 24]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 8, 17, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 12, 13, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 9, 11]}\n    ],\n    \"complexes\": [\n      \"APOBEC1 editosome\"\n    ],\n    \"partners\": [\n      \"APOBEC1\",\n      \"A1CF\",\n      \"hnRNPM\",\n      \"OTUD4\",\n      \"MAVS\",\n      \"RUNX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}