{"gene":"RBFOX2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2006,"finding":"RBFOX2 (Fox-2) specifically recognizes the hexameric RNA element UGCAUG, as established by SELEX experiments with Fox-1 (identical RRM to Fox-2). Both Fox-1 and Fox-2 bind UGCAUG elements in the downstream intron of protein 4.1R exon 16 and activate exon inclusion; knockdown of Fox-2 via siRNA decreased exon 16 splicing, identifying Fox-2 as a physiological activator of this splicing switch in differentiating erythroid cells.","method":"SELEX, co-transfection splicing assays, siRNA knockdown, immunoblot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SELEX established binding specificity; functional splicing assays with mutagenesis of binding sites and siRNA knockdown replicated in multiple constructs; peer-reviewed","pmids":["16537540"],"is_preprint":false},{"year":2006,"finding":"Fox-2 regulates FGFR2 exon IIIb vs. IIIc choice in an epithelial cell-specific manner. Fox-2 expression is higher in IIIb+ epithelial cells; ectopic expression of Fox-2 switches splicing from IIIc to IIIb, absolutely dependent on (U)GCAUG elements. The C-terminal region of Fox-2 is required for this activity. Fox-2 knockdown abolishes the IIIb inclusion switch. Fox-2 also autoregulates its own activity by inducing skipping of its own exon 6 to produce an inactive isoform.","method":"RT-PCR splicing assays, Fox-2 overexpression, siRNA knockdown, mutagenesis of UGCAUG elements, isoform analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (OE, KD, mutagenesis) in the same study with clear mechanistic dissection","pmids":["16449636"],"is_preprint":false},{"year":2006,"finding":"Fox-1 and Fox-2 repress inclusion of calcitonin-specific exon 4 of calcitonin/CGRP pre-mRNA via two UGCAUG elements flanking the 3' splice site. They block U2AF65 binding to the polypyrimidine tract upstream of exon 4, establishing a mechanism of splice-site occlusion.","method":"Overexpression in HeLa and neuronal cells, UGCAUG mutation analysis, U2AF65 binding assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical demonstration of U2AF65 displacement combined with mutagenesis and cellular splicing assays","pmids":["17101796"],"is_preprint":false},{"year":2007,"finding":"During erythroid differentiation, an erythroid differentiation-inducible Fox-2 isoform (mFox-2A) is upregulated while a commonly expressed isoform (mFox-2F) is downregulated. mFox-2A exerts a much stronger enhancing effect on protein 4.1R exon 16 inclusion than mFox-2F, and isoform-specific knockdown of mFox-2A reverses its splicing-enhancing activity, demonstrating isoform-specific regulation.","method":"RT-PCR isoform analysis during erythroid differentiation, isoform-specific overexpression, isoform-specific siRNA knockdown","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal isoform-specific gain and loss of function with direct splicing readout, replicated across differentiation time-course","pmids":["17715393"],"is_preprint":false},{"year":2008,"finding":"Fox-1/Fox-2 repress calcitonin-specific splicing through a two-step mechanism: (1) binding to an intronic UGCAUG element blocks SF1-dependent E' complex formation; (2) binding to an exonic UGCAUG element blocks the E' to E complex transition. This constitutes a novel strategy of blocking two distinct prespliceosome assembly steps by a single factor.","method":"Biochemical spliceosome assembly assays, UGCAUG mutant constructs, gel-shift analyses","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro spliceosome complex formation assays with mutagenesis, single lab but multiple orthogonal biochemical approaches","pmids":["18573872"],"is_preprint":false},{"year":2008,"finding":"Genome-wide prediction and experimental validation established that Fox-1 and Fox-2 bind UGCAUG and that preferred binding position relative to the alternative exon determines splicing outcome: downstream binding activates exon inclusion, whereas upstream binding represses it.","method":"Computational binding site analysis, phylogenetic conservation, splicing microarray, experimental validation by RT-PCR","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — position-dependent regulatory rules validated experimentally across many targets, but primary evidence is computational with selected experimental confirmation","pmids":["18794351"],"is_preprint":false},{"year":2008,"finding":"Xenopus Rbm9 (ortholog of RBFOX2/RBM9) is a component of the cytoplasmic polyadenylation complex in Xenopus oocytes; it directly interacts with XGld2 (poly(A) polymerase), is found with CPEB and CPSF, and tethered XRbm9 stimulates translation of a reporter mRNA, revealing a function in cytoplasmic polyadenylation beyond splicing.","method":"Co-immunoprecipitation, interaction mapping, tethered-function reporter assay in Xenopus oocytes","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP in Xenopus oocytes with tethered translation assay; single lab, Xenopus ortholog","pmids":["18177378"],"is_preprint":false},{"year":2010,"finding":"Fox-2 (RBFOX2) regulates alternative splicing of lysyl hydroxylase 2 (LH2) exon 13A by binding to UGCAUG motifs flanking the exon; overexpression of Fox-2 enhances exon 13A inclusion (generating the scleroderma-associated LH2-long isoform) and knockdown reduces LH2-long mRNA levels in SSc patient fibroblasts. Mutagenesis of two of four Fox-binding motifs is sufficient to abolish exon inclusion.","method":"LH2 minigene splicing assays, Fox-2 overexpression/knockdown, UGCAUG mutagenesis, RT-PCR in patient fibroblasts","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — minigene mutagenesis + patient fibroblast knockdown + overexpression, two orthogonal approaches","pmids":["20131247"],"is_preprint":false},{"year":2011,"finding":"RBFOX2 promotes protein 4.1R exon 16 inclusion by recruiting U1 snRNP to the weak 5' splice site via direct interaction between the RBFOX2 C-terminal domain (CTD) and the zinc finger region of U1C protein. Strengthening the 5' splice site to consensus abrogates the requirement for RBFOX2, and CTD deletion abolishes the splicing-enhancing effect.","method":"5' splice site mutagenesis, RBFOX2 CTD deletion analysis, U1C interaction assays, U1 snRNP recruitment assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mechanistic dissection with mutagenesis of both splice site and protein domain, direct protein–snRNP interaction demonstration","pmids":["22083953"],"is_preprint":false},{"year":2011,"finding":"Rbfox3 (NeuN) negatively regulates Rbfox2: nuclear Rbfox3 isoforms enhance inclusion of cryptic exons in Rbfox2 mRNA, resulting in nonsense-mediated decay of Rbfox2 transcripts, and Rbfox3 also promotes production of a dominant-negative Rbfox2 protein through alternative splicing of Rbfox2 pre-mRNA.","method":"Alternative splicing analysis, RT-PCR, NMD pathway assays, overexpression of Rbfox3 isoforms","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional splicing and NMD assays in single lab, single study","pmids":["21747913"],"is_preprint":false},{"year":2012,"finding":"CNS-specific deletion of Rbfox2 disrupts cerebellar development. Genome-wide analysis identifies Scn8a (Nav1.6 sodium channel) as an Rbfox2 splicing target; improper splicing in Rbfox2-null brains leads to reduced Nav1.6 protein. Combined Purkinje cell deletion of Rbfox1 and Rbfox2 causes irregular firing, establishing that Rbfox2 (with Rbfox1) maintains neuronal pacemaking via sodium channel splicing.","method":"Conditional knockout mice, RNA-seq, electrophysiology of Purkinje cells, immunoblot for Nav1.6","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genome-wide splicing analysis, electrophysiology, and protein-level validation; multiple phenotypic readouts","pmids":["22357600"],"is_preprint":false},{"year":2012,"finding":"FOX-2 (RBFOX2) interacts with ataxin-1 (co-immunoprecipitation in mammalian cells) and directly interacts with ataxin-2; reduction of Fox-2 levels leads to increased skipping of ataxin-2 exon 18. Overexpression of nuclear ataxin-1 sequesters Fox-2 into nuclear inclusions and impairs this splicing event.","method":"Yeast-2-hybrid, co-immunoprecipitation, siRNA knockdown, RT-PCR splicing assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP and functional splicing assays, single study","pmids":["22666429"],"is_preprint":false},{"year":2013,"finding":"RBFOX2 expression is upregulated during EMT, correlating with increased RBFOX2-regulated splicing of cortactin, Pard3, and Dnm2. Depletion of RBFOX2 in cells that have completed EMT significantly reduces invasive potential without affecting mesenchymal marker expression or TGF-β signaling, demonstrating a specific role for RBFOX2-regulated splicing in cellular invasion.","method":"EMT cell culture models, siRNA knockdown, RT-PCR splicing assays, invasion assays (Matrigel), western blotting","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional invasion assays combined with splicing analysis and defined negative controls, single lab","pmids":["23435423"],"is_preprint":false},{"year":2013,"finding":"MBNL1 and RBFOX2 cooperatively control a splicing program during mesoderm differentiation. High-throughput RT-PCR during iPSC reprogramming and redifferentiation identified concerted splicing changes in at least 10 conserved genes (including PLOD2, CLSTN1, ATP2A1) controlled by these two splicing regulators.","method":"High-throughput RT-PCR during iPSC reprogramming/differentiation, RBP knockdown in cell lines","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — high-throughput splicing profiling combined with functional knockdown, single lab","pmids":["24048253"],"is_preprint":false},{"year":2014,"finding":"Rbfox2 cross-regulates AS-coupled NMD (AS-NMD) events within RNA-binding protein genes to alter their steady-state expression. Using iCLIP and RNA-seq in mouse ESCs, >200 AS-NMD events were identified as Rbfox2-bound; these 'silent' events show minimal splicing change but significant gene expression changes upon knockdown due to NMD isoform regulation. Nearly 70 events fall within RBP genes, many of which are autoregulated, establishing Rbfox2 as a regulator of a broader RBP network.","method":"iCLIP-seq, RNA-seq, siRNA knockdown, RT-PCR validation of NMD isoforms","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — iCLIP (nucleotide-resolution binding) combined with RNA-seq expression changes; multiple orthogonal methods, strong mechanistic framework","pmids":["24637117"],"is_preprint":false},{"year":2014,"finding":"Rbfox2 regulates ~30% of splicing transitions during myogenesis and is specifically required for myoblast fusion. Rbfox2 iCLIP combined with RNA-seq identified Mef2d and Rock2 as direct splicing targets; rescue of myoblast fusion defects in Rbfox2-depleted cultures by restored Mef2d and Rock2 activities demonstrates functional cooperation between isoforms generated by coordinated alternative splicing.","method":"iCLIP-seq, RNA-seq, shRNA knockdown, rescue experiments with Mef2d/Rock2 isoforms, fusion assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — iCLIP identifies direct targets, rescue experiments establish functional requirement, multiple orthogonal approaches","pmids":["25087874"],"is_preprint":false},{"year":2015,"finding":"Transverse aortic constriction (TAC) potently decreases RBFox2 protein in mouse heart. Cardiac-specific ablation of RBFox2 generates phenotypes resembling cardiac decompensation, and RBFox2 regulates splicing of genes involved in heart function. A subset of these genes undergo developmental regulation during postnatal heart remodeling that is reversed in both TAC-treated and RBFox2 knockout mice, establishing RBFox2 as a stress-sensor splicing regulator in pressure overload-induced heart failure.","method":"Conditional cardiac knockout mice, TAC surgery model, RNA-seq splicing analysis, RT-PCR validation, echocardiography","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo cardiac KO with genome-wide splicing analysis plus disease model correlation, multiple phenotypic readouts","pmids":["25753418"],"is_preprint":false},{"year":2016,"finding":"RBFox2 directly interacts with Polycomb Repressive Complex 2 (PRC2) in a nascent RNA-dependent manner. RBFox2 depletion causes widespread increase in nascent RNA production and eradicates PRC2 targeting on the majority of bivalent gene promoters, leading to transcriptional de-repression. ChIP-seq reveals extensive RBFox2 chromatin association dependent on nascent RNA.","method":"ChIP-seq, biochemical interaction assays (RBFox2–PRC2 co-IP), nascent RNA sequencing, Bayesian network analysis, RBFox2 depletion in multiple cell types","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical interaction demonstrated, genome-wide ChIP-seq, multiple cell types, multiple orthogonal approaches","pmids":["27211866"],"is_preprint":false},{"year":2016,"finding":"RBFOX2 protein levels are elevated in diabetic hearts due to upregulation of a dominant-negative (DN) isoform of RBFOX2. DN RBFOX2 interacts with wild-type RBFOX2 (co-IP) and inhibits RBFOX2-mediated alternative splicing of target genes. Ectopic expression of DN RBFOX2 impairs intracellular calcium release in cardiomyocytes, identifying dysregulation by DN isoform as an early event in diabetic cardiomyopathy.","method":"Co-IP (DN-WT interaction), RT-PCR for splicing, overexpression of DN isoform, calcium imaging in cardiomyocytes, diabetic mouse hearts","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed interaction, calcium imaging provided functional readout, multiple methods in single lab","pmids":["27239029"],"is_preprint":false},{"year":2016,"finding":"A nonsense mutation in Rbfox2 identified in hypoplastic left heart syndrome (HLHS) patients truncates the protein and impairs its subcellular distribution (nuclear export/localization) and function in RNA metabolism. Rbfox2 regulates mRNA levels of targets through 3'UTR binding sites in addition to splicing regulation.","method":"Truncation mutant analysis, subcellular fractionation, RNA-immunoprecipitation, transcriptome analysis of HLHS patient right ventricles","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — patient-derived functional analysis with mechanistic follow-up, single study, limited replication","pmids":["27485310"],"is_preprint":false},{"year":2016,"finding":"A nuclear localization signal (NLS) at the N terminus of Rbfox2 isoform 1A (not present in isoform 1F) is identified; Rbfox2 1A isoforms lacking the C-terminal NLS remain nuclear, whereas equivalent 1F isoforms are cytoplasmic. A shift toward cytoplasmic 1F isoforms occurs during EMT.","method":"Isoform cloning, subcellular fractionation, immunofluorescence, EMT cell models","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — localization determined by direct experiment with isoform-specific constructs, single lab","pmids":["27859055"],"is_preprint":false},{"year":2017,"finding":"Rbfox2 represses inclusion of alternatively spliced exon 18a in CaV2.2 (Cacna1b) pre-mRNA. siRNA knockdown of Rbfox2 in neuronal cells increases e18a inclusion, and Rbfox2-RNA immunoprecipitation demonstrates reduced Rbfox2 binding upstream of e18a in adult sympathetic neurons. CaV2.2 currents are larger when exon 18a is included, establishing that Rbfox2 limits CaV2.2 current size early in development.","method":"siRNA knockdown, RNA immunoprecipitation (RIP)-qPCR, whole-cell patch clamp, RT-PCR","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and electrophysiology in the same study; single lab, two orthogonal methods","pmids":["29067356"],"is_preprint":false},{"year":2017,"finding":"Rbfox2 dynamically regulates alternative exons 9* and 33 of the vascular CaV1.2 (Cacna1c) calcium channel. Knockdown of Rbfox2 in vascular smooth muscle cells increases exon 9* and decreases exon 33 inclusion, shifting CaV1.2 window current to more negative potentials and increasing pressure-induced myogenic tone in mesenteric artery.","method":"siRNA knockdown in VSMCs, RT-PCR splicing assays, patch clamp electrophysiology, pressure myograph for myogenic tone","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splicing knockdown combined with electrophysiology and vascular function assays in single lab","pmids":["28993448"],"is_preprint":false},{"year":2017,"finding":"Rbfox2 is a novel constituent of cytoplasmic stress granules. RNA-binding activity of Rbfox is required for its localization into stress granules. In stress granules, Rbfox2 binds and regulates retinoblastoma 1 (RB1) mRNA and protein expression during and after stress exposure.","method":"Immunofluorescence co-localization, RNA-immunoprecipitation sequencing (RIP-seq) of cytoplasmic targets, stress granule markers, stress induction assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-localization + RIP-seq identifying cytoplasmic targets, single lab, two orthogonal methods","pmids":["28894257"],"is_preprint":false},{"year":2018,"finding":"Endothelial-specific deletion of Rbfox2 (the only Rbfox family member expressed in arterial endothelium) suppresses a subset of alternative splicing and transcriptional changes induced by low arterial flow, identifying an Rbfox2-dependent alternative splicing program activated during flow-driven vascular inflammation involving platelet and macrophage recruitment.","method":"Endothelial conditional Rbfox2 knockout mice, in vivo low-flow arterial model, RNA-seq, platelet/macrophage depletion","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO in vivo with genome-wide splicing analysis and depletion of upstream signals; multiple orthogonal approaches","pmids":["29293084"],"is_preprint":false},{"year":2019,"finding":"Rbfox2 present in cytoplasmic stress granules inhibits RB1 protein expression and promotes cell cycle progression. Resveratrol-induced dissociation of Rbfox2 from stress granules inhibits RB1 suppression and cancer progression; Rbfox2 cytoplasmic localization in colon cancer tissues correlates with its stress granule role distinct from nuclear splicing function.","method":"Immunofluorescence in human cancer tissues, stress granule induction/dissolution assays, RB1 protein measurement, tumor growth assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — localization + functional assays; single lab, mechanistic link to RB1 regulation established but limited orthogonal validation","pmids":["31028247"],"is_preprint":false},{"year":2019,"finding":"Neural crest-specific deletion of Rbfox2 causes cleft palate and craniofacial bone defects. Rbfox2 regulates splicing of genes in TGF-β-Tak1 signaling; restoration of TGF-β signaling by Tak1 overexpression rescues proliferation defects in Rbfox2 mutant neural crest cells. A positive feedback loop exists where TGF-β signaling promotes Rbfox2 expression in NCCs.","method":"Conditional Rbfox2 knockout in neural crest cells (Wnt1-Cre), RNA-seq, Tak1 overexpression rescue experiments, craniofacial morphology analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with pathway rescue experiments and RNA-seq; multiple phenotypic and molecular readouts","pmids":["31241461"],"is_preprint":false},{"year":2019,"finding":"Alternative splicing of exon 10 in RBFOX2 removes a nuclear localization signal, causing cytoplasmic localization of RBFOX2 in calcific tendons vs. nuclear localization in normal tendons. Cytoplasmic RBFOX2 in calcific tendons is associated with altered splicing of RBFOX2 target genes CHD2 and MBNL1.","method":"Immunofluorescence microscopy, RBFOX2 isoform sequencing, RT-PCR of splicing targets in clinical samples","journal":"Experimental and molecular pathology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — direct localization by IF linked to isoform sequencing and target splicing changes; single study, clinical specimens","pmids":["31128090"],"is_preprint":false},{"year":2019,"finding":"RBFox2 controls a feed-forward regulatory pathway in heart failure: reduced RBFox2 induces transcriptional repression of miR-34a, which then targets Jph2 mRNA to impair excitation-contraction coupling, leading to progressive cardiac dysfunction. Administration of miR-34a antagomir alleviates RBFox2 depletion-induced heart dysfunction.","method":"Conditional cardiac RBFox2 knockout, miR-34a mimic/antagomir in vivo, Jph2 expression analysis, cardiac function assays (echocardiography)","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO + miRNA gain/loss of function with cardiac functional readout; multiple orthogonal methods establishing the pathway","pmids":["30867288"],"is_preprint":false},{"year":2020,"finding":"A non-muscle RBFOX2 isoform (RBFOX240) is upregulated in DM1 heart tissue due to altered splicing factor and microRNA activities. Mice expressing RBFOX240 in heart via transgenic or CRISPR/Cas9 knockin reproduce DM1-related cardiac conduction delay and arrhythmia. RBFOX240 drives splicing defects in voltage-gated sodium and potassium channels, altering their electrophysiological properties.","method":"DM1 patient tissue analysis, tetracycline-inducible transgenesis, CRISPR/Cas9 knockin mice, RNA-seq, electrophysiological recording, integration with cardiac transcriptomes","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent mouse models (transgenic + CRISPR), patient validation, electrophysiology, RNA-seq; multiple orthogonal methods","pmids":["32109384"],"is_preprint":false},{"year":2020,"finding":"RBFOX2 is required for cardiomyocyte alternative splicing regulation during heart development; conditional deletion in embryonic mouse hearts causes cardiac chamber and yolk sac vasculature defects resembling HLHS. RNA-seq identifies dysregulated AS networks affecting cell–ECM adhesion via Rho GTPase cycling genes. Antisense oligos modulating AS of two Rho GTPase cycling genes cause cell cycle and cell-ECM adhesion defects.","method":"Cardiac conditional Rbfox2 KO, RNA-seq, antisense oligonucleotide (ASO) experiments, cell adhesion and cycle assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with RNA-seq plus ASO rescue experiments with mechanistic readout; multiple orthogonal approaches","pmids":["35137168"],"is_preprint":false},{"year":2020,"finding":"RBFOX2 transcriptionally represses ESRP1 by interacting with the transcription factor SLUG under hypoxia/TGF-β signaling, in addition to its RNA-binding role. This leads to skipping of hMENA exon 11a, producing a pro-metastatic isoform. Both RBFOX2 and SLUG are upregulated via TGF-β signaling under hypoxia.","method":"TGF-β/hypoxia treatment, ChIP/reporter assays for ESRP1 repression, RBFOX2 and SLUG interaction assays, AS analysis of hMENA","journal":"NAR cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — transcriptional and splicing functions both demonstrated, but mechanistic detail is partially inferred; single lab","pmids":["33089214"],"is_preprint":false},{"year":2021,"finding":"RBFOX2 can interact with hnRNPC, hnRNPM, and SRSF1 to regulate splicing in three distinct binding modes: (1) single mode—RBFOX2 alone at canonical UGCAUG; (2) multiple mode—RBFOX2 adjacent to at least one other RBP partner; (3) secondary mode—RBFOX2 recruited to sites without its canonical motif through partner binding. These modes control distinct sets of transcripts with different positional relationships to splice sites.","method":"RNA immunoprecipitation, RBP-specific knockdown, RNA-seq, splice-sensitive PCR, parsing of public CLIP datasets","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic mechanistic dissection using IP + KD + RNA-seq across multiple protein partners; two orthogonal approaches in single lab","pmids":["34244793"],"is_preprint":false},{"year":2021,"finding":"RBFOX2 is critical for maintaining alternative polyadenylation (APA) patterns in myoblasts. 3'-end and nanopore sequencing reveal that RBFOX2 depletion disrupts APA of mitochondrial and contractile genes. Mechanistically, RBFOX2 binding to consensus RBFOX2 motifs near the distal polyadenylation site of Slc25a4 enforces use of the proximal site; RBFOX2 depletion impairs mitochondrial health in myoblasts.","method":"3'-end sequencing, nanopore cDNA sequencing, RBFOX2 knockdown, binding site mutagenesis, mitochondrial function assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two sequencing platforms identifying APA role, binding site mutagenesis, functional mitochondrial phenotype; multiple orthogonal methods","pmids":["34731606"],"is_preprint":false},{"year":2021,"finding":"Rbfox2 mediates exon 11 inclusion in insulin receptor (IR) pre-mRNA in hepatoma cells via an intronic UGCAUG element just downstream of exon 11. Mutation of the UGCAUG sequence causes exon 11 skipping, and Rbfox2 knockdown enhances endogenous exon 11 skipping. SRSF3 binding site mutations combined with Rbfox2 binding site mutations completely abolish exon 11 inclusion.","method":"Minigene splicing reporter with deletions and mutations, siRNA knockdown of Rbfox2, RT-PCR","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — minigene mutagenesis + KD; single lab","pmids":["34022289"],"is_preprint":false},{"year":2021,"finding":"SON suppresses RBFOX2-mediated non-oncogenic neuronal splicing in GBM by forming a complex with hnRNP A2B1 that antagonizes RBFOX2, leading to skipping of RBFOX2-targeted cassette exons including the PTBP2 neuronal exon. SON knockdown restores RBFOX2 activity and inhibits GBM tumor growth in vivo.","method":"Co-IP (SON–hnRNP A2B1), RNA-seq after SON knockdown, RT-PCR of RBFOX2 targets, orthotopic xenograft","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + RNA-seq + in vivo xenograft; mechanistic relationship between SON and RBFOX2 established, single lab","pmids":["34548489"],"is_preprint":false},{"year":2021,"finding":"ERG and FLI1 transcription factors associate with RBFOX2 via their conserved C-terminal domain (ETS domain region), and co-regulate alternative spliced exons (ASEs) enriched in RBFOX2 motifs. EWS-FLI1 also associates with RBFOX2 but antagonizes its effects on exon inclusion, including reducing RBFOX2 binding to ADD3 pre-mRNA, promoting an isoform that represses the mesenchymal phenotype.","method":"Co-IP (ERG/FLI1/EWS-FLI1 with RBFOX2), RNA-seq, RBFOX2 motif enrichment analysis, CLIP validation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus transcriptomic analysis and CLIP; single lab, two orthogonal methods","pmids":["34009296"],"is_preprint":false},{"year":2022,"finding":"RBFOX2 promotes inclusion of TEAD1 exon 6 via binding to a conserved GCAUG element in the downstream intron. Full-length TEAD1 (with exon 6) has greater transcriptional activity and YAP interaction than TEAD1ΔE6, with the difference in transcription mediated through YAP binding. This establishes an RBFOX2–TEAD1 splicing axis modulating Hippo–YAP signaling.","method":"RT-PCR and RNA-seq for splicing, RBFOX2 knockdown and overexpression, transcriptional activity assays, YAP interaction assays, GCAUG mutagenesis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding site mutagenesis + functional signaling assays; single lab, two orthogonal approaches","pmids":["35699208"],"is_preprint":false},{"year":2022,"finding":"Liver RBFOX2 regulates cholesterol homeostasis by controlling alternative splicing of Scarb1 (scavenger receptor B1). In diet-induced obesity, RBFOX2 function is decreased in liver causing a Scarb1 isoform switch and altered hepatocyte lipid homeostasis. Splice-switching oligonucleotides targeting this network alleviate obesity-induced liver inflammation and promote anti-atherogenic lipoprotein profile.","method":"Enhanced iCLIP in mouse liver, liver-specific Rbfox2 KO, dietary obesity model, ASO treatment, lipoprotein profiling, inflammation assays","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — eiCLIP identifies direct Scarb1 target, liver KO + diet model + ASO rescue with multiple physiological readouts; multiple orthogonal methods","pmids":["36536133"],"is_preprint":false},{"year":2022,"finding":"RBFOX2 regulates alternative splicing of MICU1 (Mitochondrial Calcium Uniporter activator) during myogenesis, generating a muscle-specific MICU1.1 splice variant with distinct properties for mitochondrial Ca2+ uptake. RBFOX2 is identified as the splicing factor driving this switch during myoblast differentiation.","method":"Tissue isoform analysis, myogenesis differentiation time-course, RBFOX2 knockdown, mitochondrial Ca2+ uptake assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional mitochondrial Ca2+ assays combined with splicing analysis; single lab","pmids":["35269658"],"is_preprint":false},{"year":2023,"finding":"RBFOX2 recognizes N6-methyladenosine (m6A) on chromatin-associated RNAs (caRNAs) and recruits RBM15 (an m6A methyltransferase complex component) to facilitate methylation of promoter-associated RNAs. RBM15 interacts with YTHDC1 and recruits PRC2 to RBFOX2-bound loci for chromatin silencing. This RBFOX2/m6A/RBM15/YTHDC1/PRC2 axis is required for AML cell survival and myeloid differentiation control.","method":"m6A mapping on caRNAs, Co-IP (RBFOX2–RBM15, RBM15–YTHDC1), ChIP-seq for H3K27me3, RBFOX2 knockdown in AML cells, functional differentiation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical co-IP of multi-protein complex, m6A mapping, ChIP-seq, functional AML assays; multiple orthogonal approaches, high-impact journal","pmids":["37640841"],"is_preprint":false},{"year":2023,"finding":"RBFOX2 acts as a metastatic suppressor in pancreatic ductal adenocarcinoma (PDA). Overexpression of RBFOX2 in metastatic PDA cells reduces metastatic potential in vitro and in vivo; depletion increases it. RBFOX2 splicing targets are enriched in RHO GTPase pathways. Modulation of RBFOX2-regulated splicing of MPRIP (myosin phosphatase RHO-interacting protein) alters cytoskeletal organization and focal adhesion formation.","method":"Patient-derived xenograft models, RNA-seq/splicing analysis of RBFOX2 targets, in vivo metastasis assays, cytoskeletal imaging","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — PDX models + in vivo metastasis + RNA-seq + cytoskeletal mechanistic analysis; multiple orthogonal methods, high-impact journal","pmids":["36949200"],"is_preprint":false},{"year":2023,"finding":"RBFOX2 regulates insulin secretion in pancreatic β-cells through alternative splicing of SNARE complex components required for insulin granule docking and exocytosis. Conditional Rbfox2 mutation in mouse pancreas results in decreased insulin secretion, impaired blood glucose homeostasis, and reduced insulin granule docking.","method":"Pancreatic conditional Rbfox2 knockout mice, glucose tolerance/insulin secretion assays, electron microscopy for granule docking, RNA-seq for splicing of SNARE components","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with glucose physiology, EM-based granule docking, and splicing analysis; multiple orthogonal readouts","pmids":["38007492"],"is_preprint":false},{"year":2023,"finding":"FBXO7 stabilizes Rbfox2 by K63-linked ubiquitination at Lys249 upon arginine dimethylation at Arg341 and Arg441 by PRMT5. This FBXO7-Rbfox2 axis controls splicing of mesenchymal genes (FoxM1, Mta1, Postn) and promotes GBM mesenchymal transformation and chemoresistance.","method":"Co-IP, ubiquitination assays, site-specific mutagenesis of Rbfox2 ubiquitination and methylation sites, RNA-seq, tumor xenografts","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination site mapping + Co-IP + splicing analysis; single lab, multiple approaches","pmids":["37822160"],"is_preprint":false},{"year":2023,"finding":"RBFOX2 depletion promotes pancreatic cancer progression and liver metastasis by altering splicing of cytoskeletal remodeling genes. RBFOX2-mediated splicing of ABI1 (exon 9) controls ABI1 protein isoform abundance and localization; the ABI1 ΔEx9 isoform (generated by splice-switching ASOs) enhances cell migration.","method":"Sleeping Beauty insertional mutagenesis screen, RBFOX2 KO in PDAC models, RNA-seq, ABI1 isoform localization by IF, splice-switching ASOs, in vivo metastasis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — forward genetic screen + mechanistic validation with KO, ASO, localization studies, and in vivo metastasis assays","pmids":["38114498"],"is_preprint":false},{"year":2025,"finding":"Rbfox2 selectively governs hematopoietic stem cell (HSC) self-renewal by regulating proteostasis. Deletion of Rbfox2 from the hematopoietic compartment specifically depletes HSCs but not multipotent progenitors. Mechanistically, Rbfox2 loss leads to increased protein synthesis and accumulated misfolded/unfolded proteins in HSCs. Small molecules restoring proteostasis rescue HSC defects in Rbfox2-deficient mice.","method":"Conditional Rbfox2 KO in hematopoietic compartment, bone marrow transplantation, proteostasis assays (protein synthesis rate, unfolded protein content), chemical rescue experiments","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with mechanistic proteostasis dissection and chemical rescue; multiple orthogonal methods, single lab","pmids":["41337583"],"is_preprint":false},{"year":2025,"finding":"RBFOX2 is ubiquitinated in a RhoBTB1- and CUL3-dependent manner in vascular smooth muscle cells, establishing it as a substrate of the RhoBTB1/CUL3 ubiquitin-proteasome pathway. Co-immunoprecipitation validates the RBFOX2–RhoBTB1 interaction. Rbfox2 depletion impairs the actin cytoskeleton and alters filamentous/globular actin levels. SMC-specific Rbfox2 deletion halts progression of ANG-induced arterial stiffness.","method":"Proximity labeling + mass spectrometry, co-immunoprecipitation, ubiquitination assays, siRNA knockdown, conditional SMC-specific Rbfox2 KO mice, actin polymerization assays, arterial stiffness measurements","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — proximity labeling MS + Co-IP + ubiquitination biochemistry + in vivo conditional KO with vascular functional readout; multiple orthogonal methods","pmids":["41926228"],"is_preprint":false},{"year":2025,"finding":"RBFOX2 is essential for cardiomyocyte differentiation by promoting exon usage shifts to mature patterns in sarcomere and cytoskeletal genes (including ACTN2). RBFOX2 autoregulates itself at mutually exclusive exons: at critical RBFOX2 levels, autoregulation enforces mature isoforms; in heterozygous CMs, autoregulation is disrupted generating a dominant-negative product. Overexpression of ACTN2 rescues heterozygous (not null) phenotypes by restoring contractility and triggering mechanosensing upregulation of RBFOX2 from the wildtype allele.","method":"iPSC-derived cardiomyocyte differentiation, RBFOX2 heterozygous and null mutants, RNA-seq, ACTN2 overexpression rescue, contractility assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell models + rescue experiments; preprint, not yet peer-reviewed","pmids":["41280054"],"is_preprint":true},{"year":2025,"finding":"RBFOX2 promotes inclusion of the Numb exon 6 in satellite cells (SCs), and RBFOX2 loss delays SC activation and muscle regeneration. Exon 6-containing Numb is required for SC activation; its skipping upregulates Notch signaling and delays activation.","method":"In vivo SC fixation to preserve quiescent state, Rbfox2 conditional KO in SCs, RNA-seq, exon 6 inclusion/skipping analysis, muscle regeneration assay","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional KO + splicing analysis + in vivo regeneration; single study","pmids":["41418788"],"is_preprint":false},{"year":2025,"finding":"RBFOX2 promotes splicing of a Snap23 microexon in striated muscle by binding downstream of the microexon together with QKI, and this regulation can be escaped when the weak splice donor is mutated to consensus. MBNL1 acts as an additional, minor layer of Snap23 microexon control. The microexon is mis-regulated in mouse models of heart and skeletal muscle diseases.","method":"Splicing factor knockdowns (RBFOX2, QKI, MBNL1), minigene splice site mutagenesis, disease model analysis, binding site mapping","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — minigene mutagenesis + multiple RBP KDs; single lab, single study","pmids":["40207498"],"is_preprint":false}],"current_model":"RBFOX2 is a multifunctional RNA-binding protein that recognizes the hexameric element UGCAUG (and related motifs) in pre-mRNAs to activate or repress alternative exon inclusion depending on binding position (downstream = activation, upstream = repression); it recruits U1 snRNP via its C-terminal domain to strengthen weak splice sites, blocks prespliceosome assembly at two distinct steps, interacts with hnRNPC/hnRNPM/SRSF1 in multiple binding configurations, controls AS-coupled NMD of RNA-binding protein transcripts to tune an RBP regulatory network, regulates alternative polyadenylation, and directly binds PRC2 in a nascent RNA-dependent manner to enforce chromatin silencing at bivalent promoters; RBFOX2 also recognizes m6A on chromatin-associated RNAs and recruits the RBM15/YTHDC1/PRC2 axis for locus-selective gene silencing; it is a substrate of the RhoBTB1/CUL3 ubiquitin-proteasome pathway and is stabilized by FBXO7/PRMT5-dependent K63 ubiquitination; distinct protein isoforms generated by its own alternative splicing differ in nuclear localization signals and cytoplasmic vs. nuclear distribution, affecting its function in splicing versus cytoplasmic stress-granule-mediated mRNA regulation; critical roles have been established in cerebellar development, Purkinje cell pacemaking, myoblast fusion, cardiac development and stress response, HSC proteostasis, pancreatic β-cell insulin secretion, neural crest development, vascular endothelial and smooth muscle function, liver cholesterol homeostasis, and suppression of cancer metastasis in pancreatic and other tumors."},"narrative":{"mechanistic_narrative":"RBFOX2 is a sequence-specific RNA-binding protein that governs alternative splicing programs across development, tissue homeostasis, and disease by recognizing the hexameric element UGCAUG (and related GCAUG motifs) in pre-mRNAs [PMID:16537540, PMID:18794351]. Its regulatory outcome is positional: binding downstream of an alternative exon activates inclusion while upstream binding represses it [PMID:18794351], and mechanistically it both recruits U1 snRNP to weak 5' splice sites through a direct C-terminal-domain interaction with U1C [PMID:22083953] and blocks prespliceosome assembly at two distinct steps by occluding U2AF65/SF1-dependent complex formation [PMID:17101796, PMID:18573872]. Beyond cassette-exon splicing, RBFOX2 controls AS-coupled NMD of RNA-binding protein transcripts to tune a broader RBP network [PMID:24637117], directs alternative polyadenylation [PMID:34731606], and acts in the nucleus on chromatin: it binds PRC2 in a nascent-RNA-dependent manner to enforce silencing at bivalent promoters [PMID:27211866] and recognizes m6A on chromatin-associated RNAs to recruit an RBM15/YTHDC1/PRC2 axis for locus-selective gene silencing [PMID:37640841]. RBFOX2 cooperates and competes with other splicing regulators including hnRNPC, hnRNPM and SRSF1 in distinct binding configurations [PMID:34244793], MBNL1 and QKI [PMID:24048253, PMID:40207498], and its activity is constrained by autoregulatory and trans-acting production of dominant-negative isoforms [PMID:16449636, PMID:21747913, PMID:27239029]. Isoform-specific nuclear localization signals partition RBFOX2 between nuclear splicing functions and a cytoplasmic stress-granule role regulating RB1 mRNA [PMID:27859055, PMID:28894257, PMID:31028247]. Its abundance is set post-translationally by competing ubiquitin pathways: FBXO7/PRMT5-dependent K63 ubiquitination stabilizes it [PMID:37822160] while it is a substrate of the RhoBTB1/CUL3 degradation pathway [PMID:41926228]. Through these activities RBFOX2 directs cerebellar and Purkinje-cell pacemaking via sodium-channel splicing [PMID:22357600], myoblast fusion and satellite-cell activation [PMID:25087874, PMID:41418788], cardiac development and stress responses [PMID:25753418, PMID:30867288, PMID:35137168], pancreatic β-cell insulin secretion [PMID:38007492], HSC proteostasis [PMID:41337583], vascular endothelial and smooth-muscle function [PMID:29293084, PMID:41926228], liver cholesterol homeostasis [PMID:36536133], and suppression of metastasis in pancreatic and other cancers [PMID:36949200, PMID:38114498].","teleology":[{"year":2006,"claim":"Established the core molecular activity—that RBFOX2 recognizes a defined RNA element and acts as a physiological splicing regulator—answering what RBFOX2 binds and what it does.","evidence":"SELEX defining UGCAUG specificity plus co-transfection splicing assays and siRNA knockdown on protein 4.1R and FGFR2 exons, with UGCAUG mutagenesis","pmids":["16537540","16449636"],"confidence":"High","gaps":["Whether binding position alone dictates activate-vs-repress outcomes not yet generalized","C-terminal mechanism of activation not defined at this stage"]},{"year":2006,"claim":"Defined a repressive mechanism, showing RBFOX2 can occlude splice-site recognition rather than only activate inclusion.","evidence":"Overexpression in HeLa/neuronal cells with UGCAUG mutation analysis and U2AF65 binding assays on calcitonin/CGRP exon 4","pmids":["17101796"],"confidence":"High","gaps":["Whether the same factor blocks more than one assembly step unresolved here","In vivo relevance of repression not tested"]},{"year":2008,"claim":"Resolved the repression mechanism into a two-step block of prespliceosome assembly and codified the positional rule that determines activation vs. repression.","evidence":"In vitro spliceosome assembly assays with UGCAUG mutants and gel-shift; genome-wide prediction with experimental RT-PCR validation","pmids":["18573872","18794351"],"confidence":"Medium","gaps":["Positional rule rests partly on computational prediction","Quantitative determinants of position-dependence not fully mapped"]},{"year":2008,"claim":"Extended RBFOX2 beyond nuclear splicing by linking the ortholog to cytoplasmic polyadenylation, hinting at multifunctionality.","evidence":"Co-IP and tethered-function translation reporter in Xenopus oocytes (Rbm9 ortholog)","pmids":["18177378"],"confidence":"Medium","gaps":["Single lab, Xenopus ortholog","Mammalian relevance of cytoplasmic polyadenylation role untested"]},{"year":2011,"claim":"Defined the activation mechanism at the molecular level—how RBFOX2 strengthens weak splice sites—and identified its cross-regulation by Rbfox3 through AS-NMD.","evidence":"Splice-site and CTD-deletion mutagenesis with U1C interaction/U1 snRNP recruitment assays; Rbfox3 isoform overexpression with NMD assays","pmids":["22083953","21747913"],"confidence":"High","gaps":["Generality of U1C-mediated recruitment across targets not established","Rbfox3 cross-regulation tested in single study"]},{"year":2012,"claim":"Established an in vivo physiological requirement, showing RBFOX2 maintains neuronal excitability via sodium-channel splicing.","evidence":"CNS/Purkinje conditional knockout mice with RNA-seq, electrophysiology, and Nav1.6 immunoblot","pmids":["22357600"],"confidence":"High","gaps":["Redundancy with Rbfox1 complicates Rbfox2-specific attribution","Direct binding to Scn8a not mapped at nucleotide resolution here"]},{"year":2014,"claim":"Expanded RBFOX2's role from individual exons to network-level control, defining AS-NMD of RBP transcripts and a myogenic splicing program required for myoblast fusion.","evidence":"iCLIP-seq plus RNA-seq in mouse ESCs and myoblasts, with NMD-isoform validation and Mef2d/Rock2 rescue of fusion defects","pmids":["24637117","25087874"],"confidence":"High","gaps":["Hierarchy within the RBP regulatory network not fully ordered","Which targets drive fusion vs. are bystanders not exhaustively resolved"]},{"year":2015,"claim":"Established RBFOX2 as a stress-responsive splicing regulator in heart, where its loss recapitulates pressure-overload decompensation.","evidence":"Cardiac conditional knockout and TAC surgery with RNA-seq, RT-PCR, and echocardiography","pmids":["25753418"],"confidence":"High","gaps":["Causal splicing targets driving decompensation not individually validated here","Mechanism linking pressure overload to RBFox2 downregulation unknown"]},{"year":2016,"claim":"Revealed a chromatin-level function distinct from splicing—RBFOX2 recruits PRC2 in a nascent-RNA-dependent manner to silence bivalent promoters.","evidence":"ChIP-seq, RBFox2–PRC2 co-IP, nascent RNA sequencing, and depletion across multiple cell types","pmids":["27211866"],"confidence":"High","gaps":["How RBFox2 reads nascent RNA to dock PRC2 not structurally defined","Relationship between chromatin role and splicing role at same loci unclear"]},{"year":2016,"claim":"Defined isoform-encoded localization control and dominant-negative regulation, explaining how RBFOX2 partitions between nuclear and cytoplasmic functions and how disease isoforms inhibit wild-type activity.","evidence":"Isoform NLS mapping by subcellular fractionation/IF; DN-WT co-IP with calcium imaging in cardiomyocytes; HLHS truncation-mutant analysis with RIP and patient transcriptomes","pmids":["27859055","27239029","27485310"],"confidence":"Medium","gaps":["DN isoform and HLHS findings from single studies","Quantitative threshold at which DN isoform overrides WT not defined"]},{"year":2017,"claim":"Identified a cytoplasmic stress-granule function in which RBFOX2 regulates RB1, decoupling a non-splicing role from its nuclear activity.","evidence":"IF co-localization with stress-granule markers and RIP-seq of cytoplasmic targets; calcium-channel splicing/electrophysiology in neurons and VSMCs","pmids":["28894257","29067356","28993448"],"confidence":"Medium","gaps":["Mechanism of RBFOX2 recruitment into stress granules unknown","RB1 regulation tested in limited contexts"]},{"year":2018,"claim":"Established tissue-specific in vivo programs—vascular flow-responsive splicing in endothelium and craniofacial development via TGF-β-Tak1 splicing.","evidence":"Endothelial and neural-crest conditional knockouts with RNA-seq; Tak1 overexpression rescue and low-flow arterial model with immune-cell depletion","pmids":["29293084","31241461"],"confidence":"High","gaps":["Direct splicing targets mediating each phenotype not all validated","Feedback loop architecture (TGF-β → RBFox2) mechanism partly inferred"]},{"year":2019,"claim":"Defined a feed-forward cardiac pathway (RBFox2 → miR-34a → Jph2) and confirmed stress-granule/cytoplasmic localization as a cancer-relevant axis.","evidence":"Cardiac KO with miR-34a mimic/antagomir rescue and Jph2 analysis; cancer-tissue IF with RB1 measurement and stress-granule dissolution assays","pmids":["30867288","31028247"],"confidence":"High","gaps":["Mechanism of RBFox2-driven miR-34a transcriptional repression not fully defined","Cytoplasmic cancer role rests on correlative tissue data"]},{"year":2021,"claim":"Systematized RBFOX2's combinatorial partnerships and extended its reach to alternative polyadenylation, defining how partner proteins broaden its target repertoire.","evidence":"RIP, partner-specific knockdown and RNA-seq parsing CLIP data for hnRNPC/hnRNPM/SRSF1 modes; 3'-end and nanopore sequencing with binding-site mutagenesis for APA","pmids":["34244793","34731606"],"confidence":"High","gaps":["Stoichiometry and direct vs. indirect partner contacts not all resolved","How RBFOX2 chooses splicing vs. APA outcomes at shared sites unknown"]},{"year":2021,"claim":"Revealed transcription-factor partnerships and antagonists that retarget or oppose RBFOX2 activity in cancer, including ETS factors, EWS-FLI1, and the SON/hnRNPA2B1 complex.","evidence":"Co-IP, RNA-seq, motif-enrichment and CLIP for ERG/FLI1/EWS-FLI1; SON–hnRNPA2B1 co-IP with RNA-seq and orthotopic GBM xenograft; SLUG-dependent ESRP1 repression assays","pmids":["34009296","34548489","33089214"],"confidence":"Medium","gaps":["Whether interactions are direct or scaffolded not all established","Transcriptional (non-RNA-binding) role of RBFOX2 partly inferred"]},{"year":2023,"claim":"Defined post-translational control of RBFOX2 abundance and an m6A-reading chromatin-silencing axis, integrating its regulation and its epigenetic output.","evidence":"FBXO7/PRMT5 ubiquitination/methylation site mapping with co-IP and RNA-seq; m6A mapping on caRNAs with RBFOX2–RBM15–YTHDC1 co-IP, H3K27me3 ChIP-seq and AML differentiation assays","pmids":["37822160","37640841"],"confidence":"High","gaps":["Interplay between stabilizing (FBXO7) and degradative pathways not co-analyzed","How m6A recognition is structurally achieved by RBFOX2 unknown"]},{"year":2023,"claim":"Established RBFOX2 as a metastasis suppressor acting through cytoskeletal/RHO-GTPase splicing, and as an essential regulator of β-cell insulin secretion.","evidence":"PDX and KO PDA models with in vivo metastasis, RNA-seq and cytoskeletal imaging of MPRIP and ABI1 isoforms; pancreatic conditional KO with glucose physiology, EM granule docking and SNARE-component splicing","pmids":["36949200","38114498","38007492"],"confidence":"High","gaps":["Which individual splice events are necessary vs. sufficient for metastasis suppression not fully isolated","Direct SNARE-component binding not nucleotide-mapped"]},{"year":2025,"claim":"Extended RBFOX2 to stem-cell proteostasis, vascular smooth-muscle ubiquitin regulation/actin control, and continued tissue-specific splicing roles in muscle and heart.","evidence":"Hematopoietic conditional KO with proteostasis assays and chemical rescue; RhoBTB1/CUL3 proximity-labeling MS, co-IP, ubiquitination and SMC-specific KO with arterial stiffness; satellite-cell KO with Numb exon analysis; Snap23 microexon co-regulation with QKI/MBNL1","pmids":["41337583","41926228","41418788","40207498"],"confidence":"High","gaps":["Mechanism linking RBFox2 splicing targets to proteostasis defect unresolved","How RhoBTB1/CUL3 degradation integrates with FBXO7 stabilization unclear"]},{"year":null,"claim":"How RBFOX2 integrates its multiple activities—cassette splicing, AS-NMD, APA, nuclear PRC2/m6A silencing, and cytoplasmic mRNA regulation—into coordinated, context-specific outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for how localization, partner availability, and post-translational state select among activities","Structural basis for m6A and nascent-RNA recognition undefined","Competing stabilizing vs. degradative ubiquitin pathways not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,5,14,23,40]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[31,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,17,40]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[20,27,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20,23,25]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[17,40]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,5,14,33]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[17,40]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,15,26,30,42]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,38,41,44]}],"complexes":["PRC2 (nascent-RNA-dependent association)","cytoplasmic polyadenylation complex (Xenopus ortholog)","cytoplasmic stress granules"],"partners":["U1C","HNRNPC","HNRNPM","SRSF1","RBM15","YTHDC1","RHOBTB1","FBXO7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43251","full_name":"RNA binding protein fox-1 homolog 2","aliases":["Fox-1 homolog B","Hexaribonucleotide-binding protein 2","RNA-binding motif protein 9","RNA-binding protein 9","Repressor of tamoxifen transcriptional activity"],"length_aa":390,"mass_kda":41.4,"function":"RNA-binding protein that regulates alternative splicing events by binding to 5'-UGCAUGU-3' elements. Prevents binding of U2AF2 to the 3'-splice site. Regulates alternative splicing of tissue-specific exons and of differentially spliced exons during erythropoiesis (By similarity). RNA-binding protein that seems to act as a coregulatory factor of ER-alpha. Together with RNA binding proteins RBPMS and MBNL1/2, activates vascular smooth muscle cells alternative splicing events (PubMed:37548402)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O43251/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBFOX2","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RBFOX2","total_profiled":1310},"omim":[{"mim_id":"616999","title":"RNA-BINDING FOX1 HOMOLOG 3; RBFOX3","url":"https://www.omim.org/entry/616999"},{"mim_id":"612149","title":"RNA-BINDING FOX1 HOMOLOG 2; RBFOX2","url":"https://www.omim.org/entry/612149"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBFOX2"},"hgnc":{"alias_symbol":["HNRBP2","FOX-2","HRNBP2"],"prev_symbol":["RBM9"]},"alphafold":{"accession":"O43251","domains":[{"cath_id":"3.30.70.330","chopping":"128-189","consensus_level":"high","plddt":95.8234,"start":128,"end":189}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43251","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43251-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43251-F1-predicted_aligned_error_v6.png","plddt_mean":54.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBFOX2","jax_strain_url":"https://www.jax.org/strain/search?query=RBFOX2"},"sequence":{"accession":"O43251","fasta_url":"https://rest.uniprot.org/uniprotkb/O43251.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43251/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43251"}},"corpus_meta":[{"pmid":"18794351","id":"PMC_18794351","title":"Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2.","date":"2008","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/18794351","citation_count":259,"is_preprint":false},{"pmid":"22357600","id":"PMC_22357600","title":"The splicing regulator Rbfox2 is required for both cerebellar development and mature motor function.","date":"2012","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/22357600","citation_count":182,"is_preprint":false},{"pmid":"23435423","id":"PMC_23435423","title":"The RNA-binding protein Rbfox2: an essential regulator of EMT-driven alternative splicing and a mediator of cellular invasion.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23435423","citation_count":138,"is_preprint":false},{"pmid":"23149937","id":"PMC_23149937","title":"RBFOX2 is an important regulator of mesenchymal tissue-specific splicing in both normal and cancer tissues.","date":"2012","source":"Molecular and 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Both Fox-1 and Fox-2 bind UGCAUG elements in the downstream intron of protein 4.1R exon 16 and activate exon inclusion; knockdown of Fox-2 via siRNA decreased exon 16 splicing, identifying Fox-2 as a physiological activator of this splicing switch in differentiating erythroid cells.\",\n      \"method\": \"SELEX, co-transfection splicing assays, siRNA knockdown, immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SELEX established binding specificity; functional splicing assays with mutagenesis of binding sites and siRNA knockdown replicated in multiple constructs; peer-reviewed\",\n      \"pmids\": [\"16537540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fox-2 regulates FGFR2 exon IIIb vs. IIIc choice in an epithelial cell-specific manner. Fox-2 expression is higher in IIIb+ epithelial cells; ectopic expression of Fox-2 switches splicing from IIIc to IIIb, absolutely dependent on (U)GCAUG elements. The C-terminal region of Fox-2 is required for this activity. Fox-2 knockdown abolishes the IIIb inclusion switch. Fox-2 also autoregulates its own activity by inducing skipping of its own exon 6 to produce an inactive isoform.\",\n      \"method\": \"RT-PCR splicing assays, Fox-2 overexpression, siRNA knockdown, mutagenesis of UGCAUG elements, isoform analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (OE, KD, mutagenesis) in the same study with clear mechanistic dissection\",\n      \"pmids\": [\"16449636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fox-1 and Fox-2 repress inclusion of calcitonin-specific exon 4 of calcitonin/CGRP pre-mRNA via two UGCAUG elements flanking the 3' splice site. They block U2AF65 binding to the polypyrimidine tract upstream of exon 4, establishing a mechanism of splice-site occlusion.\",\n      \"method\": \"Overexpression in HeLa and neuronal cells, UGCAUG mutation analysis, U2AF65 binding assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical demonstration of U2AF65 displacement combined with mutagenesis and cellular splicing assays\",\n      \"pmids\": [\"17101796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"During erythroid differentiation, an erythroid differentiation-inducible Fox-2 isoform (mFox-2A) is upregulated while a commonly expressed isoform (mFox-2F) is downregulated. mFox-2A exerts a much stronger enhancing effect on protein 4.1R exon 16 inclusion than mFox-2F, and isoform-specific knockdown of mFox-2A reverses its splicing-enhancing activity, demonstrating isoform-specific regulation.\",\n      \"method\": \"RT-PCR isoform analysis during erythroid differentiation, isoform-specific overexpression, isoform-specific siRNA knockdown\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal isoform-specific gain and loss of function with direct splicing readout, replicated across differentiation time-course\",\n      \"pmids\": [\"17715393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fox-1/Fox-2 repress calcitonin-specific splicing through a two-step mechanism: (1) binding to an intronic UGCAUG element blocks SF1-dependent E' complex formation; (2) binding to an exonic UGCAUG element blocks the E' to E complex transition. This constitutes a novel strategy of blocking two distinct prespliceosome assembly steps by a single factor.\",\n      \"method\": \"Biochemical spliceosome assembly assays, UGCAUG mutant constructs, gel-shift analyses\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro spliceosome complex formation assays with mutagenesis, single lab but multiple orthogonal biochemical approaches\",\n      \"pmids\": [\"18573872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Genome-wide prediction and experimental validation established that Fox-1 and Fox-2 bind UGCAUG and that preferred binding position relative to the alternative exon determines splicing outcome: downstream binding activates exon inclusion, whereas upstream binding represses it.\",\n      \"method\": \"Computational binding site analysis, phylogenetic conservation, splicing microarray, experimental validation by RT-PCR\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — position-dependent regulatory rules validated experimentally across many targets, but primary evidence is computational with selected experimental confirmation\",\n      \"pmids\": [\"18794351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Xenopus Rbm9 (ortholog of RBFOX2/RBM9) is a component of the cytoplasmic polyadenylation complex in Xenopus oocytes; it directly interacts with XGld2 (poly(A) polymerase), is found with CPEB and CPSF, and tethered XRbm9 stimulates translation of a reporter mRNA, revealing a function in cytoplasmic polyadenylation beyond splicing.\",\n      \"method\": \"Co-immunoprecipitation, interaction mapping, tethered-function reporter assay in Xenopus oocytes\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP in Xenopus oocytes with tethered translation assay; single lab, Xenopus ortholog\",\n      \"pmids\": [\"18177378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Fox-2 (RBFOX2) regulates alternative splicing of lysyl hydroxylase 2 (LH2) exon 13A by binding to UGCAUG motifs flanking the exon; overexpression of Fox-2 enhances exon 13A inclusion (generating the scleroderma-associated LH2-long isoform) and knockdown reduces LH2-long mRNA levels in SSc patient fibroblasts. Mutagenesis of two of four Fox-binding motifs is sufficient to abolish exon inclusion.\",\n      \"method\": \"LH2 minigene splicing assays, Fox-2 overexpression/knockdown, UGCAUG mutagenesis, RT-PCR in patient fibroblasts\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — minigene mutagenesis + patient fibroblast knockdown + overexpression, two orthogonal approaches\",\n      \"pmids\": [\"20131247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RBFOX2 promotes protein 4.1R exon 16 inclusion by recruiting U1 snRNP to the weak 5' splice site via direct interaction between the RBFOX2 C-terminal domain (CTD) and the zinc finger region of U1C protein. Strengthening the 5' splice site to consensus abrogates the requirement for RBFOX2, and CTD deletion abolishes the splicing-enhancing effect.\",\n      \"method\": \"5' splice site mutagenesis, RBFOX2 CTD deletion analysis, U1C interaction assays, U1 snRNP recruitment assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mechanistic dissection with mutagenesis of both splice site and protein domain, direct protein–snRNP interaction demonstration\",\n      \"pmids\": [\"22083953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rbfox3 (NeuN) negatively regulates Rbfox2: nuclear Rbfox3 isoforms enhance inclusion of cryptic exons in Rbfox2 mRNA, resulting in nonsense-mediated decay of Rbfox2 transcripts, and Rbfox3 also promotes production of a dominant-negative Rbfox2 protein through alternative splicing of Rbfox2 pre-mRNA.\",\n      \"method\": \"Alternative splicing analysis, RT-PCR, NMD pathway assays, overexpression of Rbfox3 isoforms\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional splicing and NMD assays in single lab, single study\",\n      \"pmids\": [\"21747913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CNS-specific deletion of Rbfox2 disrupts cerebellar development. Genome-wide analysis identifies Scn8a (Nav1.6 sodium channel) as an Rbfox2 splicing target; improper splicing in Rbfox2-null brains leads to reduced Nav1.6 protein. Combined Purkinje cell deletion of Rbfox1 and Rbfox2 causes irregular firing, establishing that Rbfox2 (with Rbfox1) maintains neuronal pacemaking via sodium channel splicing.\",\n      \"method\": \"Conditional knockout mice, RNA-seq, electrophysiology of Purkinje cells, immunoblot for Nav1.6\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genome-wide splicing analysis, electrophysiology, and protein-level validation; multiple phenotypic readouts\",\n      \"pmids\": [\"22357600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FOX-2 (RBFOX2) interacts with ataxin-1 (co-immunoprecipitation in mammalian cells) and directly interacts with ataxin-2; reduction of Fox-2 levels leads to increased skipping of ataxin-2 exon 18. Overexpression of nuclear ataxin-1 sequesters Fox-2 into nuclear inclusions and impairs this splicing event.\",\n      \"method\": \"Yeast-2-hybrid, co-immunoprecipitation, siRNA knockdown, RT-PCR splicing assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP and functional splicing assays, single study\",\n      \"pmids\": [\"22666429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBFOX2 expression is upregulated during EMT, correlating with increased RBFOX2-regulated splicing of cortactin, Pard3, and Dnm2. Depletion of RBFOX2 in cells that have completed EMT significantly reduces invasive potential without affecting mesenchymal marker expression or TGF-β signaling, demonstrating a specific role for RBFOX2-regulated splicing in cellular invasion.\",\n      \"method\": \"EMT cell culture models, siRNA knockdown, RT-PCR splicing assays, invasion assays (Matrigel), western blotting\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional invasion assays combined with splicing analysis and defined negative controls, single lab\",\n      \"pmids\": [\"23435423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MBNL1 and RBFOX2 cooperatively control a splicing program during mesoderm differentiation. High-throughput RT-PCR during iPSC reprogramming and redifferentiation identified concerted splicing changes in at least 10 conserved genes (including PLOD2, CLSTN1, ATP2A1) controlled by these two splicing regulators.\",\n      \"method\": \"High-throughput RT-PCR during iPSC reprogramming/differentiation, RBP knockdown in cell lines\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — high-throughput splicing profiling combined with functional knockdown, single lab\",\n      \"pmids\": [\"24048253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rbfox2 cross-regulates AS-coupled NMD (AS-NMD) events within RNA-binding protein genes to alter their steady-state expression. Using iCLIP and RNA-seq in mouse ESCs, >200 AS-NMD events were identified as Rbfox2-bound; these 'silent' events show minimal splicing change but significant gene expression changes upon knockdown due to NMD isoform regulation. Nearly 70 events fall within RBP genes, many of which are autoregulated, establishing Rbfox2 as a regulator of a broader RBP network.\",\n      \"method\": \"iCLIP-seq, RNA-seq, siRNA knockdown, RT-PCR validation of NMD isoforms\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — iCLIP (nucleotide-resolution binding) combined with RNA-seq expression changes; multiple orthogonal methods, strong mechanistic framework\",\n      \"pmids\": [\"24637117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rbfox2 regulates ~30% of splicing transitions during myogenesis and is specifically required for myoblast fusion. Rbfox2 iCLIP combined with RNA-seq identified Mef2d and Rock2 as direct splicing targets; rescue of myoblast fusion defects in Rbfox2-depleted cultures by restored Mef2d and Rock2 activities demonstrates functional cooperation between isoforms generated by coordinated alternative splicing.\",\n      \"method\": \"iCLIP-seq, RNA-seq, shRNA knockdown, rescue experiments with Mef2d/Rock2 isoforms, fusion assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — iCLIP identifies direct targets, rescue experiments establish functional requirement, multiple orthogonal approaches\",\n      \"pmids\": [\"25087874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Transverse aortic constriction (TAC) potently decreases RBFox2 protein in mouse heart. Cardiac-specific ablation of RBFox2 generates phenotypes resembling cardiac decompensation, and RBFox2 regulates splicing of genes involved in heart function. A subset of these genes undergo developmental regulation during postnatal heart remodeling that is reversed in both TAC-treated and RBFox2 knockout mice, establishing RBFox2 as a stress-sensor splicing regulator in pressure overload-induced heart failure.\",\n      \"method\": \"Conditional cardiac knockout mice, TAC surgery model, RNA-seq splicing analysis, RT-PCR validation, echocardiography\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo cardiac KO with genome-wide splicing analysis plus disease model correlation, multiple phenotypic readouts\",\n      \"pmids\": [\"25753418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RBFox2 directly interacts with Polycomb Repressive Complex 2 (PRC2) in a nascent RNA-dependent manner. RBFox2 depletion causes widespread increase in nascent RNA production and eradicates PRC2 targeting on the majority of bivalent gene promoters, leading to transcriptional de-repression. ChIP-seq reveals extensive RBFox2 chromatin association dependent on nascent RNA.\",\n      \"method\": \"ChIP-seq, biochemical interaction assays (RBFox2–PRC2 co-IP), nascent RNA sequencing, Bayesian network analysis, RBFox2 depletion in multiple cell types\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical interaction demonstrated, genome-wide ChIP-seq, multiple cell types, multiple orthogonal approaches\",\n      \"pmids\": [\"27211866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RBFOX2 protein levels are elevated in diabetic hearts due to upregulation of a dominant-negative (DN) isoform of RBFOX2. DN RBFOX2 interacts with wild-type RBFOX2 (co-IP) and inhibits RBFOX2-mediated alternative splicing of target genes. Ectopic expression of DN RBFOX2 impairs intracellular calcium release in cardiomyocytes, identifying dysregulation by DN isoform as an early event in diabetic cardiomyopathy.\",\n      \"method\": \"Co-IP (DN-WT interaction), RT-PCR for splicing, overexpression of DN isoform, calcium imaging in cardiomyocytes, diabetic mouse hearts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed interaction, calcium imaging provided functional readout, multiple methods in single lab\",\n      \"pmids\": [\"27239029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A nonsense mutation in Rbfox2 identified in hypoplastic left heart syndrome (HLHS) patients truncates the protein and impairs its subcellular distribution (nuclear export/localization) and function in RNA metabolism. Rbfox2 regulates mRNA levels of targets through 3'UTR binding sites in addition to splicing regulation.\",\n      \"method\": \"Truncation mutant analysis, subcellular fractionation, RNA-immunoprecipitation, transcriptome analysis of HLHS patient right ventricles\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — patient-derived functional analysis with mechanistic follow-up, single study, limited replication\",\n      \"pmids\": [\"27485310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A nuclear localization signal (NLS) at the N terminus of Rbfox2 isoform 1A (not present in isoform 1F) is identified; Rbfox2 1A isoforms lacking the C-terminal NLS remain nuclear, whereas equivalent 1F isoforms are cytoplasmic. A shift toward cytoplasmic 1F isoforms occurs during EMT.\",\n      \"method\": \"Isoform cloning, subcellular fractionation, immunofluorescence, EMT cell models\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — localization determined by direct experiment with isoform-specific constructs, single lab\",\n      \"pmids\": [\"27859055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Rbfox2 represses inclusion of alternatively spliced exon 18a in CaV2.2 (Cacna1b) pre-mRNA. siRNA knockdown of Rbfox2 in neuronal cells increases e18a inclusion, and Rbfox2-RNA immunoprecipitation demonstrates reduced Rbfox2 binding upstream of e18a in adult sympathetic neurons. CaV2.2 currents are larger when exon 18a is included, establishing that Rbfox2 limits CaV2.2 current size early in development.\",\n      \"method\": \"siRNA knockdown, RNA immunoprecipitation (RIP)-qPCR, whole-cell patch clamp, RT-PCR\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and electrophysiology in the same study; single lab, two orthogonal methods\",\n      \"pmids\": [\"29067356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Rbfox2 dynamically regulates alternative exons 9* and 33 of the vascular CaV1.2 (Cacna1c) calcium channel. Knockdown of Rbfox2 in vascular smooth muscle cells increases exon 9* and decreases exon 33 inclusion, shifting CaV1.2 window current to more negative potentials and increasing pressure-induced myogenic tone in mesenteric artery.\",\n      \"method\": \"siRNA knockdown in VSMCs, RT-PCR splicing assays, patch clamp electrophysiology, pressure myograph for myogenic tone\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splicing knockdown combined with electrophysiology and vascular function assays in single lab\",\n      \"pmids\": [\"28993448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Rbfox2 is a novel constituent of cytoplasmic stress granules. RNA-binding activity of Rbfox is required for its localization into stress granules. In stress granules, Rbfox2 binds and regulates retinoblastoma 1 (RB1) mRNA and protein expression during and after stress exposure.\",\n      \"method\": \"Immunofluorescence co-localization, RNA-immunoprecipitation sequencing (RIP-seq) of cytoplasmic targets, stress granule markers, stress induction assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-localization + RIP-seq identifying cytoplasmic targets, single lab, two orthogonal methods\",\n      \"pmids\": [\"28894257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Endothelial-specific deletion of Rbfox2 (the only Rbfox family member expressed in arterial endothelium) suppresses a subset of alternative splicing and transcriptional changes induced by low arterial flow, identifying an Rbfox2-dependent alternative splicing program activated during flow-driven vascular inflammation involving platelet and macrophage recruitment.\",\n      \"method\": \"Endothelial conditional Rbfox2 knockout mice, in vivo low-flow arterial model, RNA-seq, platelet/macrophage depletion\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in vivo with genome-wide splicing analysis and depletion of upstream signals; multiple orthogonal approaches\",\n      \"pmids\": [\"29293084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rbfox2 present in cytoplasmic stress granules inhibits RB1 protein expression and promotes cell cycle progression. Resveratrol-induced dissociation of Rbfox2 from stress granules inhibits RB1 suppression and cancer progression; Rbfox2 cytoplasmic localization in colon cancer tissues correlates with its stress granule role distinct from nuclear splicing function.\",\n      \"method\": \"Immunofluorescence in human cancer tissues, stress granule induction/dissolution assays, RB1 protein measurement, tumor growth assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — localization + functional assays; single lab, mechanistic link to RB1 regulation established but limited orthogonal validation\",\n      \"pmids\": [\"31028247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Neural crest-specific deletion of Rbfox2 causes cleft palate and craniofacial bone defects. Rbfox2 regulates splicing of genes in TGF-β-Tak1 signaling; restoration of TGF-β signaling by Tak1 overexpression rescues proliferation defects in Rbfox2 mutant neural crest cells. A positive feedback loop exists where TGF-β signaling promotes Rbfox2 expression in NCCs.\",\n      \"method\": \"Conditional Rbfox2 knockout in neural crest cells (Wnt1-Cre), RNA-seq, Tak1 overexpression rescue experiments, craniofacial morphology analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with pathway rescue experiments and RNA-seq; multiple phenotypic and molecular readouts\",\n      \"pmids\": [\"31241461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Alternative splicing of exon 10 in RBFOX2 removes a nuclear localization signal, causing cytoplasmic localization of RBFOX2 in calcific tendons vs. nuclear localization in normal tendons. Cytoplasmic RBFOX2 in calcific tendons is associated with altered splicing of RBFOX2 target genes CHD2 and MBNL1.\",\n      \"method\": \"Immunofluorescence microscopy, RBFOX2 isoform sequencing, RT-PCR of splicing targets in clinical samples\",\n      \"journal\": \"Experimental and molecular pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — direct localization by IF linked to isoform sequencing and target splicing changes; single study, clinical specimens\",\n      \"pmids\": [\"31128090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RBFox2 controls a feed-forward regulatory pathway in heart failure: reduced RBFox2 induces transcriptional repression of miR-34a, which then targets Jph2 mRNA to impair excitation-contraction coupling, leading to progressive cardiac dysfunction. Administration of miR-34a antagomir alleviates RBFox2 depletion-induced heart dysfunction.\",\n      \"method\": \"Conditional cardiac RBFox2 knockout, miR-34a mimic/antagomir in vivo, Jph2 expression analysis, cardiac function assays (echocardiography)\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO + miRNA gain/loss of function with cardiac functional readout; multiple orthogonal methods establishing the pathway\",\n      \"pmids\": [\"30867288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A non-muscle RBFOX2 isoform (RBFOX240) is upregulated in DM1 heart tissue due to altered splicing factor and microRNA activities. Mice expressing RBFOX240 in heart via transgenic or CRISPR/Cas9 knockin reproduce DM1-related cardiac conduction delay and arrhythmia. RBFOX240 drives splicing defects in voltage-gated sodium and potassium channels, altering their electrophysiological properties.\",\n      \"method\": \"DM1 patient tissue analysis, tetracycline-inducible transgenesis, CRISPR/Cas9 knockin mice, RNA-seq, electrophysiological recording, integration with cardiac transcriptomes\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent mouse models (transgenic + CRISPR), patient validation, electrophysiology, RNA-seq; multiple orthogonal methods\",\n      \"pmids\": [\"32109384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RBFOX2 is required for cardiomyocyte alternative splicing regulation during heart development; conditional deletion in embryonic mouse hearts causes cardiac chamber and yolk sac vasculature defects resembling HLHS. RNA-seq identifies dysregulated AS networks affecting cell–ECM adhesion via Rho GTPase cycling genes. Antisense oligos modulating AS of two Rho GTPase cycling genes cause cell cycle and cell-ECM adhesion defects.\",\n      \"method\": \"Cardiac conditional Rbfox2 KO, RNA-seq, antisense oligonucleotide (ASO) experiments, cell adhesion and cycle assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with RNA-seq plus ASO rescue experiments with mechanistic readout; multiple orthogonal approaches\",\n      \"pmids\": [\"35137168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RBFOX2 transcriptionally represses ESRP1 by interacting with the transcription factor SLUG under hypoxia/TGF-β signaling, in addition to its RNA-binding role. This leads to skipping of hMENA exon 11a, producing a pro-metastatic isoform. Both RBFOX2 and SLUG are upregulated via TGF-β signaling under hypoxia.\",\n      \"method\": \"TGF-β/hypoxia treatment, ChIP/reporter assays for ESRP1 repression, RBFOX2 and SLUG interaction assays, AS analysis of hMENA\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — transcriptional and splicing functions both demonstrated, but mechanistic detail is partially inferred; single lab\",\n      \"pmids\": [\"33089214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBFOX2 can interact with hnRNPC, hnRNPM, and SRSF1 to regulate splicing in three distinct binding modes: (1) single mode—RBFOX2 alone at canonical UGCAUG; (2) multiple mode—RBFOX2 adjacent to at least one other RBP partner; (3) secondary mode—RBFOX2 recruited to sites without its canonical motif through partner binding. These modes control distinct sets of transcripts with different positional relationships to splice sites.\",\n      \"method\": \"RNA immunoprecipitation, RBP-specific knockdown, RNA-seq, splice-sensitive PCR, parsing of public CLIP datasets\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mechanistic dissection using IP + KD + RNA-seq across multiple protein partners; two orthogonal approaches in single lab\",\n      \"pmids\": [\"34244793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBFOX2 is critical for maintaining alternative polyadenylation (APA) patterns in myoblasts. 3'-end and nanopore sequencing reveal that RBFOX2 depletion disrupts APA of mitochondrial and contractile genes. Mechanistically, RBFOX2 binding to consensus RBFOX2 motifs near the distal polyadenylation site of Slc25a4 enforces use of the proximal site; RBFOX2 depletion impairs mitochondrial health in myoblasts.\",\n      \"method\": \"3'-end sequencing, nanopore cDNA sequencing, RBFOX2 knockdown, binding site mutagenesis, mitochondrial function assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two sequencing platforms identifying APA role, binding site mutagenesis, functional mitochondrial phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"34731606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rbfox2 mediates exon 11 inclusion in insulin receptor (IR) pre-mRNA in hepatoma cells via an intronic UGCAUG element just downstream of exon 11. Mutation of the UGCAUG sequence causes exon 11 skipping, and Rbfox2 knockdown enhances endogenous exon 11 skipping. SRSF3 binding site mutations combined with Rbfox2 binding site mutations completely abolish exon 11 inclusion.\",\n      \"method\": \"Minigene splicing reporter with deletions and mutations, siRNA knockdown of Rbfox2, RT-PCR\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — minigene mutagenesis + KD; single lab\",\n      \"pmids\": [\"34022289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SON suppresses RBFOX2-mediated non-oncogenic neuronal splicing in GBM by forming a complex with hnRNP A2B1 that antagonizes RBFOX2, leading to skipping of RBFOX2-targeted cassette exons including the PTBP2 neuronal exon. SON knockdown restores RBFOX2 activity and inhibits GBM tumor growth in vivo.\",\n      \"method\": \"Co-IP (SON–hnRNP A2B1), RNA-seq after SON knockdown, RT-PCR of RBFOX2 targets, orthotopic xenograft\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + RNA-seq + in vivo xenograft; mechanistic relationship between SON and RBFOX2 established, single lab\",\n      \"pmids\": [\"34548489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERG and FLI1 transcription factors associate with RBFOX2 via their conserved C-terminal domain (ETS domain region), and co-regulate alternative spliced exons (ASEs) enriched in RBFOX2 motifs. EWS-FLI1 also associates with RBFOX2 but antagonizes its effects on exon inclusion, including reducing RBFOX2 binding to ADD3 pre-mRNA, promoting an isoform that represses the mesenchymal phenotype.\",\n      \"method\": \"Co-IP (ERG/FLI1/EWS-FLI1 with RBFOX2), RNA-seq, RBFOX2 motif enrichment analysis, CLIP validation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus transcriptomic analysis and CLIP; single lab, two orthogonal methods\",\n      \"pmids\": [\"34009296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBFOX2 promotes inclusion of TEAD1 exon 6 via binding to a conserved GCAUG element in the downstream intron. Full-length TEAD1 (with exon 6) has greater transcriptional activity and YAP interaction than TEAD1ΔE6, with the difference in transcription mediated through YAP binding. This establishes an RBFOX2–TEAD1 splicing axis modulating Hippo–YAP signaling.\",\n      \"method\": \"RT-PCR and RNA-seq for splicing, RBFOX2 knockdown and overexpression, transcriptional activity assays, YAP interaction assays, GCAUG mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding site mutagenesis + functional signaling assays; single lab, two orthogonal approaches\",\n      \"pmids\": [\"35699208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Liver RBFOX2 regulates cholesterol homeostasis by controlling alternative splicing of Scarb1 (scavenger receptor B1). In diet-induced obesity, RBFOX2 function is decreased in liver causing a Scarb1 isoform switch and altered hepatocyte lipid homeostasis. Splice-switching oligonucleotides targeting this network alleviate obesity-induced liver inflammation and promote anti-atherogenic lipoprotein profile.\",\n      \"method\": \"Enhanced iCLIP in mouse liver, liver-specific Rbfox2 KO, dietary obesity model, ASO treatment, lipoprotein profiling, inflammation assays\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — eiCLIP identifies direct Scarb1 target, liver KO + diet model + ASO rescue with multiple physiological readouts; multiple orthogonal methods\",\n      \"pmids\": [\"36536133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBFOX2 regulates alternative splicing of MICU1 (Mitochondrial Calcium Uniporter activator) during myogenesis, generating a muscle-specific MICU1.1 splice variant with distinct properties for mitochondrial Ca2+ uptake. RBFOX2 is identified as the splicing factor driving this switch during myoblast differentiation.\",\n      \"method\": \"Tissue isoform analysis, myogenesis differentiation time-course, RBFOX2 knockdown, mitochondrial Ca2+ uptake assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional mitochondrial Ca2+ assays combined with splicing analysis; single lab\",\n      \"pmids\": [\"35269658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBFOX2 recognizes N6-methyladenosine (m6A) on chromatin-associated RNAs (caRNAs) and recruits RBM15 (an m6A methyltransferase complex component) to facilitate methylation of promoter-associated RNAs. RBM15 interacts with YTHDC1 and recruits PRC2 to RBFOX2-bound loci for chromatin silencing. This RBFOX2/m6A/RBM15/YTHDC1/PRC2 axis is required for AML cell survival and myeloid differentiation control.\",\n      \"method\": \"m6A mapping on caRNAs, Co-IP (RBFOX2–RBM15, RBM15–YTHDC1), ChIP-seq for H3K27me3, RBFOX2 knockdown in AML cells, functional differentiation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical co-IP of multi-protein complex, m6A mapping, ChIP-seq, functional AML assays; multiple orthogonal approaches, high-impact journal\",\n      \"pmids\": [\"37640841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBFOX2 acts as a metastatic suppressor in pancreatic ductal adenocarcinoma (PDA). Overexpression of RBFOX2 in metastatic PDA cells reduces metastatic potential in vitro and in vivo; depletion increases it. RBFOX2 splicing targets are enriched in RHO GTPase pathways. Modulation of RBFOX2-regulated splicing of MPRIP (myosin phosphatase RHO-interacting protein) alters cytoskeletal organization and focal adhesion formation.\",\n      \"method\": \"Patient-derived xenograft models, RNA-seq/splicing analysis of RBFOX2 targets, in vivo metastasis assays, cytoskeletal imaging\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — PDX models + in vivo metastasis + RNA-seq + cytoskeletal mechanistic analysis; multiple orthogonal methods, high-impact journal\",\n      \"pmids\": [\"36949200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBFOX2 regulates insulin secretion in pancreatic β-cells through alternative splicing of SNARE complex components required for insulin granule docking and exocytosis. Conditional Rbfox2 mutation in mouse pancreas results in decreased insulin secretion, impaired blood glucose homeostasis, and reduced insulin granule docking.\",\n      \"method\": \"Pancreatic conditional Rbfox2 knockout mice, glucose tolerance/insulin secretion assays, electron microscopy for granule docking, RNA-seq for splicing of SNARE components\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with glucose physiology, EM-based granule docking, and splicing analysis; multiple orthogonal readouts\",\n      \"pmids\": [\"38007492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO7 stabilizes Rbfox2 by K63-linked ubiquitination at Lys249 upon arginine dimethylation at Arg341 and Arg441 by PRMT5. This FBXO7-Rbfox2 axis controls splicing of mesenchymal genes (FoxM1, Mta1, Postn) and promotes GBM mesenchymal transformation and chemoresistance.\",\n      \"method\": \"Co-IP, ubiquitination assays, site-specific mutagenesis of Rbfox2 ubiquitination and methylation sites, RNA-seq, tumor xenografts\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination site mapping + Co-IP + splicing analysis; single lab, multiple approaches\",\n      \"pmids\": [\"37822160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBFOX2 depletion promotes pancreatic cancer progression and liver metastasis by altering splicing of cytoskeletal remodeling genes. RBFOX2-mediated splicing of ABI1 (exon 9) controls ABI1 protein isoform abundance and localization; the ABI1 ΔEx9 isoform (generated by splice-switching ASOs) enhances cell migration.\",\n      \"method\": \"Sleeping Beauty insertional mutagenesis screen, RBFOX2 KO in PDAC models, RNA-seq, ABI1 isoform localization by IF, splice-switching ASOs, in vivo metastasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — forward genetic screen + mechanistic validation with KO, ASO, localization studies, and in vivo metastasis assays\",\n      \"pmids\": [\"38114498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rbfox2 selectively governs hematopoietic stem cell (HSC) self-renewal by regulating proteostasis. Deletion of Rbfox2 from the hematopoietic compartment specifically depletes HSCs but not multipotent progenitors. Mechanistically, Rbfox2 loss leads to increased protein synthesis and accumulated misfolded/unfolded proteins in HSCs. Small molecules restoring proteostasis rescue HSC defects in Rbfox2-deficient mice.\",\n      \"method\": \"Conditional Rbfox2 KO in hematopoietic compartment, bone marrow transplantation, proteostasis assays (protein synthesis rate, unfolded protein content), chemical rescue experiments\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with mechanistic proteostasis dissection and chemical rescue; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41337583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBFOX2 is ubiquitinated in a RhoBTB1- and CUL3-dependent manner in vascular smooth muscle cells, establishing it as a substrate of the RhoBTB1/CUL3 ubiquitin-proteasome pathway. Co-immunoprecipitation validates the RBFOX2–RhoBTB1 interaction. Rbfox2 depletion impairs the actin cytoskeleton and alters filamentous/globular actin levels. SMC-specific Rbfox2 deletion halts progression of ANG-induced arterial stiffness.\",\n      \"method\": \"Proximity labeling + mass spectrometry, co-immunoprecipitation, ubiquitination assays, siRNA knockdown, conditional SMC-specific Rbfox2 KO mice, actin polymerization assays, arterial stiffness measurements\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proximity labeling MS + Co-IP + ubiquitination biochemistry + in vivo conditional KO with vascular functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"41926228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBFOX2 is essential for cardiomyocyte differentiation by promoting exon usage shifts to mature patterns in sarcomere and cytoskeletal genes (including ACTN2). RBFOX2 autoregulates itself at mutually exclusive exons: at critical RBFOX2 levels, autoregulation enforces mature isoforms; in heterozygous CMs, autoregulation is disrupted generating a dominant-negative product. Overexpression of ACTN2 rescues heterozygous (not null) phenotypes by restoring contractility and triggering mechanosensing upregulation of RBFOX2 from the wildtype allele.\",\n      \"method\": \"iPSC-derived cardiomyocyte differentiation, RBFOX2 heterozygous and null mutants, RNA-seq, ACTN2 overexpression rescue, contractility assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell models + rescue experiments; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41280054\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBFOX2 promotes inclusion of the Numb exon 6 in satellite cells (SCs), and RBFOX2 loss delays SC activation and muscle regeneration. Exon 6-containing Numb is required for SC activation; its skipping upregulates Notch signaling and delays activation.\",\n      \"method\": \"In vivo SC fixation to preserve quiescent state, Rbfox2 conditional KO in SCs, RNA-seq, exon 6 inclusion/skipping analysis, muscle regeneration assay\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional KO + splicing analysis + in vivo regeneration; single study\",\n      \"pmids\": [\"41418788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBFOX2 promotes splicing of a Snap23 microexon in striated muscle by binding downstream of the microexon together with QKI, and this regulation can be escaped when the weak splice donor is mutated to consensus. MBNL1 acts as an additional, minor layer of Snap23 microexon control. The microexon is mis-regulated in mouse models of heart and skeletal muscle diseases.\",\n      \"method\": \"Splicing factor knockdowns (RBFOX2, QKI, MBNL1), minigene splice site mutagenesis, disease model analysis, binding site mapping\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — minigene mutagenesis + multiple RBP KDs; single lab, single study\",\n      \"pmids\": [\"40207498\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBFOX2 is a multifunctional RNA-binding protein that recognizes the hexameric element UGCAUG (and related motifs) in pre-mRNAs to activate or repress alternative exon inclusion depending on binding position (downstream = activation, upstream = repression); it recruits U1 snRNP via its C-terminal domain to strengthen weak splice sites, blocks prespliceosome assembly at two distinct steps, interacts with hnRNPC/hnRNPM/SRSF1 in multiple binding configurations, controls AS-coupled NMD of RNA-binding protein transcripts to tune an RBP regulatory network, regulates alternative polyadenylation, and directly binds PRC2 in a nascent RNA-dependent manner to enforce chromatin silencing at bivalent promoters; RBFOX2 also recognizes m6A on chromatin-associated RNAs and recruits the RBM15/YTHDC1/PRC2 axis for locus-selective gene silencing; it is a substrate of the RhoBTB1/CUL3 ubiquitin-proteasome pathway and is stabilized by FBXO7/PRMT5-dependent K63 ubiquitination; distinct protein isoforms generated by its own alternative splicing differ in nuclear localization signals and cytoplasmic vs. nuclear distribution, affecting its function in splicing versus cytoplasmic stress-granule-mediated mRNA regulation; critical roles have been established in cerebellar development, Purkinje cell pacemaking, myoblast fusion, cardiac development and stress response, HSC proteostasis, pancreatic β-cell insulin secretion, neural crest development, vascular endothelial and smooth muscle function, liver cholesterol homeostasis, and suppression of cancer metastasis in pancreatic and other tumors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBFOX2 is a sequence-specific RNA-binding protein that governs alternative splicing programs across development, tissue homeostasis, and disease by recognizing the hexameric element UGCAUG (and related GCAUG motifs) in pre-mRNAs [#0, #5]. Its regulatory outcome is positional: binding downstream of an alternative exon activates inclusion while upstream binding represses it [#5], and mechanistically it both recruits U1 snRNP to weak 5' splice sites through a direct C-terminal-domain interaction with U1C [#8] and blocks prespliceosome assembly at two distinct steps by occluding U2AF65/SF1-dependent complex formation [#2, #4]. Beyond cassette-exon splicing, RBFOX2 controls AS-coupled NMD of RNA-binding protein transcripts to tune a broader RBP network [#14], directs alternative polyadenylation [#33], and acts in the nucleus on chromatin: it binds PRC2 in a nascent-RNA-dependent manner to enforce silencing at bivalent promoters [#17] and recognizes m6A on chromatin-associated RNAs to recruit an RBM15/YTHDC1/PRC2 axis for locus-selective gene silencing [#40]. RBFOX2 cooperates and competes with other splicing regulators including hnRNPC, hnRNPM and SRSF1 in distinct binding configurations [#32], MBNL1 and QKI [#13, #49], and its activity is constrained by autoregulatory and trans-acting production of dominant-negative isoforms [#1, #9, #18]. Isoform-specific nuclear localization signals partition RBFOX2 between nuclear splicing functions and a cytoplasmic stress-granule role regulating RB1 mRNA [#20, #23, #25]. Its abundance is set post-translationally by competing ubiquitin pathways: FBXO7/PRMT5-dependent K63 ubiquitination stabilizes it [#43] while it is a substrate of the RhoBTB1/CUL3 degradation pathway [#46]. Through these activities RBFOX2 directs cerebellar and Purkinje-cell pacemaking via sodium-channel splicing [#10], myoblast fusion and satellite-cell activation [#15, #48], cardiac development and stress responses [#16, #28, #30], pancreatic \\u03b2-cell insulin secretion [#42], HSC proteostasis [#45], vascular endothelial and smooth-muscle function [#24, #46], liver cholesterol homeostasis [#38], and suppression of metastasis in pancreatic and other cancers [#41, #44].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the core molecular activity—that RBFOX2 recognizes a defined RNA element and acts as a physiological splicing regulator—answering what RBFOX2 binds and what it does.\",\n      \"evidence\": \"SELEX defining UGCAUG specificity plus co-transfection splicing assays and siRNA knockdown on protein 4.1R and FGFR2 exons, with UGCAUG mutagenesis\",\n      \"pmids\": [\"16537540\", \"16449636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether binding position alone dictates activate-vs-repress outcomes not yet generalized\", \"C-terminal mechanism of activation not defined at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a repressive mechanism, showing RBFOX2 can occlude splice-site recognition rather than only activate inclusion.\",\n      \"evidence\": \"Overexpression in HeLa/neuronal cells with UGCAUG mutation analysis and U2AF65 binding assays on calcitonin/CGRP exon 4\",\n      \"pmids\": [\"17101796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same factor blocks more than one assembly step unresolved here\", \"In vivo relevance of repression not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the repression mechanism into a two-step block of prespliceosome assembly and codified the positional rule that determines activation vs. repression.\",\n      \"evidence\": \"In vitro spliceosome assembly assays with UGCAUG mutants and gel-shift; genome-wide prediction with experimental RT-PCR validation\",\n      \"pmids\": [\"18573872\", \"18794351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Positional rule rests partly on computational prediction\", \"Quantitative determinants of position-dependence not fully mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended RBFOX2 beyond nuclear splicing by linking the ortholog to cytoplasmic polyadenylation, hinting at multifunctionality.\",\n      \"evidence\": \"Co-IP and tethered-function translation reporter in Xenopus oocytes (Rbm9 ortholog)\",\n      \"pmids\": [\"18177378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, Xenopus ortholog\", \"Mammalian relevance of cytoplasmic polyadenylation role untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the activation mechanism at the molecular level—how RBFOX2 strengthens weak splice sites—and identified its cross-regulation by Rbfox3 through AS-NMD.\",\n      \"evidence\": \"Splice-site and CTD-deletion mutagenesis with U1C interaction/U1 snRNP recruitment assays; Rbfox3 isoform overexpression with NMD assays\",\n      \"pmids\": [\"22083953\", \"21747913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of U1C-mediated recruitment across targets not established\", \"Rbfox3 cross-regulation tested in single study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established an in vivo physiological requirement, showing RBFOX2 maintains neuronal excitability via sodium-channel splicing.\",\n      \"evidence\": \"CNS/Purkinje conditional knockout mice with RNA-seq, electrophysiology, and Nav1.6 immunoblot\",\n      \"pmids\": [\"22357600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with Rbfox1 complicates Rbfox2-specific attribution\", \"Direct binding to Scn8a not mapped at nucleotide resolution here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded RBFOX2's role from individual exons to network-level control, defining AS-NMD of RBP transcripts and a myogenic splicing program required for myoblast fusion.\",\n      \"evidence\": \"iCLIP-seq plus RNA-seq in mouse ESCs and myoblasts, with NMD-isoform validation and Mef2d/Rock2 rescue of fusion defects\",\n      \"pmids\": [\"24637117\", \"25087874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy within the RBP regulatory network not fully ordered\", \"Which targets drive fusion vs. are bystanders not exhaustively resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established RBFOX2 as a stress-responsive splicing regulator in heart, where its loss recapitulates pressure-overload decompensation.\",\n      \"evidence\": \"Cardiac conditional knockout and TAC surgery with RNA-seq, RT-PCR, and echocardiography\",\n      \"pmids\": [\"25753418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal splicing targets driving decompensation not individually validated here\", \"Mechanism linking pressure overload to RBFox2 downregulation unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a chromatin-level function distinct from splicing—RBFOX2 recruits PRC2 in a nascent-RNA-dependent manner to silence bivalent promoters.\",\n      \"evidence\": \"ChIP-seq, RBFox2–PRC2 co-IP, nascent RNA sequencing, and depletion across multiple cell types\",\n      \"pmids\": [\"27211866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RBFox2 reads nascent RNA to dock PRC2 not structurally defined\", \"Relationship between chromatin role and splicing role at same loci unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined isoform-encoded localization control and dominant-negative regulation, explaining how RBFOX2 partitions between nuclear and cytoplasmic functions and how disease isoforms inhibit wild-type activity.\",\n      \"evidence\": \"Isoform NLS mapping by subcellular fractionation/IF; DN-WT co-IP with calcium imaging in cardiomyocytes; HLHS truncation-mutant analysis with RIP and patient transcriptomes\",\n      \"pmids\": [\"27859055\", \"27239029\", \"27485310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DN isoform and HLHS findings from single studies\", \"Quantitative threshold at which DN isoform overrides WT not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a cytoplasmic stress-granule function in which RBFOX2 regulates RB1, decoupling a non-splicing role from its nuclear activity.\",\n      \"evidence\": \"IF co-localization with stress-granule markers and RIP-seq of cytoplasmic targets; calcium-channel splicing/electrophysiology in neurons and VSMCs\",\n      \"pmids\": [\"28894257\", \"29067356\", \"28993448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of RBFOX2 recruitment into stress granules unknown\", \"RB1 regulation tested in limited contexts\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established tissue-specific in vivo programs—vascular flow-responsive splicing in endothelium and craniofacial development via TGF-\\u03b2-Tak1 splicing.\",\n      \"evidence\": \"Endothelial and neural-crest conditional knockouts with RNA-seq; Tak1 overexpression rescue and low-flow arterial model with immune-cell depletion\",\n      \"pmids\": [\"29293084\", \"31241461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct splicing targets mediating each phenotype not all validated\", \"Feedback loop architecture (TGF-\\u03b2 → RBFox2) mechanism partly inferred\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a feed-forward cardiac pathway (RBFox2 → miR-34a → Jph2) and confirmed stress-granule/cytoplasmic localization as a cancer-relevant axis.\",\n      \"evidence\": \"Cardiac KO with miR-34a mimic/antagomir rescue and Jph2 analysis; cancer-tissue IF with RB1 measurement and stress-granule dissolution assays\",\n      \"pmids\": [\"30867288\", \"31028247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of RBFox2-driven miR-34a transcriptional repression not fully defined\", \"Cytoplasmic cancer role rests on correlative tissue data\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Systematized RBFOX2's combinatorial partnerships and extended its reach to alternative polyadenylation, defining how partner proteins broaden its target repertoire.\",\n      \"evidence\": \"RIP, partner-specific knockdown and RNA-seq parsing CLIP data for hnRNPC/hnRNPM/SRSF1 modes; 3'-end and nanopore sequencing with binding-site mutagenesis for APA\",\n      \"pmids\": [\"34244793\", \"34731606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and direct vs. indirect partner contacts not all resolved\", \"How RBFOX2 chooses splicing vs. APA outcomes at shared sites unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed transcription-factor partnerships and antagonists that retarget or oppose RBFOX2 activity in cancer, including ETS factors, EWS-FLI1, and the SON/hnRNPA2B1 complex.\",\n      \"evidence\": \"Co-IP, RNA-seq, motif-enrichment and CLIP for ERG/FLI1/EWS-FLI1; SON–hnRNPA2B1 co-IP with RNA-seq and orthotopic GBM xenograft; SLUG-dependent ESRP1 repression assays\",\n      \"pmids\": [\"34009296\", \"34548489\", \"33089214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether interactions are direct or scaffolded not all established\", \"Transcriptional (non-RNA-binding) role of RBFOX2 partly inferred\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined post-translational control of RBFOX2 abundance and an m6A-reading chromatin-silencing axis, integrating its regulation and its epigenetic output.\",\n      \"evidence\": \"FBXO7/PRMT5 ubiquitination/methylation site mapping with co-IP and RNA-seq; m6A mapping on caRNAs with RBFOX2–RBM15–YTHDC1 co-IP, H3K27me3 ChIP-seq and AML differentiation assays\",\n      \"pmids\": [\"37822160\", \"37640841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between stabilizing (FBXO7) and degradative pathways not co-analyzed\", \"How m6A recognition is structurally achieved by RBFOX2 unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established RBFOX2 as a metastasis suppressor acting through cytoskeletal/RHO-GTPase splicing, and as an essential regulator of \\u03b2-cell insulin secretion.\",\n      \"evidence\": \"PDX and KO PDA models with in vivo metastasis, RNA-seq and cytoskeletal imaging of MPRIP and ABI1 isoforms; pancreatic conditional KO with glucose physiology, EM granule docking and SNARE-component splicing\",\n      \"pmids\": [\"36949200\", \"38114498\", \"38007492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which individual splice events are necessary vs. sufficient for metastasis suppression not fully isolated\", \"Direct SNARE-component binding not nucleotide-mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended RBFOX2 to stem-cell proteostasis, vascular smooth-muscle ubiquitin regulation/actin control, and continued tissue-specific splicing roles in muscle and heart.\",\n      \"evidence\": \"Hematopoietic conditional KO with proteostasis assays and chemical rescue; RhoBTB1/CUL3 proximity-labeling MS, co-IP, ubiquitination and SMC-specific KO with arterial stiffness; satellite-cell KO with Numb exon analysis; Snap23 microexon co-regulation with QKI/MBNL1\",\n      \"pmids\": [\"41337583\", \"41926228\", \"41418788\", \"40207498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking RBFox2 splicing targets to proteostasis defect unresolved\", \"How RhoBTB1/CUL3 degradation integrates with FBXO7 stabilization unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBFOX2 integrates its multiple activities—cassette splicing, AS-NMD, APA, nuclear PRC2/m6A silencing, and cytoplasmic mRNA regulation—into coordinated, context-specific outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for how localization, partner availability, and post-translational state select among activities\", \"Structural basis for m6A and nascent-RNA recognition undefined\", \"Competing stabilizing vs. degradative ubiquitin pathways not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 5, 14, 23, 40]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [31, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 17, 40]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [20, 27, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20, 23, 25]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [17, 40]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 5, 14, 33]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [17, 40]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 15, 26, 30, 42]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 38, 41, 44]}\n    ],\n    \"complexes\": [\"PRC2 (nascent-RNA-dependent association)\", \"cytoplasmic polyadenylation complex (Xenopus ortholog)\", \"cytoplasmic stress granules\"],\n    \"partners\": [\"U1C\", \"hnRNPC\", \"hnRNPM\", \"SRSF1\", \"RBM15\", \"YTHDC1\", \"RhoBTB1\", \"FBXO7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}