{"gene":"RBM25","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2008,"finding":"RBM25 binds directly to a CGGGCA sequence within exon 2 of BCL-x pre-mRNA and stimulates proapoptotic Bcl-xS 5' splice site selection in a dose-dependent manner; mutation of the CGGGCA element abolished Bcl-xS isoform promotion. RBM25 binding promotes recruitment of U1 snRNP to the weak 5' splice site and is not required when a strong consensus 5' ss is present.","method":"RNA binding assay, site-directed mutagenesis of exonic element, U1 snRNP recruitment assay, dose-dependent overexpression/depletion experiments","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (RNA binding, mutagenesis, U1 snRNP recruitment, co-IP with hLuc7A), replicated phenotype with both gain- and loss-of-function","pmids":["18663000"],"is_preprint":false},{"year":2008,"finding":"RBM25 selectively associates with the human homolog of yeast U1 snRNP-associated factor hLuc7A, suggesting RBM25 stabilizes pre-mRNA-U1 snRNP interactions through hLuc7A to activate weak 5' splice site selection.","method":"Co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP but supported by functional mutagenesis data in same paper","pmids":["18663000"],"is_preprint":false},{"year":2011,"finding":"RBM25 (together with LUC7L3) mediates truncation of SCN5A (cardiac sodium channel) mRNA in Jurkat cells and human embryonic stem cell-derived cardiomyocytes; overexpression of either splicing factor increased truncated SCN5A mRNA and decreased full-length SCN5A transcript and Na+ channel current by ~91%.","method":"Gene array, overexpression in Jurkat cells and hESC-derived cardiomyocytes, mRNA/protein quantification, electrophysiology","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (expression, functional splicing assay, electrophysiology) in relevant human cardiac model","pmids":["21859973"],"is_preprint":false},{"year":2012,"finding":"Angiotensin II and hypoxia (signals common to heart failure) increase LUC7L3 and RBM25 levels, resulting in increased RBM25 binding to SCN5A mRNA, increased SCN5A splice variants, and decreased full-length SCN5A mRNA, protein, and Na+ current.","method":"RIP (RNA immunoprecipitation), qPCR, Western blot, electrophysiology in cardiac cells treated with angiotensin II/hypoxia","journal":"Trends in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus functional readout, single lab","pmids":["22939879"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of the RBM25 PWI domain and its flanking basic region revealed a conserved four-helix bundle; the flanking basic region forms two alpha-helices that associate with helix H4 of the PWI domain, enlarging the nucleic-acid-binding platform. Structure-guided mutagenesis identified a positively charged nucleic-acid-binding surface distinct from SRm160 PWI domain. The PWI domain is required in vivo for promotion of pro-apoptotic Bcl-xS isoform expression.","method":"X-ray crystallography, structure-guided mutagenesis, in vivo splicing reporter assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis and functional validation, single lab but multiple orthogonal methods","pmids":["23190262"],"is_preprint":false},{"year":2017,"finding":"RBM25 is required for viability of multiple human cell lines and globally promotes inclusion of alternatively spliced exons across the human transcriptome. Proteomic analysis showed RBM25 interacts with components of the early spliceosome and regulators of alternative splicing. RBM25 is mono-methylated at lysine 77 (RBM25-K77me1); the region spanning K77 binds SRSF2 (crucial for exon definition) with high affinity only when K77 is unmethylated, providing a mechanism by which lysine methylation regulates RBM25 activity.","method":"shRNA knockdown viability assays, transcriptome-wide RNA-seq splicing analysis, quantitative mass spectrometry (proteomics), affinity binding assay for SRSF2 interaction with methylated vs. unmethylated peptides","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (transcriptomics, proteomics, mass spectrometry, biochemical binding assay), comprehensive mechanistic dissection in one study","pmids":["28655759"],"is_preprint":false},{"year":2019,"finding":"RBM25 controls alternative splicing of BCL-X (promoting pro-apoptotic Bcl-xS) and BIN1 (MYC inhibitor) in AML cells; knockdown of RBM25 promotes proliferation, decreases apoptosis, and increases MYC activity. RBM25 acts as a tumor suppressor in AML and was identified via in vivo shRNA screen in a mouse model of CEBPA-mutant AML.","method":"In vivo shRNA screen, splicing analysis by RT-PCR, knockdown in multiple human leukemic cell lines with proliferation/apoptosis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo shRNA screen validated in multiple human cell lines with mechanistic splicing readout","pmids":["30635567"],"is_preprint":false},{"year":2018,"finding":"RBM25 binds directly to circAMOTL1L RNA and induces its biogenesis; p53 activates RBM25 gene transcription, thereby regulating EMT via the circAMOTL1L-miR-193a-5p-Pcdha pathway in prostate cancer cells.","method":"RNA immunoprecipitation (RIP), p53 ChIP/reporter assay, circRNA overexpression/knockdown with EMT marker analysis, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RIP showing direct binding plus functional rescue, single lab; note: the circRNA is the primary focus but RBM25 mechanism is experimentally established","pmids":["30531834"],"is_preprint":false},{"year":2023,"finding":"RBM25 directly and specifically binds to GQ-2, an RNA G-quadruplex (rG4) of BCL-x pre-mRNA located near the alternative 5' splice site for Bcl-xS, through its RE (arginine-glutamate-rich) motif; this RBM25/rG4 interaction is required for Bcl-xS production. G4 ligands (PhenDC3, PhenDH8, PhenDH9) that enhance RBM25 binding to GQ-2 promote Bcl-xS isoform and apoptosis.","method":"RNA binding assays (EMSA/pull-down with rG4), domain mutagenesis (RE motif), splicing reporter assays, ligand screening with G4-stabilizing compounds","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding demonstrated with mutagenesis of both RNA element and protein domain, functionally validated with pharmacological perturbation","pmids":["37811881"],"is_preprint":false},{"year":2023,"finding":"RBM25 directly binds to ACLY pre-mRNA and mediates skipping of exon 14, generating two distinct Acly isoforms (Acly L and Acly S). In proinflammatory macrophages, Acly L (but not Acly S) undergoes protein lactylation at K918/K995, affecting metabolic substrate affinity. RBM25 deficiency shifts splicing toward Acly S, enhancing glycolysis and acetyl-CoA production for epigenetic remodeling and macrophage overactivation. Macrophage-specific RBM25 knockout leads to spontaneous arthritis in mice.","method":"RBM25 KO mice (conditional, macrophage-specific), multiomics (RNA-seq, proteomics, ChIP-seq), RIP, in vivo arthritis model, Acly inhibitor rescue","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional KO with defined molecular mechanism (splicing, PTM, metabolic rewiring, epigenetic remodeling), multiple orthogonal methods","pmids":["39251781"],"is_preprint":false},{"year":2023,"finding":"METTL3-mediated m6A methylation of RBM25 mRNA stabilizes RBM25 mRNA and maintains its expression in multiple myeloma cells; metformin reduces METTL3 activity, thereby decreasing m6A on RBM25 mRNA and reducing RBM25 mRNA stability and expression. RBM25 knockdown reverses METTL3-overexpression-driven MM cell malignancy.","method":"MeRIP (m6A immunoprecipitation), METTL3 knockdown/overexpression, mRNA stability assay, rescue experiments, in vivo xenograft","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP with rescue experiments, single lab","pmids":["36762777"],"is_preprint":false},{"year":2023,"finding":"RBM25 is localized to the nucleus in cardiomyocytes both in vitro and in vivo under hypoxia/ischemic conditions; ER stress stimulates RBM25 upregulation and promotes apoptosis via the CHOP signaling pathway. RBM25 knockdown blocks CHOP activation and reduces apoptosis, improving cardiac function.","method":"Immunofluorescence (nuclear localization), Western blot, ER-tracker, siRNA knockdown in OGD model and in vivo ischemic HF rat model, TUNEL, echocardiography","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization experiment combined with loss-of-function phenotype and defined pathway (CHOP), single lab","pmids":["37736860"],"is_preprint":false},{"year":2023,"finding":"RBM25 binds to a poly-G-rich region in exon 14a of MNK2 pre-mRNA (shown by iRIP-seq and validated by RT-PCR), inhibiting the proximal 3' splice site and producing the oncogenic short isoform MNK2b. RBM25 depletion shifts splicing to the MNK2a isoform; re-expression of MNK2b or ASO-blocking of the alternative splice site rescues the tumor suppression from RBM25 knockdown.","method":"iRIP-seq, RNA-seq, RT-PCR splicing assays, shRNA knockdown, ASO rescue, in vitro and in vivo tumor growth assays","journal":"Science China. Life sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — iRIP-seq binding site identification with functional splice switching validated by ASO and re-expression rescue experiments","pmids":["39110401"],"is_preprint":false},{"year":2023,"finding":"RBM25 binds to Slc38a9, Csf1, and Coro6 mRNAs (identified by iRIP-seq) and regulates their alternative splicing in H9c2 cardiomyocytes, linking RBM25 to cardiac inflammatory responses.","method":"iRIP-seq, RNA-seq, RT-qPCR validation","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — iRIP-seq binding with RT-qPCR validation, single lab, limited functional follow-up","pmids":["37953772"],"is_preprint":false},{"year":2024,"finding":"dCasRx fused to RBM25 (dCasRx-RBM25) functions as a potent activator of exon inclusion; it efficiently activates ~90% of targeted endogenous alternative exons with high on-target specificity, identified through screening >300 dCasRx-splicing factor fusion proteins.","method":"CRISPR-dCasRx fusion protein screen with splicing reporters, endogenous alternative exon activation assays, gRNA array combinatorial targeting, RNA-seq specificity analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic screen validated on endogenous targets with transcriptome-wide specificity profiling, multiple targets across cell types","pmids":["38917795"],"is_preprint":false},{"year":2025,"finding":"RBM25 induces exon 16 skipping in MAP4K4 pre-mRNA (confirmed by qPCR), generating a truncated isoform predicted to enhance MAP3K1 binding and activate the p38 MAPK/ERK pathway; RBM25 overexpression exacerbates post-infarction heart failure via this MAP4K4 splicing-dependent MAPK activation, while RBM25 knockdown is cardioprotective. P38 MAPK inhibitor (SB203580) attenuated RBM25-mediated injury.","method":"Lentiviral OE/KD in rat LAD ligation model, qPCR, echocardiography, Western blot for MAPK phosphorylation, TUNEL, pharmacological rescue with SB203580","journal":"FASEB bioAdvances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain/loss of function with defined splice event and pathway inhibitor rescue, single lab, computational prediction of isoform consequence","pmids":["41409803"],"is_preprint":false},{"year":2025,"finding":"RBM25 promotes HBV replication by binding to cccDNA through its RE/RD and PWI domains, upregulating Yin Yang 1 (YY1) expression, which enhances acetylation of cccDNA-bound histones to promote HBV transcription. HBV core protein accumulation causes nuclear translocation of RBM25, while RBM25 overexpression promotes core protein degradation, establishing a reciprocal regulatory loop.","method":"ChIP on cccDNA, domain deletion/mutagenesis (RE/RD and PWI), RBM25 KD/OE in HBV-replicating and infected cell models and mouse hydrodynamic injection model, promoter activity assays, histone acetylation assays","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with domain mutagenesis validated in vivo, single lab, non-splicing role requiring mechanistic characterization of chromatin binding","pmids":["40412480"],"is_preprint":false},{"year":2025,"finding":"lnc-536 acts as a decoy for RBM25 in pulmonary artery smooth muscle cells; when lnc-536 is elevated, it sequesters RBM25 away from SFPQ (splicing factor proline/glutamine-rich), which in turn reduces SFPQ-HOXB13 mRNA interaction, decreasing HOXB13 expression and driving PASMC hyperproliferation. RBM25 knockdown increases SFPQ-HOXB13 mRNA interaction and attenuates PASMC proliferation.","method":"lncRNA pull-down, RNA immunoprecipitation (SFPQ antibody), RBM25 knockdown with proliferation assays, in vivo GapmeR antisense oligo in PAH rat models","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNA pull-down and RIP combined with in vivo rescue, single lab","pmids":["40567228"],"is_preprint":false},{"year":2025,"finding":"Rbm25 occupies promoters of pluripotency- and DNA methylation-related genes in embryonic stem cells and directly regulates their transcription; deletion or depletion of Rbm25 impairs ESC self-renewal and promotes transition to 2-cell-like cells (2CLCs) by altering the epigenetic state of ESCs, revealing a transcriptional (non-splicing) regulatory role.","method":"ChIP-seq (promoter occupancy), Rbm25 knockout/knockdown in ESCs, RNA-seq, 2CLC reporter assay","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with KO phenotype, single lab, novel non-splicing role","pmids":["41455468"],"is_preprint":false},{"year":2023,"finding":"Rbm25 knockdown in vitro and in vivo accelerates clonal expansion of Tet2-knockout hematopoietic stem cells, placing Rbm25 as a downstream mediator of Tet2-loss-induced heterogeneous preleukemic clonal expansion.","method":"Genetic barcoding in conditional Tet2 KO mice, shRNA knockdown of Rbm25 in vitro and in vivo, hematopoietic colony assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Rbm25 KD in Tet2 KO background) with in vivo clonal tracking, single lab","pmids":["36947858"],"is_preprint":false},{"year":2026,"finding":"Conditional (homozygous) knockout of Rbm25 in mice causes collapse of multiple hematopoietic lineages including long-term hematopoietic stem cells, demonstrating that Rbm25 is essential for normal murine hematopoiesis. Mono-allelic deletion does not impair HSC self-renewal even under proliferative stress, showing Rbm25 is haplosufficient.","method":"Conditional knockout mouse model, bone marrow transplantation, flow cytometry of hematopoietic lineages","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined hematopoietic phenotype and haploinsufficiency test, in vivo model","pmids":["41819468"],"is_preprint":false}],"current_model":"RBM25 is an RNA-binding splicing factor that directly binds specific pre-mRNA elements (including CGGGCA sequences and RNA G-quadruplexes) to promote inclusion of alternative exons and activate weak 5' splice sites by recruiting U1 snRNP via hLuc7A; it globally regulates alternative splicing of apoptotic (BCL-X, MNK2), metabolic (ACLY), cardiac ion channel (SCN5A, MAP4K4), and immunoregulatory transcripts, while its activity is modulated by lysine mono-methylation at K77 (blocking SRSF2 binding) and by METTL3-mediated m6A modification of its own mRNA; in addition to splicing, RBM25 occupies gene promoters to regulate transcription in stem cells and binds HBV cccDNA via its PWI/RE domains to promote viral transcription."},"narrative":{"mechanistic_narrative":"RBM25 is an RNA-binding splicing factor that directly recognizes specific pre-mRNA elements—including CGGGCA sequences, poly-G-rich motifs, and RNA G-quadruplexes—to control alternative splice site selection across the transcriptome [PMID:18663000, PMID:37811881, PMID:39110401]. At the BCL-x locus it binds an exonic CGGGCA element and an adjacent RNA G-quadruplex (GQ-2) near the alternative 5' splice site through its RE motif to promote the pro-apoptotic Bcl-xS isoform, recruiting U1 snRNP to the otherwise weak 5' splice site via association with hLuc7A [PMID:18663000, PMID:37811881]. Its crystallized PWI domain and flanking basic region form a positively charged nucleic-acid-binding platform required in vivo for this splicing activity [PMID:23190262]. Genome-wide, RBM25 is required for cell viability, interacts with early spliceosome components, and globally promotes alternative exon inclusion, an activity directly harnessed in the dCasRx-RBM25 programmable exon-inclusion tool [PMID:28655759, PMID:38917795]. Through these splicing programs RBM25 acts as a tumor suppressor in AML by controlling BCL-X and BIN1 splicing to restrain MYC activity, governs macrophage metabolism via ACLY exon-14 skipping, and regulates cardiac function by reshaping SCN5A, MNK2, and MAP4K4 transcripts [PMID:21859973, PMID:30635567, PMID:39251781, PMID:39110401, PMID:41409803]. RBM25 activity is itself regulated post-translationally by lysine-77 mono-methylation, which blocks high-affinity binding to the exon-definition factor SRSF2, and at the transcript level by METTL3-mediated m6A modification that stabilizes RBM25 mRNA [PMID:28655759, PMID:36762777]. Beyond splicing, RBM25 occupies gene promoters to directly regulate transcription in embryonic stem cells and binds HBV cccDNA through its RE/RD and PWI domains to promote viral transcription [PMID:41455468, PMID:40412480]. Conditional knockout establishes that Rbm25 is essential for murine hematopoiesis, with collapse of multiple lineages including long-term hematopoietic stem cells [PMID:41819468].","teleology":[{"year":2008,"claim":"Established that RBM25 is a sequence-specific splicing regulator that activates a weak 5' splice site, answering how an exonic element directs apoptotic isoform choice.","evidence":"RNA binding, mutagenesis of the BCL-x CGGGCA element, U1 snRNP recruitment, and Co-IP with hLuc7A","pmids":["18663000"],"confidence":"High","gaps":["hLuc7A interaction shown by single Co-IP without reciprocal validation","scope beyond BCL-x not yet defined at this stage"]},{"year":2011,"claim":"Extended RBM25's regulatory reach to cardiac ion channels, showing it drives truncation of SCN5A mRNA with functional consequences for sodium current.","evidence":"Gene array, overexpression in Jurkat and hESC-derived cardiomyocytes, mRNA/protein quantification, and electrophysiology","pmids":["21859973"],"confidence":"High","gaps":["binding site on SCN5A not mapped","physiological trigger for this splicing not yet identified"]},{"year":2012,"claim":"Linked RBM25-mediated SCN5A splicing to pathophysiological signaling, showing heart-failure cues raise RBM25 levels and binding.","evidence":"RIP, qPCR, Western blot, and electrophysiology in cardiac cells treated with angiotensin II/hypoxia","pmids":["22939879"],"confidence":"Medium","gaps":["single lab","upstream signaling connecting stimuli to RBM25 induction unresolved"]},{"year":2013,"claim":"Defined the structural basis of RBM25 nucleic-acid binding, showing the PWI domain plus flanking basic region forms an enlarged binding surface required for splicing function.","evidence":"X-ray crystallography, structure-guided mutagenesis, and in vivo Bcl-x splicing reporter","pmids":["23190262"],"confidence":"High","gaps":["no co-structure with RNA","contribution of other RBM25 domains to specificity not resolved"]},{"year":2017,"claim":"Placed RBM25 in the global splicing machinery and uncovered methylation-based regulation, showing K77 mono-methylation blocks SRSF2 binding.","evidence":"shRNA viability assays, transcriptome-wide RNA-seq, quantitative proteomics, and methylated-peptide affinity binding for SRSF2","pmids":["28655759"],"confidence":"High","gaps":["methyltransferase/demethylase acting on K77 not identified","functional output of SRSF2 displacement in vivo not quantified"]},{"year":2018,"claim":"Connected RBM25 to circular RNA biogenesis and p53 signaling, broadening its RNA-processing repertoire in cancer.","evidence":"RIP, p53 ChIP/reporter, circRNA perturbation with EMT readouts, and xenograft","pmids":["30531834"],"confidence":"Medium","gaps":["circRNA is primary focus, RBM25 mechanism less developed","single lab"]},{"year":2019,"claim":"Defined RBM25 as a tumor suppressor in AML, showing its splicing of BCL-X and BIN1 restrains MYC-driven proliferation.","evidence":"In vivo shRNA screen in CEBPA-mutant AML, RT-PCR splicing analysis, and knockdown proliferation/apoptosis assays in multiple leukemic lines","pmids":["30635567"],"confidence":"High","gaps":["direct BIN1 binding site not mapped","whether MYC effect is solely splicing-mediated unresolved"]},{"year":2023,"claim":"Resolved the RNA structural element underlying Bcl-xS production, showing RBM25's RE motif binds a G-quadruplex that is pharmacologically tractable.","evidence":"EMSA/pull-down with rG4, RE-motif mutagenesis, splicing reporters, and G4-ligand screening","pmids":["37811881"],"confidence":"High","gaps":["generality of rG4 recognition across other RBM25 targets not established"]},{"year":2023,"claim":"Revealed a splicing-metabolism-epigenetic axis, showing RBM25 controls ACLY isoform choice to limit macrophage overactivation and autoimmunity.","evidence":"Macrophage-specific conditional KO, multiomics, RIP, arthritis model, and ACLY inhibitor rescue","pmids":["39251781"],"confidence":"High","gaps":["RBM25 binding determinants on ACLY pre-mRNA not detailed","relevance to human inflammatory disease not tested"]},{"year":2023,"claim":"Identified upstream control of RBM25 abundance, showing METTL3-mediated m6A stabilizes RBM25 mRNA in multiple myeloma.","evidence":"MeRIP, METTL3 perturbation, mRNA stability assays, rescue, and xenograft","pmids":["36762777"],"confidence":"Medium","gaps":["m6A reader mediating stabilization not identified","single lab"]},{"year":2023,"claim":"Established a stress-responsive pro-apoptotic role in cardiomyocytes via the CHOP pathway, with confirmed nuclear localization.","evidence":"Immunofluorescence, ER-tracker, siRNA knockdown in OGD and ischemic HF rat models, TUNEL, and echocardiography","pmids":["37736860"],"confidence":"Medium","gaps":["mechanism linking RBM25 to CHOP not defined","splicing targets in this context not identified"]},{"year":2023,"claim":"Mapped additional cardiac splicing targets, expanding RBM25's role in cardiac inflammatory transcript processing.","evidence":"iRIP-seq, RNA-seq, and RT-qPCR validation in H9c2 cardiomyocytes","pmids":["37953772"],"confidence":"Medium","gaps":["limited functional follow-up","phenotypic consequence of these splicing changes untested"]},{"year":2023,"claim":"Showed RBM25 controls MNK2 splicing to favor an oncogenic isoform, mechanistically validated by splice-switching rescue.","evidence":"iRIP-seq, RT-PCR splicing assays, shRNA knockdown, ASO rescue, and tumor growth assays","pmids":["39110401"],"confidence":"High","gaps":["structural basis of poly-G recognition in MNK2 not resolved"]},{"year":2023,"claim":"Positioned Rbm25 within preleukemic clonal dynamics as a downstream mediator of Tet2 loss.","evidence":"Genetic barcoding in Tet2 KO mice with shRNA knockdown and colony assays","pmids":["36947858"],"confidence":"Medium","gaps":["molecular effector linking Rbm25 to clonal expansion unknown","single lab"]},{"year":2024,"claim":"Demonstrated RBM25 is a portable exon-inclusion activator, repurposing its splicing function as a programmable tool.","evidence":"dCasRx-RBM25 fusion screen across >300 splicing factors with endogenous exon activation and transcriptome-wide specificity profiling","pmids":["38917795"],"confidence":"High","gaps":["intrinsic domain conferring activator potency not dissected here"]},{"year":2025,"claim":"Defined a cardiac injury mechanism whereby RBM25-driven MAP4K4 splicing activates p38 MAPK/ERK signaling.","evidence":"Lentiviral OE/KD in rat LAD ligation model, qPCR, MAPK phospho-blots, TUNEL, and SB203580 rescue","pmids":["41409803"],"confidence":"Medium","gaps":["isoform consequence partly computational","single lab"]},{"year":2025,"claim":"Uncovered a non-splicing role for RBM25 in viral chromatin, showing direct cccDNA binding promotes HBV transcription via YY1 and histone acetylation.","evidence":"ChIP on cccDNA, RE/RD and PWI domain mutagenesis, KD/OE in HBV models, and mouse hydrodynamic injection","pmids":["40412480"],"confidence":"Medium","gaps":["mechanism of cccDNA/chromatin recruitment not fully defined","single lab"]},{"year":2025,"claim":"Showed RBM25 can be functionally sequestered by a decoy lncRNA, modulating SFPQ-dependent HOXB13 regulation in vascular cells.","evidence":"lncRNA pull-down, SFPQ RIP, knockdown proliferation assays, and in vivo GapmeR in PAH rat models","pmids":["40567228"],"confidence":"Medium","gaps":["direct RBM25-SFPQ interaction interface not mapped","single lab"]},{"year":2025,"claim":"Revealed a transcriptional (non-splicing) role, showing Rbm25 occupies pluripotency-gene promoters to maintain ESC self-renewal.","evidence":"ChIP-seq promoter occupancy, Rbm25 KO/KD in ESCs, RNA-seq, and 2CLC reporter","pmids":["41455468"],"confidence":"Medium","gaps":["how an RNA-binding protein is recruited to promoters unresolved","single lab"]},{"year":2026,"claim":"Established RBM25 as essential and haplosufficient for hematopoiesis, defining its in vivo requirement in stem cells.","evidence":"Conditional knockout mouse, bone marrow transplantation, and flow cytometry of hematopoietic lineages","pmids":["41819468"],"confidence":"High","gaps":["splicing targets responsible for HSC collapse not identified"]},{"year":null,"claim":"How RBM25 partitions between its splicing, promoter-transcriptional, and chromatin/cccDNA-binding functions—and what determines target selection in each—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unified model of recruitment to promoters vs. pre-mRNA","enzymes regulating K77 methylation not identified","in vivo splicing targets underlying organismal phenotypes largely undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,8,12,13]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,5,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[16,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,16,18]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,5,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[16,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,6,11]}],"complexes":["spliceosome (early/U1 snRNP-associated)"],"partners":["LUC7L3","SRSF2","SFPQ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49756","full_name":"RNA-binding protein 25","aliases":["Arg/Glu/Asp-rich protein of 120 kDa","RED120","Protein S164","RNA-binding motif protein 25","RNA-binding region-containing protein 7"],"length_aa":843,"mass_kda":100.2,"function":"RNA-binding protein that acts as a regulator of alternative pre-mRNA splicing. Involved in apoptotic cell death through the regulation of the apoptotic factor BCL2L1 isoform expression. Modulates the ratio of proapoptotic BCL2L1 isoform S to antiapoptotic BCL2L1 isoform L mRNA expression. When overexpressed, stimulates proapoptotic BCL2L1 isoform S 5'-splice site (5'-ss) selection, whereas its depletion caused the accumulation of antiapoptotic BCL2L1 isoform L. Promotes BCL2L1 isoform S 5'-ss usage through the 5'-CGGGCA-3' RNA sequence. Its association with LUC7L3 promotes U1 snRNP binding to a weak 5' ss in a 5'-CGGGCA-3'-dependent manner. Binds to the exonic splicing enhancer 5'-CGGGCA-3' RNA sequence located within exon 2 of the BCL2L1 pre-mRNA. Also involved in the generation of an abnormal and truncated splice form of SCN5A in heart failure","subcellular_location":"Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P49756/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM25","classification":"Common Essential","n_dependent_lines":1200,"n_total_lines":1208,"dependency_fraction":0.9933774834437086},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000119707","cell_line_id":"CID001478","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"MARK4","stoichiometry":10.0},{"gene":"PLK1","stoichiometry":4.0},{"gene":"PRKD2","stoichiometry":4.0},{"gene":"PRPF4B","stoichiometry":4.0},{"gene":"PRPF40A","stoichiometry":4.0},{"gene":"AMBRA1","stoichiometry":0.2},{"gene":"HUS1","stoichiometry":0.2},{"gene":"LMNB1","stoichiometry":0.2},{"gene":"MARK2","stoichiometry":0.2},{"gene":"NRBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001478","total_profiled":1310},"omim":[{"mim_id":"612427","title":"RNA-BINDING MOTIF PROTEIN 25; RBM25","url":"https://www.omim.org/entry/612427"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM25"},"hgnc":{"alias_symbol":["S164","fSAP94","NET52","Snu71"],"prev_symbol":["RNPC7"]},"alphafold":{"accession":"P49756","domains":[{"cath_id":"3.30.70.330","chopping":"86-161","consensus_level":"high","plddt":91.283,"start":86,"end":161},{"cath_id":"1.20.1390.10","chopping":"745-838","consensus_level":"high","plddt":87.6499,"start":745,"end":838},{"cath_id":"1.20.5","chopping":"515-570","consensus_level":"medium","plddt":86.6191,"start":515,"end":570}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49756","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49756-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49756-F1-predicted_aligned_error_v6.png","plddt_mean":67.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM25","jax_strain_url":"https://www.jax.org/strain/search?query=RBM25"},"sequence":{"accession":"P49756","fasta_url":"https://rest.uniprot.org/uniprotkb/P49756.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49756/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49756"}},"corpus_meta":[{"pmid":"30531834","id":"PMC_30531834","title":"Dysregulation of p53-RBM25-mediated circAMOTL1L biogenesis contributes to prostate cancer progression through the circAMOTL1L-miR-193a-5p-Pcdha pathway.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30531834","citation_count":156,"is_preprint":false},{"pmid":"18663000","id":"PMC_18663000","title":"Novel splicing factor RBM25 modulates Bcl-x pre-mRNA 5' splice site selection.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18663000","citation_count":117,"is_preprint":false},{"pmid":"21859973","id":"PMC_21859973","title":"Role of RBM25/LUC7L3 in abnormal cardiac sodium channel splicing regulation in human heart failure.","date":"2011","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/21859973","citation_count":79,"is_preprint":false},{"pmid":"30635567","id":"PMC_30635567","title":"The splicing factor RBM25 controls MYC activity in acute myeloid leukemia.","date":"2019","source":"Nature 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phosphorylation at both S139 and S164 is required for 14-3-3 binding.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28943433","citation_count":13,"is_preprint":false},{"pmid":"37728157","id":"PMC_37728157","title":"RBM25 induces trophoblast epithelial-mesenchymal transition and preeclampsia disorder by enhancing the positive feedback loop between Grhl2 and RBM25.","date":"2023","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/37728157","citation_count":9,"is_preprint":false},{"pmid":"39110401","id":"PMC_39110401","title":"RBM25 depletion suppresses the growth of colon cancer cells through regulating alternative splicing of MNK2.","date":"2024","source":"Science China. 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RBM25 binding promotes recruitment of U1 snRNP to the weak 5' splice site and is not required when a strong consensus 5' ss is present.\",\n      \"method\": \"RNA binding assay, site-directed mutagenesis of exonic element, U1 snRNP recruitment assay, dose-dependent overexpression/depletion experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (RNA binding, mutagenesis, U1 snRNP recruitment, co-IP with hLuc7A), replicated phenotype with both gain- and loss-of-function\",\n      \"pmids\": [\"18663000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RBM25 selectively associates with the human homolog of yeast U1 snRNP-associated factor hLuc7A, suggesting RBM25 stabilizes pre-mRNA-U1 snRNP interactions through hLuc7A to activate weak 5' splice site selection.\",\n      \"method\": \"Co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP but supported by functional mutagenesis data in same paper\",\n      \"pmids\": [\"18663000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RBM25 (together with LUC7L3) mediates truncation of SCN5A (cardiac sodium channel) mRNA in Jurkat cells and human embryonic stem cell-derived cardiomyocytes; overexpression of either splicing factor increased truncated SCN5A mRNA and decreased full-length SCN5A transcript and Na+ channel current by ~91%.\",\n      \"method\": \"Gene array, overexpression in Jurkat cells and hESC-derived cardiomyocytes, mRNA/protein quantification, electrophysiology\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (expression, functional splicing assay, electrophysiology) in relevant human cardiac model\",\n      \"pmids\": [\"21859973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Angiotensin II and hypoxia (signals common to heart failure) increase LUC7L3 and RBM25 levels, resulting in increased RBM25 binding to SCN5A mRNA, increased SCN5A splice variants, and decreased full-length SCN5A mRNA, protein, and Na+ current.\",\n      \"method\": \"RIP (RNA immunoprecipitation), qPCR, Western blot, electrophysiology in cardiac cells treated with angiotensin II/hypoxia\",\n      \"journal\": \"Trends in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus functional readout, single lab\",\n      \"pmids\": [\"22939879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of the RBM25 PWI domain and its flanking basic region revealed a conserved four-helix bundle; the flanking basic region forms two alpha-helices that associate with helix H4 of the PWI domain, enlarging the nucleic-acid-binding platform. Structure-guided mutagenesis identified a positively charged nucleic-acid-binding surface distinct from SRm160 PWI domain. The PWI domain is required in vivo for promotion of pro-apoptotic Bcl-xS isoform expression.\",\n      \"method\": \"X-ray crystallography, structure-guided mutagenesis, in vivo splicing reporter assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis and functional validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23190262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM25 is required for viability of multiple human cell lines and globally promotes inclusion of alternatively spliced exons across the human transcriptome. Proteomic analysis showed RBM25 interacts with components of the early spliceosome and regulators of alternative splicing. RBM25 is mono-methylated at lysine 77 (RBM25-K77me1); the region spanning K77 binds SRSF2 (crucial for exon definition) with high affinity only when K77 is unmethylated, providing a mechanism by which lysine methylation regulates RBM25 activity.\",\n      \"method\": \"shRNA knockdown viability assays, transcriptome-wide RNA-seq splicing analysis, quantitative mass spectrometry (proteomics), affinity binding assay for SRSF2 interaction with methylated vs. unmethylated peptides\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (transcriptomics, proteomics, mass spectrometry, biochemical binding assay), comprehensive mechanistic dissection in one study\",\n      \"pmids\": [\"28655759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RBM25 controls alternative splicing of BCL-X (promoting pro-apoptotic Bcl-xS) and BIN1 (MYC inhibitor) in AML cells; knockdown of RBM25 promotes proliferation, decreases apoptosis, and increases MYC activity. RBM25 acts as a tumor suppressor in AML and was identified via in vivo shRNA screen in a mouse model of CEBPA-mutant AML.\",\n      \"method\": \"In vivo shRNA screen, splicing analysis by RT-PCR, knockdown in multiple human leukemic cell lines with proliferation/apoptosis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo shRNA screen validated in multiple human cell lines with mechanistic splicing readout\",\n      \"pmids\": [\"30635567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBM25 binds directly to circAMOTL1L RNA and induces its biogenesis; p53 activates RBM25 gene transcription, thereby regulating EMT via the circAMOTL1L-miR-193a-5p-Pcdha pathway in prostate cancer cells.\",\n      \"method\": \"RNA immunoprecipitation (RIP), p53 ChIP/reporter assay, circRNA overexpression/knockdown with EMT marker analysis, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RIP showing direct binding plus functional rescue, single lab; note: the circRNA is the primary focus but RBM25 mechanism is experimentally established\",\n      \"pmids\": [\"30531834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM25 directly and specifically binds to GQ-2, an RNA G-quadruplex (rG4) of BCL-x pre-mRNA located near the alternative 5' splice site for Bcl-xS, through its RE (arginine-glutamate-rich) motif; this RBM25/rG4 interaction is required for Bcl-xS production. G4 ligands (PhenDC3, PhenDH8, PhenDH9) that enhance RBM25 binding to GQ-2 promote Bcl-xS isoform and apoptosis.\",\n      \"method\": \"RNA binding assays (EMSA/pull-down with rG4), domain mutagenesis (RE motif), splicing reporter assays, ligand screening with G4-stabilizing compounds\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding demonstrated with mutagenesis of both RNA element and protein domain, functionally validated with pharmacological perturbation\",\n      \"pmids\": [\"37811881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM25 directly binds to ACLY pre-mRNA and mediates skipping of exon 14, generating two distinct Acly isoforms (Acly L and Acly S). In proinflammatory macrophages, Acly L (but not Acly S) undergoes protein lactylation at K918/K995, affecting metabolic substrate affinity. RBM25 deficiency shifts splicing toward Acly S, enhancing glycolysis and acetyl-CoA production for epigenetic remodeling and macrophage overactivation. Macrophage-specific RBM25 knockout leads to spontaneous arthritis in mice.\",\n      \"method\": \"RBM25 KO mice (conditional, macrophage-specific), multiomics (RNA-seq, proteomics, ChIP-seq), RIP, in vivo arthritis model, Acly inhibitor rescue\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional KO with defined molecular mechanism (splicing, PTM, metabolic rewiring, epigenetic remodeling), multiple orthogonal methods\",\n      \"pmids\": [\"39251781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3-mediated m6A methylation of RBM25 mRNA stabilizes RBM25 mRNA and maintains its expression in multiple myeloma cells; metformin reduces METTL3 activity, thereby decreasing m6A on RBM25 mRNA and reducing RBM25 mRNA stability and expression. RBM25 knockdown reverses METTL3-overexpression-driven MM cell malignancy.\",\n      \"method\": \"MeRIP (m6A immunoprecipitation), METTL3 knockdown/overexpression, mRNA stability assay, rescue experiments, in vivo xenograft\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP with rescue experiments, single lab\",\n      \"pmids\": [\"36762777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM25 is localized to the nucleus in cardiomyocytes both in vitro and in vivo under hypoxia/ischemic conditions; ER stress stimulates RBM25 upregulation and promotes apoptosis via the CHOP signaling pathway. RBM25 knockdown blocks CHOP activation and reduces apoptosis, improving cardiac function.\",\n      \"method\": \"Immunofluorescence (nuclear localization), Western blot, ER-tracker, siRNA knockdown in OGD model and in vivo ischemic HF rat model, TUNEL, echocardiography\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization experiment combined with loss-of-function phenotype and defined pathway (CHOP), single lab\",\n      \"pmids\": [\"37736860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM25 binds to a poly-G-rich region in exon 14a of MNK2 pre-mRNA (shown by iRIP-seq and validated by RT-PCR), inhibiting the proximal 3' splice site and producing the oncogenic short isoform MNK2b. RBM25 depletion shifts splicing to the MNK2a isoform; re-expression of MNK2b or ASO-blocking of the alternative splice site rescues the tumor suppression from RBM25 knockdown.\",\n      \"method\": \"iRIP-seq, RNA-seq, RT-PCR splicing assays, shRNA knockdown, ASO rescue, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — iRIP-seq binding site identification with functional splice switching validated by ASO and re-expression rescue experiments\",\n      \"pmids\": [\"39110401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM25 binds to Slc38a9, Csf1, and Coro6 mRNAs (identified by iRIP-seq) and regulates their alternative splicing in H9c2 cardiomyocytes, linking RBM25 to cardiac inflammatory responses.\",\n      \"method\": \"iRIP-seq, RNA-seq, RT-qPCR validation\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — iRIP-seq binding with RT-qPCR validation, single lab, limited functional follow-up\",\n      \"pmids\": [\"37953772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"dCasRx fused to RBM25 (dCasRx-RBM25) functions as a potent activator of exon inclusion; it efficiently activates ~90% of targeted endogenous alternative exons with high on-target specificity, identified through screening >300 dCasRx-splicing factor fusion proteins.\",\n      \"method\": \"CRISPR-dCasRx fusion protein screen with splicing reporters, endogenous alternative exon activation assays, gRNA array combinatorial targeting, RNA-seq specificity analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic screen validated on endogenous targets with transcriptome-wide specificity profiling, multiple targets across cell types\",\n      \"pmids\": [\"38917795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM25 induces exon 16 skipping in MAP4K4 pre-mRNA (confirmed by qPCR), generating a truncated isoform predicted to enhance MAP3K1 binding and activate the p38 MAPK/ERK pathway; RBM25 overexpression exacerbates post-infarction heart failure via this MAP4K4 splicing-dependent MAPK activation, while RBM25 knockdown is cardioprotective. P38 MAPK inhibitor (SB203580) attenuated RBM25-mediated injury.\",\n      \"method\": \"Lentiviral OE/KD in rat LAD ligation model, qPCR, echocardiography, Western blot for MAPK phosphorylation, TUNEL, pharmacological rescue with SB203580\",\n      \"journal\": \"FASEB bioAdvances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain/loss of function with defined splice event and pathway inhibitor rescue, single lab, computational prediction of isoform consequence\",\n      \"pmids\": [\"41409803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM25 promotes HBV replication by binding to cccDNA through its RE/RD and PWI domains, upregulating Yin Yang 1 (YY1) expression, which enhances acetylation of cccDNA-bound histones to promote HBV transcription. HBV core protein accumulation causes nuclear translocation of RBM25, while RBM25 overexpression promotes core protein degradation, establishing a reciprocal regulatory loop.\",\n      \"method\": \"ChIP on cccDNA, domain deletion/mutagenesis (RE/RD and PWI), RBM25 KD/OE in HBV-replicating and infected cell models and mouse hydrodynamic injection model, promoter activity assays, histone acetylation assays\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with domain mutagenesis validated in vivo, single lab, non-splicing role requiring mechanistic characterization of chromatin binding\",\n      \"pmids\": [\"40412480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"lnc-536 acts as a decoy for RBM25 in pulmonary artery smooth muscle cells; when lnc-536 is elevated, it sequesters RBM25 away from SFPQ (splicing factor proline/glutamine-rich), which in turn reduces SFPQ-HOXB13 mRNA interaction, decreasing HOXB13 expression and driving PASMC hyperproliferation. RBM25 knockdown increases SFPQ-HOXB13 mRNA interaction and attenuates PASMC proliferation.\",\n      \"method\": \"lncRNA pull-down, RNA immunoprecipitation (SFPQ antibody), RBM25 knockdown with proliferation assays, in vivo GapmeR antisense oligo in PAH rat models\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNA pull-down and RIP combined with in vivo rescue, single lab\",\n      \"pmids\": [\"40567228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rbm25 occupies promoters of pluripotency- and DNA methylation-related genes in embryonic stem cells and directly regulates their transcription; deletion or depletion of Rbm25 impairs ESC self-renewal and promotes transition to 2-cell-like cells (2CLCs) by altering the epigenetic state of ESCs, revealing a transcriptional (non-splicing) regulatory role.\",\n      \"method\": \"ChIP-seq (promoter occupancy), Rbm25 knockout/knockdown in ESCs, RNA-seq, 2CLC reporter assay\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with KO phenotype, single lab, novel non-splicing role\",\n      \"pmids\": [\"41455468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Rbm25 knockdown in vitro and in vivo accelerates clonal expansion of Tet2-knockout hematopoietic stem cells, placing Rbm25 as a downstream mediator of Tet2-loss-induced heterogeneous preleukemic clonal expansion.\",\n      \"method\": \"Genetic barcoding in conditional Tet2 KO mice, shRNA knockdown of Rbm25 in vitro and in vivo, hematopoietic colony assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Rbm25 KD in Tet2 KO background) with in vivo clonal tracking, single lab\",\n      \"pmids\": [\"36947858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Conditional (homozygous) knockout of Rbm25 in mice causes collapse of multiple hematopoietic lineages including long-term hematopoietic stem cells, demonstrating that Rbm25 is essential for normal murine hematopoiesis. Mono-allelic deletion does not impair HSC self-renewal even under proliferative stress, showing Rbm25 is haplosufficient.\",\n      \"method\": \"Conditional knockout mouse model, bone marrow transplantation, flow cytometry of hematopoietic lineages\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined hematopoietic phenotype and haploinsufficiency test, in vivo model\",\n      \"pmids\": [\"41819468\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM25 is an RNA-binding splicing factor that directly binds specific pre-mRNA elements (including CGGGCA sequences and RNA G-quadruplexes) to promote inclusion of alternative exons and activate weak 5' splice sites by recruiting U1 snRNP via hLuc7A; it globally regulates alternative splicing of apoptotic (BCL-X, MNK2), metabolic (ACLY), cardiac ion channel (SCN5A, MAP4K4), and immunoregulatory transcripts, while its activity is modulated by lysine mono-methylation at K77 (blocking SRSF2 binding) and by METTL3-mediated m6A modification of its own mRNA; in addition to splicing, RBM25 occupies gene promoters to regulate transcription in stem cells and binds HBV cccDNA via its PWI/RE domains to promote viral transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM25 is an RNA-binding splicing factor that directly recognizes specific pre-mRNA elements—including CGGGCA sequences, poly-G-rich motifs, and RNA G-quadruplexes—to control alternative splice site selection across the transcriptome [#0, #8, #12]. At the BCL-x locus it binds an exonic CGGGCA element and an adjacent RNA G-quadruplex (GQ-2) near the alternative 5' splice site through its RE motif to promote the pro-apoptotic Bcl-xS isoform, recruiting U1 snRNP to the otherwise weak 5' splice site via association with hLuc7A [#0, #1, #8]. Its crystallized PWI domain and flanking basic region form a positively charged nucleic-acid-binding platform required in vivo for this splicing activity [#4]. Genome-wide, RBM25 is required for cell viability, interacts with early spliceosome components, and globally promotes alternative exon inclusion, an activity directly harnessed in the dCasRx-RBM25 programmable exon-inclusion tool [#5, #14]. Through these splicing programs RBM25 acts as a tumor suppressor in AML by controlling BCL-X and BIN1 splicing to restrain MYC activity, governs macrophage metabolism via ACLY exon-14 skipping, and regulates cardiac function by reshaping SCN5A, MNK2, and MAP4K4 transcripts [#2, #6, #9, #12, #15]. RBM25 activity is itself regulated post-translationally by lysine-77 mono-methylation, which blocks high-affinity binding to the exon-definition factor SRSF2, and at the transcript level by METTL3-mediated m6A modification that stabilizes RBM25 mRNA [#5, #10]. Beyond splicing, RBM25 occupies gene promoters to directly regulate transcription in embryonic stem cells and binds HBV cccDNA through its RE/RD and PWI domains to promote viral transcription [#18, #16]. Conditional knockout establishes that Rbm25 is essential for murine hematopoiesis, with collapse of multiple lineages including long-term hematopoietic stem cells [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that RBM25 is a sequence-specific splicing regulator that activates a weak 5' splice site, answering how an exonic element directs apoptotic isoform choice.\",\n      \"evidence\": \"RNA binding, mutagenesis of the BCL-x CGGGCA element, U1 snRNP recruitment, and Co-IP with hLuc7A\",\n      \"pmids\": [\"18663000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"hLuc7A interaction shown by single Co-IP without reciprocal validation\", \"scope beyond BCL-x not yet defined at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended RBM25's regulatory reach to cardiac ion channels, showing it drives truncation of SCN5A mRNA with functional consequences for sodium current.\",\n      \"evidence\": \"Gene array, overexpression in Jurkat and hESC-derived cardiomyocytes, mRNA/protein quantification, and electrophysiology\",\n      \"pmids\": [\"21859973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"binding site on SCN5A not mapped\", \"physiological trigger for this splicing not yet identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked RBM25-mediated SCN5A splicing to pathophysiological signaling, showing heart-failure cues raise RBM25 levels and binding.\",\n      \"evidence\": \"RIP, qPCR, Western blot, and electrophysiology in cardiac cells treated with angiotensin II/hypoxia\",\n      \"pmids\": [\"22939879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single lab\", \"upstream signaling connecting stimuli to RBM25 induction unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the structural basis of RBM25 nucleic-acid binding, showing the PWI domain plus flanking basic region forms an enlarged binding surface required for splicing function.\",\n      \"evidence\": \"X-ray crystallography, structure-guided mutagenesis, and in vivo Bcl-x splicing reporter\",\n      \"pmids\": [\"23190262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no co-structure with RNA\", \"contribution of other RBM25 domains to specificity not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed RBM25 in the global splicing machinery and uncovered methylation-based regulation, showing K77 mono-methylation blocks SRSF2 binding.\",\n      \"evidence\": \"shRNA viability assays, transcriptome-wide RNA-seq, quantitative proteomics, and methylated-peptide affinity binding for SRSF2\",\n      \"pmids\": [\"28655759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"methyltransferase/demethylase acting on K77 not identified\", \"functional output of SRSF2 displacement in vivo not quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected RBM25 to circular RNA biogenesis and p53 signaling, broadening its RNA-processing repertoire in cancer.\",\n      \"evidence\": \"RIP, p53 ChIP/reporter, circRNA perturbation with EMT readouts, and xenograft\",\n      \"pmids\": [\"30531834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"circRNA is primary focus, RBM25 mechanism less developed\", \"single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined RBM25 as a tumor suppressor in AML, showing its splicing of BCL-X and BIN1 restrains MYC-driven proliferation.\",\n      \"evidence\": \"In vivo shRNA screen in CEBPA-mutant AML, RT-PCR splicing analysis, and knockdown proliferation/apoptosis assays in multiple leukemic lines\",\n      \"pmids\": [\"30635567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct BIN1 binding site not mapped\", \"whether MYC effect is solely splicing-mediated unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the RNA structural element underlying Bcl-xS production, showing RBM25's RE motif binds a G-quadruplex that is pharmacologically tractable.\",\n      \"evidence\": \"EMSA/pull-down with rG4, RE-motif mutagenesis, splicing reporters, and G4-ligand screening\",\n      \"pmids\": [\"37811881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"generality of rG4 recognition across other RBM25 targets not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a splicing-metabolism-epigenetic axis, showing RBM25 controls ACLY isoform choice to limit macrophage overactivation and autoimmunity.\",\n      \"evidence\": \"Macrophage-specific conditional KO, multiomics, RIP, arthritis model, and ACLY inhibitor rescue\",\n      \"pmids\": [\"39251781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RBM25 binding determinants on ACLY pre-mRNA not detailed\", \"relevance to human inflammatory disease not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified upstream control of RBM25 abundance, showing METTL3-mediated m6A stabilizes RBM25 mRNA in multiple myeloma.\",\n      \"evidence\": \"MeRIP, METTL3 perturbation, mRNA stability assays, rescue, and xenograft\",\n      \"pmids\": [\"36762777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A reader mediating stabilization not identified\", \"single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a stress-responsive pro-apoptotic role in cardiomyocytes via the CHOP pathway, with confirmed nuclear localization.\",\n      \"evidence\": \"Immunofluorescence, ER-tracker, siRNA knockdown in OGD and ischemic HF rat models, TUNEL, and echocardiography\",\n      \"pmids\": [\"37736860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism linking RBM25 to CHOP not defined\", \"splicing targets in this context not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped additional cardiac splicing targets, expanding RBM25's role in cardiac inflammatory transcript processing.\",\n      \"evidence\": \"iRIP-seq, RNA-seq, and RT-qPCR validation in H9c2 cardiomyocytes\",\n      \"pmids\": [\"37953772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"limited functional follow-up\", \"phenotypic consequence of these splicing changes untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed RBM25 controls MNK2 splicing to favor an oncogenic isoform, mechanistically validated by splice-switching rescue.\",\n      \"evidence\": \"iRIP-seq, RT-PCR splicing assays, shRNA knockdown, ASO rescue, and tumor growth assays\",\n      \"pmids\": [\"39110401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of poly-G recognition in MNK2 not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Positioned Rbm25 within preleukemic clonal dynamics as a downstream mediator of Tet2 loss.\",\n      \"evidence\": \"Genetic barcoding in Tet2 KO mice with shRNA knockdown and colony assays\",\n      \"pmids\": [\"36947858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular effector linking Rbm25 to clonal expansion unknown\", \"single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated RBM25 is a portable exon-inclusion activator, repurposing its splicing function as a programmable tool.\",\n      \"evidence\": \"dCasRx-RBM25 fusion screen across >300 splicing factors with endogenous exon activation and transcriptome-wide specificity profiling\",\n      \"pmids\": [\"38917795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"intrinsic domain conferring activator potency not dissected here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a cardiac injury mechanism whereby RBM25-driven MAP4K4 splicing activates p38 MAPK/ERK signaling.\",\n      \"evidence\": \"Lentiviral OE/KD in rat LAD ligation model, qPCR, MAPK phospho-blots, TUNEL, and SB203580 rescue\",\n      \"pmids\": [\"41409803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"isoform consequence partly computational\", \"single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a non-splicing role for RBM25 in viral chromatin, showing direct cccDNA binding promotes HBV transcription via YY1 and histone acetylation.\",\n      \"evidence\": \"ChIP on cccDNA, RE/RD and PWI domain mutagenesis, KD/OE in HBV models, and mouse hydrodynamic injection\",\n      \"pmids\": [\"40412480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism of cccDNA/chromatin recruitment not fully defined\", \"single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed RBM25 can be functionally sequestered by a decoy lncRNA, modulating SFPQ-dependent HOXB13 regulation in vascular cells.\",\n      \"evidence\": \"lncRNA pull-down, SFPQ RIP, knockdown proliferation assays, and in vivo GapmeR in PAH rat models\",\n      \"pmids\": [\"40567228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct RBM25-SFPQ interaction interface not mapped\", \"single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a transcriptional (non-splicing) role, showing Rbm25 occupies pluripotency-gene promoters to maintain ESC self-renewal.\",\n      \"evidence\": \"ChIP-seq promoter occupancy, Rbm25 KO/KD in ESCs, RNA-seq, and 2CLC reporter\",\n      \"pmids\": [\"41455468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how an RNA-binding protein is recruited to promoters unresolved\", \"single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established RBM25 as essential and haplosufficient for hematopoiesis, defining its in vivo requirement in stem cells.\",\n      \"evidence\": \"Conditional knockout mouse, bone marrow transplantation, and flow cytometry of hematopoietic lineages\",\n      \"pmids\": [\"41819468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"splicing targets responsible for HSC collapse not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBM25 partitions between its splicing, promoter-transcriptional, and chromatin/cccDNA-binding functions—and what determines target selection in each—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unified model of recruitment to promoters vs. pre-mRNA\", \"enzymes regulating K77 methylation not identified\", \"in vivo splicing targets underlying organismal phenotypes largely undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 8, 12, 13]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 5, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [16, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 16, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 5, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [16, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 6, 11]}\n    ],\n    \"complexes\": [\"spliceosome (early/U1 snRNP-associated)\"],\n    \"partners\": [\"LUC7L3\", \"SRSF2\", \"SFPQ\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}