{"gene":"ESRP1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2009,"finding":"ESRP1 (and its paralog ESRP2) are epithelial cell-type-specific RNA-binding proteins that directly regulate mutually exclusive splicing of FGFR2 exons IIIb and IIIc: ectopic expression of ESRP1 in mesenchymal cells switches endogenous FGFR2 splicing to the epithelial IIIb isoform, while RNAi knockdown of both ESRPs in epithelial cells switches splicing to the mesenchymal IIIc isoform. ESRP1 also regulates splicing of CD44, CTNND1 (p120-catenin), and ENAH (hMena).","method":"cDNA expression screen, ectopic expression in cell lines, RNAi knockdown, RT-PCR isoform analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments across multiple transcripts, independently replicated in subsequent studies","pmids":["19285943"],"is_preprint":false},{"year":2009,"finding":"Genome-wide profiling via splicing-sensitive exon arrays following RNAi knockdown of ESRP1/2 in human epithelial cells identified >100 ESRP-regulated splicing events (38 independently validated by RT-PCR), encompassing cassette exons and alternative 3′ terminal exons; regulated transcripts encode proteins involved in actin cytoskeleton organization, cell-cell adhesion, cell polarity, and cell migration.","method":"Affymetrix Exon ST1.0 array after RNAi knockdown, RT-PCR validation","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide loss-of-function with 38 independently validated targets, consistent with PMID 19285943","pmids":["19829082"],"is_preprint":false},{"year":2012,"finding":"ESRP1 controls alternative splicing of CD44 pre-mRNA, promoting expression of CD44 variant isoforms (CD44v) over the standard isoform (CD44s); knockdown of ESRP1 in CD44v+ breast cancer cells causes an isoform switch from CD44v to CD44s, leading to reduced cell-surface xCT (cystine transporter) and suppressed lung colonization.","method":"RNAi knockdown, RT-PCR isoform analysis, orthotopic transplantation mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined molecular mechanism (CD44v→CD44s→xCT stability) validated in vivo","pmids":["22673910"],"is_preprint":false},{"year":2014,"finding":"ESRP1 suppresses cancer cell motility through regulation of actin cytoskeleton dynamics via Rac1b: knockdown of ESRP1 (but not ESRP2) in head and neck carcinoma cells induces Rac1b expression and alters actin cytoskeleton dynamics, promoting a motile phenotype.","method":"RNAi knockdown, cell motility assays, western blot for Rac1b","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single method with phenotypic readout but limited mechanistic depth for Rac1b pathway","pmids":["25143390"],"is_preprint":false},{"year":2015,"finding":"Esrp1 knockout mice develop fully penetrant bilateral cleft lip and palate; combined Esrp1/Esrp2 double knockout produces widespread developmental defects. Epidermal deletion of Esrps disrupts skin barrier function, demonstrating that Esrp1-mediated alternative splicing is essential for epithelial cell function in vivo.","method":"Conditional and germline knockout mice, RNA-Seq of epidermis, phenotypic analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with RNA-Seq profiling of splicing changes and defined developmental phenotypes","pmids":["26371508"],"is_preprint":false},{"year":2017,"finding":"ESRP1 mutations in humans cause sensorineural hearing loss (SNHL) by disrupting alternative splicing of target genes; in Esrp1−/− mouse embryos, aberrant splicing of Fgfr2 blocks stria vascularis formation due to erroneous FGF ligand usage, which was corrected by reducing Fgf9 gene dosage — establishing a genetic epistasis between Fgfr2 splicing and Fgf9 signaling downstream of ESRP1.","method":"Whole-exome sequencing of SNHL patients, iPSC allele repair, Esrp1-KO mouse cochlear analysis, RNA-Seq, Fgf9 genetic rescue","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including genetic epistasis rescue, patient-derived iPSC, and transcriptome analysis","pmids":["29107558"],"is_preprint":false},{"year":2017,"finding":"ESRP1 regulates alternative splicing of GPR137 to produce isoforms that differentially activate the Wnt signaling pathway; reduced ESRP1 function impairs intestinal barrier integrity and alters colorectal cancer development through GPR137 isoform switching.","method":"Mouse genetic model (reduced Esrp1 function), Wnt pathway reporter assays, RT-PCR isoform analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model plus mechanistic Wnt pathway readout, single lab","pmids":["28975893"],"is_preprint":false},{"year":2017,"finding":"Alternative splicing of Esrp1 exon 12 via competing 5′ splice sites produces protein isoforms with distinct nuclear versus cytoplasmic localization; a specific peptide encoded by exon 12 is sufficient to confer nuclear localization. This differential subcellular localization is phylogenetically conserved (also found in Drosophila fusilli, the Esrp1 ortholog).","method":"RT-PCR isoform characterization, subcellular fractionation, fluorescence microscopy, Drosophila ortholog analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with peptide sufficiency test and cross-species conservation, single lab","pmids":["28634384"],"is_preprint":false},{"year":2013,"finding":"ESRP1 protein physically associates with PNN (Pinin) in nuclear speckles of corneal epithelial cells (co-immunoprecipitation), and both regulate overlapping but distinct sets of alternative splicing events in corneal epithelium.","method":"Co-immunoprecipitation, deconvolution microscopy co-localization, genome-wide splicing array after knockdown","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and localization with functional splicing consequence, single lab","pmids":["23299472"],"is_preprint":false},{"year":2013,"finding":"ESRP1 binds to Oct4 and Sox2 mRNAs in mouse embryonic stem cells and decreases their polysomal loading (translational repression), thereby acting as a physiological regulator of pluripotency; Esrp1 knockdown increases Oct4, Nanog, and Sox2 expression and enhances self-renewal.","method":"RNA immunoprecipitation (RIP) for Oct4/Sox2 mRNA binding, polysome fractionation, RNAi knockdown, in vitro/in vivo differentiation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP binding evidence plus polysome fractionation functional readout, single lab","pmids":["24015231"],"is_preprint":false},{"year":2019,"finding":"ESRP1 knockdown in tamoxifen-resistant breast cancer cells affects lipid metabolism and oxidoreductase processes, reducing expression of fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), and phosphoglycerate dehydrogenase (PHGDH), and increases basal and spare mitochondrial respiration capacity.","method":"RNAi knockdown, western blot, RT-qPCR, Seahorse metabolic flux analysis","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with multiple orthogonal metabolic readouts, single lab","pmids":["30665944"],"is_preprint":false},{"year":2018,"finding":"hnRNPM and ESRP1 co-regulate a set of cassette exon splicing events in an antagonistic (discordant) manner; motif enrichment near co-regulated exons identifies GU-rich motifs downstream of hnRNPM-repressed/ESRP1-enhanced exons, supporting a model of competitive binding to cis-regulatory elements.","method":"Comparative splicing analysis of hnRNPM and ESRP1 knockdown datasets, motif enrichment analysis, EMT correlation","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide comparative knockdown analysis with motif evidence, single lab","pmids":["30042172"],"is_preprint":false},{"year":2020,"finding":"Transcriptional repression of ESRP1 under hypoxia is mediated by SLUG (downstream of TGF-β signaling) and by RBFOX2, which transcriptionally represses ESRP1 while interacting with SLUG; hypoxia-driven ESRP1 depletion causes skipping of hMENA exon 11a, producing a pro-metastatic hMENAΔ11a isoform.","method":"qRT-PCR, western blot, RNAi knockdown, chromatin immunoprecipitation for SLUG binding to ESRP1 promoter, RT-PCR isoform analysis","journal":"NAR cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP evidence for direct transcriptional repression plus splicing consequence, single lab","pmids":["33089214"],"is_preprint":false},{"year":2021,"finding":"E2F1 and CpG hydroxymethylation (mediated by TET3) at the E2F1 binding motif in the ESRP1 promoter conjointly induce ESRP1 expression in breast carcinoma; under hypoxia, reduced TET3 activity causes loss of hydroxymethylation and gain of methylation at these CpG sites, preventing E2F1 binding and reducing ESRP1 transcription.","method":"ChIP, dual luciferase reporter, bisulfite sequencing, western blot, RNAi knockdown","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays establishing transcriptional mechanism, single lab","pmids":["34362878"],"is_preprint":false},{"year":2020,"finding":"ESRP1 upregulates ISG15 expression through CREB (with CREB enriched at the ISG15 promoter), and in turn ISG15 promotes ISGylation of ESRP1 protein, slowing its degradation and forming a positive feedback loop that jointly suppresses EMT in lung adenocarcinoma.","method":"Co-immunoprecipitation for ISGylation, chromatin immunoprecipitation for CREB at ISG15 promoter, dual luciferase reporter, western blot","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for ISGylation plus ChIP for transcriptional activation, single lab","pmids":["32641707"],"is_preprint":false},{"year":2021,"finding":"ESRP1 regulates alternative splicing of CARM1 pre-mRNA to produce two transcripts (CARM1FL and CARM1ΔE15); the resulting CARM1 isoform ratio controls arginine methylation of Smad7, modulating TGF-β/Smad pathway activation and thereby influencing chemoresistance in small cell lung cancer.","method":"mRNA transcriptome sequencing, RT-PCR isoform analysis, overexpression/knockdown, western blot for Smad7 methylation","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with isoform validation and downstream pathway readout, single lab","pmids":["33495408"],"is_preprint":false},{"year":2021,"finding":"Loss of ESRP1 in mouse oocytes disrupts alternative splicing of maternal mRNA transcripts (528 aberrant AS events identified by single-cell RNA-seq), particularly in microtubule cytoskeletal genes including Rac1, Kif2c, Kif23, Ndel1, and Bora, leading to abnormal spindle organization, blocked first polar body extrusion, and female infertility.","method":"Esrp1 conditional knockout mice, single-cell RNA-seq, spindle assembly checkpoint analysis, oocyte meiosis assays","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with transcriptome analysis and defined cellular phenotype, single lab","pmids":["33318146"],"is_preprint":false},{"year":2022,"finding":"eCLIP mapping of ESRP1 binding sites in mouse epidermis revealed that ESRP1 functions in splicing through direct, position-dependent RNA binding to promote exon inclusion or skipping, and also binds widely to 3′ and 5′ UTRs of epithelial genes, indicating post-transcriptional regulatory functions beyond splicing.","method":"Enhanced CLIP-seq (eCLIP) in mouse epidermis, RNA-Seq of Esrp1/2-null epidermis, integration of binding and splicing data","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide direct binding map integrated with functional splicing data in vivo","pmids":["36238894"],"is_preprint":false},{"year":2022,"finding":"ESRP1 regulates isoform switching of LRRFIP2 between epithelial (variant 2) and mesenchymal (variant 3) isoforms; the epithelial LRRFIP2 isoform inhibits oncogenic CARM1 function through direct protein–protein interaction, and CRISPR-mediated deletion of LRRFIP2 exon 7 causes isoform switch and suppresses liver metastasis of gastric cancer cells.","method":"Ectopic expression, CRISPR/Cas9 exon deletion, liver metastasis mouse model, co-immunoprecipitation for LRRFIP2-CARM1 interaction","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR isoform switch in vivo plus Co-IP mechanistic evidence, single lab with multiple orthogonal methods","pmids":["36307405"],"is_preprint":false},{"year":2024,"finding":"ESRP1 controls biogenesis of the large circRNA circDOCK1(2-27) by binding GGU-containing repeat sequences in intron 1 of DOCK1 pre-mRNA, detaining splicing to enable back-splicing to exon 27. X-ray crystal structure of RNA-bound ESRP1 qRRM2 domain shows GGU motifs embedded in clamp-like aromatic pockets. CircDOCK1(2-27) represses cell motility both by diverting transcripts from DOCK1 mRNA production and by direct inhibition of migration.","method":"HITS-CLIP, CRISPR-mediated deletions, BioID proximity biotinylation, X-ray crystallography of qRRM2-RNA complex, cell motility assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus HITS-CLIP binding map plus CRISPR functional validation, multiple orthogonal methods","pmids":["38015468"],"is_preprint":false},{"year":2019,"finding":"ESRP1 overexpression in CRC cells enhances FGFR1/2 signaling and Akt activation in anchorage-independent conditions, and promotes macrometastasis formation in mouse livers, establishing a pro-oncogenic role for ESRP1 in colorectal cancer through enhanced growth factor receptor signaling.","method":"Gain- and loss-of-function in CRC cell lines, mouse liver metastasis model, western blot for FGFR/Akt signaling","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional studies with signaling pathway readout, single lab","pmids":["28052020"],"is_preprint":false},{"year":2019,"finding":"ESRP1 binds to the GGUGGU sequence in the 3′UTR of cyclin A2 mRNA, decreasing its stability; ESRP1 overexpression increases CDC20 expression (promoting cyclin A2 protein degradation) and induces G1-phase cell cycle arrest in cervical cancer cells.","method":"RNA immunoprecipitation, mRNA stability assay, overexpression, cell cycle analysis by flow cytometry, western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP binding to defined sequence motif plus functional mRNA stability and cell cycle readout, single lab","pmids":["31362365"],"is_preprint":false},{"year":2023,"finding":"ESRP1 promotes exon 11 alternative splicing of CLSTN1 pre-mRNA; the resulting short CLSTN1 isoform stabilizes the E-cadherin/β-catenin complex and promotes β-catenin ubiquitination and degradation, thereby inhibiting gastric cancer cell migration and invasion.","method":"RNAi knockdown, overexpression, RT-PCR isoform analysis, co-immunoprecipitation, ubiquitination assay, in vitro/in vivo invasion assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splicing followed by mechanistic Co-IP and ubiquitination readout, single lab","pmids":["38114495"],"is_preprint":false},{"year":2016,"finding":"Esrp1 overexpression in chicken stomach smooth muscle cells (SMCs) impairs SMC differentiation and switches FGFR2 splicing to the IIIb isoform; Esrp1 physically interacts with the RNA-binding protein RBPMS2 and RBPMS2-mediated SMC dedifferentiation requires Esrp1.","method":"Gain-of-function in chicken embryos, co-immunoprecipitation for ESRP1-RBPMS2 interaction, SMC differentiation assays, RT-PCR FGFR2 isoform analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo functional requirement established, single lab","pmids":["27108394"],"is_preprint":false},{"year":2020,"finding":"Full-length APC expression in SW480 colorectal cancer cells increases ESRP1 expression, and ESRP1 depletion in SW480+APC cells reverts p120-catenin isoform switching (from isoform 3A back to isoform 1A) and reduces cell-cell adhesion, placing ESRP1 downstream of APC in the regulation of p120-catenin splicing and adhesion.","method":"APC re-expression, ESRP1 knockdown, RT-PCR p120-catenin isoform analysis, cell-cell adhesion assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (APC→ESRP1→p120-catenin isoform) with functional adhesion readout, single lab","pmids":["33237836"],"is_preprint":false},{"year":2020,"finding":"Irf6 regulates the expression of esrp1 in zebrafish periderm and orofacial epithelium; genetic disruption of irf6 and esrp1/2 in zebrafish causes cleft of the anterior neurocranium through impaired chondrogenesis (not neural crest cell migration defects), and Irf6 heterozygosity reduces cleft severity in Esrp1/2 mutants, demonstrating genetic interaction.","method":"Zebrafish genetic mutants, compound mouse mutants (Irf6;Esrp1;Esrp2), cranial neural crest lineage tracing, in situ hybridization","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with lineage tracing, single lab across two model organisms","pmids":["33234718"],"is_preprint":false},{"year":2020,"finding":"Cleft lip in Esrp1 knockout mice is associated with altered epithelial-mesenchymal crosstalk; transcriptomic analysis of ectoderm and mesenchyme in Esrp1 embryos identified altered expression of genes in multiple signaling pathways (including those previously implicated in cleft lip/palate).","method":"Esrp1 KO mouse models, transcriptomic analysis of separated ectoderm and mesenchyme, histological analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with tissue-specific transcriptomics, single lab","pmids":["32253237"],"is_preprint":false},{"year":2023,"finding":"Decreased ESRP1 expression reduces MENA11a isoform expression by altering MENA alternative splicing; matrix stiffness decreases ESRP1 expression, triggering this splicing switch, which enhances cancer cell contractility via focal adhesion kinase activity and promotes intravasation.","method":"In vitro hydrogel stiffness systems, mouse model, western blot and RT-PCR, ESRP1 knockdown, intravasation assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems (in vitro stiffness, mouse, patient specimens) with mechanistic pathway readout, single lab","pmids":["37027295"],"is_preprint":false},{"year":2023,"finding":"ESRP1 binds to PHGDH mRNA at its 5′UTR and increases PHGDH mRNA stability in tamoxifen-resistant breast cancer cells; ESRP1 knockdown significantly decreases PHGDH mRNA stability in resistant cells.","method":"RNA-binding protein immunoprecipitation followed by microarray (RIP-Chip), immunoprecipitation-mass spectrometry, RNA EMSA, RIP-qRT-PCR, mRNA stability assay","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding validation methods (EMSA, RIP-qRT-PCR) plus mRNA stability functional assay, single lab","pmids":["36925195"],"is_preprint":false},{"year":2018,"finding":"Snail transcription factor directly represses ESRP1 transcription by binding to the ESRP1 promoter in epithelial ovarian cancer cells, establishing ESRP1 as a downstream transcriptional target of Snail during EMT.","method":"Chromatin immunoprecipitation (ChIP) for Snail at ESRP1 promoter, luciferase reporter, RNAi","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay for direct transcriptional repression, single lab","pmids":["29131012"],"is_preprint":false},{"year":2018,"finding":"In non-small cell lung cancer, Snail-mediated silencing of ESRP1 is required for anchorage-independent growth and metastatic behavior; ESRP1 loss is a critical event in Snail-dependent malignant transformation of pulmonary epithelial cells, acting in an ALDH+CD44+CD24− stem cell subset.","method":"RNAi knockdown/rescue, anchorage-independent growth assay, in vivo primary tumor and metastasis models, FACS for stem cell markers","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiment (Snail requires ESRP1 loss) validated in vivo, single lab","pmids":["29431637"],"is_preprint":false},{"year":2024,"finding":"ESRP1 binds to pre-PTPN12 RNA and promotes the biogenesis of circPTPN12; circPTPN12 interacts with the PDZ domain of PDLIM2 and promotes PDLIM2-mediated ubiquitination of NF-κB p65, placing ESRP1 upstream of circPTPN12 in a circRNA biogenesis and NF-κB suppression axis in hepatocellular carcinoma.","method":"RNA immunoprecipitation, biotin-coupled probe pull-down, FISH, RNA sequencing, in vitro/in vivo functional assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding validation methods plus functional pathway readout, single lab","pmids":["38992675"],"is_preprint":false},{"year":2025,"finding":"In zebrafish, Esrp1 and Esrp2 directly bind tmc1 and tmc2a mRNAs in sensory hair cells and regulate their stability; loss of esrp1/2 reduces tmc1/2a mRNA levels and impairs mechano-electrical transduction (MET) function of hair cells.","method":"Esrp1/2 double knockout zebrafish, RNA-sequencing, RNA binding assay for tmc1/tmc2a mRNA, electrophysiological MET assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding plus in vivo functional KO with electrophysiological readout, single lab","pmids":["40086870"],"is_preprint":false},{"year":2024,"finding":"Overexpression of CTNND1 (p120-catenin) is sufficient to rescue morphogenesis of epithelial-derived structures in esrp1/2 zebrafish mutants, placing Ctnnd1 as a key downstream effector of Esrp1-regulated splicing in palatogenesis.","method":"esrp1/2 zebrafish mutants, CTNND1 overexpression rescue experiments, RT-PCR for Ctnnd1 isoforms","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment establishing epistasis in vivo, single lab","pmids":["39179789"],"is_preprint":false},{"year":2026,"finding":"Lactylation of ESRP1 at lysine 43 (K43) stabilizes ESRP1 protein; glycolytic lactate promotes this modification. ESRP1 regulates biogenesis of circPHGDH, and circPHGDH knockdown suppresses ESRP1 lactylation, forming a positive feedback loop driving prostate cancer progression.","method":"RNA immunoprecipitation, immunoprecipitation, western blot for lactylation, site-directed mutagenesis (K43), luciferase reporter, RNA pull-down","journal":"Experimental & molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic evidence for lactylation is Co-IP/western blot only, no structural validation","pmids":["41760734"],"is_preprint":false},{"year":2025,"finding":"ESRP1 interacts with DHCR7 protein and upregulates DHCR7 expression, enhancing ferroptosis susceptibility in diffuse-type gastric cancer cells; both in vitro and in vivo models confirm ESRP1 inhibits DGC malignant progression through this mechanism.","method":"Co-immunoprecipitation for ESRP1-DHCR7 interaction, overexpression/knockdown, xenograft mouse model, ferroptosis assays","journal":"Journal of experimental & clinical cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus functional assay, single lab","pmids":["40528239"],"is_preprint":false},{"year":2025,"finding":"ESRP1 overexpression in alveolar epithelial cells promotes EMT via activation of the Epac-Rap1a signaling axis; Co-IP demonstrated direct interaction between ESRP1, Epac, and Rap1a. Silencing of Epac or Rap1a did not alter ESRP1 expression, confirming ESRP1 is upstream.","method":"Single-cell RNA-seq, co-immunoprecipitation, lentiviral overexpression, siRNA knockdown, TGF-β1-induced EMT model","journal":"Frontiers in medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with epistasis test by knockdown, single lab","pmids":["41728622"],"is_preprint":false}],"current_model":"ESRP1 is an epithelial cell-type-specific RNA-binding protein (containing three RNA recognition motifs including a structurally characterized qRRM2 domain that recognizes GGU motifs) that coordinates a global epithelial alternative splicing program by binding pre-mRNA in a position-dependent manner—promoting exon inclusion or skipping—and also stabilizes or represses target mRNAs via 3′/5′ UTR binding; its key substrates include FGFR2 (IIIb/IIIc switch), CD44 (variant/standard switch), ENAH/MENA (exon 11a), CTNND1, LRRFIP2, CLSTN1, CARM1, and others that collectively regulate actin cytoskeleton dynamics, cell adhesion, polarity, and migration, and it is transcriptionally repressed by Snail and RBFOX2 (downstream of TGF-β/hypoxia) and transcriptionally induced by E2F1/TET3-mediated promoter hydroxymethylation, while its own protein stability is regulated by ISGylation; loss of Esrp1 in mice causes cleft lip/palate, hearing loss, kidney branching defects, skin barrier failure, oocyte meiosis failure, and widespread developmental abnormalities, establishing ESRP1 as an essential post-transcriptional regulator of epithelial cell identity and organogenesis."},"narrative":{"mechanistic_narrative":"ESRP1 is an epithelial cell-type-specific RNA-binding protein that coordinates a global epithelial post-transcriptional program, regulating >100 alternative splicing events in transcripts governing actin cytoskeleton organization, cell-cell adhesion, polarity, and migration [PMID:19285943, PMID:19829082]. Reciprocal gain- and loss-of-function established its defining activity as a regulator of mutually exclusive FGFR2 IIIb/IIIc splicing and of CD44, CTNND1, and ENAH/MENA isoform choice [PMID:19285943, PMID:22673910]. eCLIP in epidermis showed that ESRP1 acts through direct, position-dependent binding that promotes exon inclusion or skipping, and also binds widely to 3′ and 5′ UTRs, extending its role beyond splicing to mRNA stability control [PMID:36238894]; a crystal structure of its qRRM2 domain bound to GGU motifs embedded in aromatic clamp-like pockets provides the molecular basis for sequence-specific recognition [PMID:38015468]. Through its UTR-binding activity ESRP1 stabilizes target mRNAs such as PHGDH and destabilizes others including cyclin A2, and it drives back-splicing of circular RNAs (circDOCK1, circPTPN12) by detaining splicing at GGU-rich introns [PMID:38015468, PMID:31362365, PMID:36925195, PMID:38992675]. The splicing program it controls converges on epithelial morphogenesis: Esrp1 knockout mice develop fully penetrant cleft lip and palate, skin barrier failure, hearing loss through aberrant Fgfr2 splicing that mis-routes FGF9 signaling, and oocyte meiotic spindle defects [PMID:26371508, PMID:29107558, PMID:33318146], and CTNND1 (p120-catenin) is a key downstream effector whose overexpression rescues epithelial morphogenesis in esrp1/2 mutants [PMID:39179789]. ESRP1 is transcriptionally repressed by Snail/SLUG and RBFOX2 during EMT and induced by E2F1 together with TET3-mediated promoter hydroxymethylation [PMID:33089214, PMID:34362878, PMID:29131012], and its protein level is further controlled by ISGylation [PMID:32641707]. Direct evidence links ESRP1 mutations to human sensorineural hearing loss via disrupted target splicing [PMID:29107558].","teleology":[{"year":2009,"claim":"Established ESRP1's foundational identity by showing an epithelial-specific RNA-binding protein directly controls the FGFR2 IIIb/IIIc splicing switch, defining the molecular determinant of an epithelial splicing program.","evidence":"cDNA expression screen with reciprocal ectopic expression and RNAi in epithelial/mesenchymal cell lines, RT-PCR isoform analysis","pmids":["19285943"],"confidence":"High","gaps":["Direct RNA binding sites not yet mapped","Did not distinguish direct splicing targets from indirect effects"]},{"year":2009,"claim":"Defined the scope of ESRP1 as a master splicing regulator by genome-wide profiling, showing it controls a coordinated program of >100 events in cytoskeleton, adhesion, polarity, and migration genes.","evidence":"Exon ST1.0 splicing array after ESRP1/2 RNAi with RT-PCR validation of 38 targets","pmids":["19829082"],"confidence":"High","gaps":["Array does not resolve direct vs indirect targets","No binding map to assign mechanism per exon"]},{"year":2012,"claim":"Connected ESRP1 splicing activity to disease phenotype by showing CD44v/CD44s isoform control governs xCT surface stability and metastatic lung colonization.","evidence":"RNAi knockdown, RT-PCR, orthotopic transplantation mouse model","pmids":["22673910"],"confidence":"High","gaps":["Mechanism of CD44v stabilizing xCT not fully resolved","Generalizability beyond breast cancer model unaddressed"]},{"year":2013,"claim":"Revealed ESRP1 functions beyond splicing as a translational regulator and nuclear-speckle partner, binding Oct4/Sox2 mRNAs to limit pluripotency and associating with PNN.","evidence":"RIP and polysome fractionation in ES cells; co-IP and co-localization with PNN in corneal epithelium","pmids":["24015231","23299472"],"confidence":"Medium","gaps":["PNN co-IP not reciprocally validated for direct contact","Translational repression mechanism on Oct4/Sox2 not defined"]},{"year":2015,"claim":"Demonstrated in vivo essentiality by showing germline Esrp1 loss causes fully penetrant cleft lip/palate and epidermal Esrp loss disrupts skin barrier, establishing ESRP-dependent splicing as required for epithelial organogenesis.","evidence":"Conditional and germline knockout mice with RNA-Seq of epidermis and phenotypic analysis","pmids":["26371508"],"confidence":"High","gaps":["Which specific splicing changes drive each phenotype not isolated","Esrp1 vs Esrp2 contributions partially redundant"]},{"year":2017,"claim":"Linked ESRP1 to human Mendelian disease and resolved a signaling epistasis, showing mutations cause sensorineural hearing loss via aberrant Fgfr2 splicing that mis-routes FGF9 ligand usage.","evidence":"Whole-exome sequencing of patients, iPSC allele repair, Esrp1-KO cochlear RNA-Seq, Fgf9 genetic rescue","pmids":["29107558"],"confidence":"High","gaps":["Full target set underlying stria vascularis defect not enumerated","Penetrance and allelic spectrum in humans limited"]},{"year":2017,"claim":"Showed ESRP1 itself is autoregulated and spatially partitioned, with exon 12 alternative splicing producing nuclear versus cytoplasmic isoforms in a conserved manner.","evidence":"RT-PCR isoform characterization, subcellular fractionation, microscopy, Drosophila ortholog comparison","pmids":["28634384"],"confidence":"Medium","gaps":["Functional consequence of isoform localization difference not tested","Regulation of exon 12 choice unknown"]},{"year":2018,"claim":"Placed ESRP1 within a competitive splicing-factor network by showing it acts antagonistically to hnRNPM at shared GU-rich cis-elements, and is transcriptionally silenced by Snail during EMT.","evidence":"Comparative knockdown splicing analysis with motif enrichment; ChIP and reporter assays for Snail at ESRP1 promoter","pmids":["30042172","29131012","29431637"],"confidence":"Medium","gaps":["Direct competition at individual exons not biochemically reconstituted","Snail-ESRP1 axis context-dependence across tissues unclear"]},{"year":2020,"claim":"Expanded the transcriptional and post-translational control of ESRP1, showing SLUG/RBFOX2 repress it under hypoxia while ISGylation stabilizes its protein in a CREB-ISG15 feedback loop.","evidence":"ChIP, RNAi, co-IP for ISGylation, reporter assays in cancer cell lines","pmids":["33089214","32641707"],"confidence":"Medium","gaps":["ISGylation site on ESRP1 not mapped","Crosstalk between transcriptional and ISGylation control not integrated"]},{"year":2021,"claim":"Established the E2F1/TET3 hydroxymethylation axis as the inductive arm of ESRP1 regulation and extended ESRP1 phenotypes to oocyte meiosis through splicing of microtubule cytoskeletal genes.","evidence":"ChIP, bisulfite sequencing, reporter assays; Esrp1 conditional KO mice with single-cell RNA-seq of oocytes","pmids":["34362878","33318146"],"confidence":"Medium","gaps":["Direct splicing targets causing spindle defects not validated individually","TET3-E2F1 mechanism shown in one cancer context"]},{"year":2022,"claim":"Provided the first in vivo direct binding map and showed ESRP1 binds UTRs as well as splice sites, mechanistically unifying its splicing and mRNA-fate functions.","evidence":"eCLIP in mouse epidermis integrated with Esrp1/2-null RNA-Seq","pmids":["36238894"],"confidence":"High","gaps":["UTR-binding consequences (stability/translation) not assayed transcriptome-wide","Position rules derived from epidermis only"]},{"year":2024,"claim":"Delivered the structural basis of sequence recognition and a novel function in circRNA biogenesis, showing the qRRM2 domain clamps GGU motifs to detain splicing and drive back-splicing of circDOCK1.","evidence":"HITS-CLIP, X-ray crystallography of qRRM2-RNA complex, CRISPR deletions, motility assays","pmids":["38015468"],"confidence":"High","gaps":["Generality of GGU-clamp recognition across all targets not demonstrated","Contribution of the other two RRMs unresolved"]},{"year":null,"claim":"How ESRP1's position-dependent binding code, UTR-mediated stability control, and circRNA biogenesis activity are integrated into a single tissue-specific regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking splice-site vs UTR binding outcomes","Roles of the three RRMs and isoform localization in target selection undefined","Lactylation and other PTMs reported only at Low confidence"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,17,19,21,28]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,17,19]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[8,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,17,19]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5,25,26,33]}],"complexes":[],"partners":["PNN","RBPMS2","HNRNPM","RBFOX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6NXG1","full_name":"Epithelial splicing regulatory protein 1","aliases":["RNA-binding motif protein 35A","RNA-binding protein 35A"],"length_aa":681,"mass_kda":75.6,"function":"mRNA splicing factor that regulates the formation of epithelial cell-specific isoforms. 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/39005284","citation_count":0,"is_preprint":false},{"pmid":"41111330","id":"PMC_41111330","title":"Genetic requirement for Esrp1 and Esrp2 in vertebrate pituitary morphogenesis.","date":"2025","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41111330","citation_count":0,"is_preprint":false},{"pmid":"40236426","id":"PMC_40236426","title":"Genetic requirement for Esrp1/2 in vertebrate pituitary morphogenesis.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40236426","citation_count":0,"is_preprint":false},{"pmid":"40866976","id":"PMC_40866976","title":"The ESRP1 promoter reporter can function as an in vivo sensor of DNA methyltransferase inhibition.","date":"2025","source":"BMC biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/40866976","citation_count":0,"is_preprint":false},{"pmid":"40667548","id":"PMC_40667548","title":"ESRP1 drives subtype-specific breast cancer progression through ER-regulated transcriptional programs and EMT-related splicing switch.","date":"2025","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/40667548","citation_count":0,"is_preprint":false},{"pmid":"41503216","id":"PMC_41503216","title":"EMT-induced stem cell and mesenchymal programs can be decoupled via cell division and ESRP1-dependent mechanisms.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41503216","citation_count":0,"is_preprint":false},{"pmid":"41728622","id":"PMC_41728622","title":"ESRP1 drives epithelial-mesenchymal transition by activating EPAC-RAP1A signaling axis.","date":"2026","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41728622","citation_count":0,"is_preprint":false},{"pmid":"26522352","id":"PMC_26522352","title":"[The myeloid cell leukemia-1 mRNA splicing mediated by epithelial splicing regulatory protein 1 (ESRP1) in glioma U251 cell lines].","date":"2015","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26522352","citation_count":0,"is_preprint":false},{"pmid":"41751394","id":"PMC_41751394","title":"ESRP1-Associated CD44 Alternative Splicing Stratifies Epithelial-Mesenchymal Identity States in a Non-Transformed Human Cell System.","date":"2026","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41751394","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.02.25325077","title":"Genetic requirement for<i>Esrp1/2</i>in vertebrate pituitary morphogenesis","date":"2025-04-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.02.25325077","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.02.601574","title":"Functional analysis of  <i>ESRP1/2</i>  gene variants and  <i>CTNND1</i>  isoforms in orofacial cleft pathogenesis","date":"2024-07-02","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.02.601574","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.21.25320889","title":"Variants in<i>CALD1</i>,<i>ESRP1</i>, and<i>RBFOX1</i>are associated with orofacial cleft risk","date":"2025-01-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.21.25320889","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.12.642815","title":"Delta-catenin is required for cell proliferation in virus positive Merkel cell carcinoma cell lines but not in human fibroblasts","date":"2025-03-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.12.642815","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.05.611385","title":"A Distinct Alternative mRNA Splicing Profile Identifies the Oncogenic CD44 Transcript Variant 3 in KMT2A-Rearranged Pediatric T-cell Acute Lymphoblastic Leukemia Cells","date":"2024-09-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.05.611385","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39222,"output_tokens":9006,"usd":0.126378,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18869,"output_tokens":4095,"usd":0.09836,"stage2_stop_reason":"end_turn"},"total_usd":0.224738,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"ESRP1 (and its paralog ESRP2) are epithelial cell-type-specific RNA-binding proteins that directly regulate mutually exclusive splicing of FGFR2 exons IIIb and IIIc: ectopic expression of ESRP1 in mesenchymal cells switches endogenous FGFR2 splicing to the epithelial IIIb isoform, while RNAi knockdown of both ESRPs in epithelial cells switches splicing to the mesenchymal IIIc isoform. ESRP1 also regulates splicing of CD44, CTNND1 (p120-catenin), and ENAH (hMena).\",\n      \"method\": \"cDNA expression screen, ectopic expression in cell lines, RNAi knockdown, RT-PCR isoform analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments across multiple transcripts, independently replicated in subsequent studies\",\n      \"pmids\": [\"19285943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Genome-wide profiling via splicing-sensitive exon arrays following RNAi knockdown of ESRP1/2 in human epithelial cells identified >100 ESRP-regulated splicing events (38 independently validated by RT-PCR), encompassing cassette exons and alternative 3′ terminal exons; regulated transcripts encode proteins involved in actin cytoskeleton organization, cell-cell adhesion, cell polarity, and cell migration.\",\n      \"method\": \"Affymetrix Exon ST1.0 array after RNAi knockdown, RT-PCR validation\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide loss-of-function with 38 independently validated targets, consistent with PMID 19285943\",\n      \"pmids\": [\"19829082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ESRP1 controls alternative splicing of CD44 pre-mRNA, promoting expression of CD44 variant isoforms (CD44v) over the standard isoform (CD44s); knockdown of ESRP1 in CD44v+ breast cancer cells causes an isoform switch from CD44v to CD44s, leading to reduced cell-surface xCT (cystine transporter) and suppressed lung colonization.\",\n      \"method\": \"RNAi knockdown, RT-PCR isoform analysis, orthotopic transplantation mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined molecular mechanism (CD44v→CD44s→xCT stability) validated in vivo\",\n      \"pmids\": [\"22673910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ESRP1 suppresses cancer cell motility through regulation of actin cytoskeleton dynamics via Rac1b: knockdown of ESRP1 (but not ESRP2) in head and neck carcinoma cells induces Rac1b expression and alters actin cytoskeleton dynamics, promoting a motile phenotype.\",\n      \"method\": \"RNAi knockdown, cell motility assays, western blot for Rac1b\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single method with phenotypic readout but limited mechanistic depth for Rac1b pathway\",\n      \"pmids\": [\"25143390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Esrp1 knockout mice develop fully penetrant bilateral cleft lip and palate; combined Esrp1/Esrp2 double knockout produces widespread developmental defects. Epidermal deletion of Esrps disrupts skin barrier function, demonstrating that Esrp1-mediated alternative splicing is essential for epithelial cell function in vivo.\",\n      \"method\": \"Conditional and germline knockout mice, RNA-Seq of epidermis, phenotypic analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with RNA-Seq profiling of splicing changes and defined developmental phenotypes\",\n      \"pmids\": [\"26371508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ESRP1 mutations in humans cause sensorineural hearing loss (SNHL) by disrupting alternative splicing of target genes; in Esrp1−/− mouse embryos, aberrant splicing of Fgfr2 blocks stria vascularis formation due to erroneous FGF ligand usage, which was corrected by reducing Fgf9 gene dosage — establishing a genetic epistasis between Fgfr2 splicing and Fgf9 signaling downstream of ESRP1.\",\n      \"method\": \"Whole-exome sequencing of SNHL patients, iPSC allele repair, Esrp1-KO mouse cochlear analysis, RNA-Seq, Fgf9 genetic rescue\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including genetic epistasis rescue, patient-derived iPSC, and transcriptome analysis\",\n      \"pmids\": [\"29107558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ESRP1 regulates alternative splicing of GPR137 to produce isoforms that differentially activate the Wnt signaling pathway; reduced ESRP1 function impairs intestinal barrier integrity and alters colorectal cancer development through GPR137 isoform switching.\",\n      \"method\": \"Mouse genetic model (reduced Esrp1 function), Wnt pathway reporter assays, RT-PCR isoform analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model plus mechanistic Wnt pathway readout, single lab\",\n      \"pmids\": [\"28975893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Alternative splicing of Esrp1 exon 12 via competing 5′ splice sites produces protein isoforms with distinct nuclear versus cytoplasmic localization; a specific peptide encoded by exon 12 is sufficient to confer nuclear localization. This differential subcellular localization is phylogenetically conserved (also found in Drosophila fusilli, the Esrp1 ortholog).\",\n      \"method\": \"RT-PCR isoform characterization, subcellular fractionation, fluorescence microscopy, Drosophila ortholog analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with peptide sufficiency test and cross-species conservation, single lab\",\n      \"pmids\": [\"28634384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ESRP1 protein physically associates with PNN (Pinin) in nuclear speckles of corneal epithelial cells (co-immunoprecipitation), and both regulate overlapping but distinct sets of alternative splicing events in corneal epithelium.\",\n      \"method\": \"Co-immunoprecipitation, deconvolution microscopy co-localization, genome-wide splicing array after knockdown\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and localization with functional splicing consequence, single lab\",\n      \"pmids\": [\"23299472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ESRP1 binds to Oct4 and Sox2 mRNAs in mouse embryonic stem cells and decreases their polysomal loading (translational repression), thereby acting as a physiological regulator of pluripotency; Esrp1 knockdown increases Oct4, Nanog, and Sox2 expression and enhances self-renewal.\",\n      \"method\": \"RNA immunoprecipitation (RIP) for Oct4/Sox2 mRNA binding, polysome fractionation, RNAi knockdown, in vitro/in vivo differentiation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP binding evidence plus polysome fractionation functional readout, single lab\",\n      \"pmids\": [\"24015231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ESRP1 knockdown in tamoxifen-resistant breast cancer cells affects lipid metabolism and oxidoreductase processes, reducing expression of fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), and phosphoglycerate dehydrogenase (PHGDH), and increases basal and spare mitochondrial respiration capacity.\",\n      \"method\": \"RNAi knockdown, western blot, RT-qPCR, Seahorse metabolic flux analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with multiple orthogonal metabolic readouts, single lab\",\n      \"pmids\": [\"30665944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"hnRNPM and ESRP1 co-regulate a set of cassette exon splicing events in an antagonistic (discordant) manner; motif enrichment near co-regulated exons identifies GU-rich motifs downstream of hnRNPM-repressed/ESRP1-enhanced exons, supporting a model of competitive binding to cis-regulatory elements.\",\n      \"method\": \"Comparative splicing analysis of hnRNPM and ESRP1 knockdown datasets, motif enrichment analysis, EMT correlation\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide comparative knockdown analysis with motif evidence, single lab\",\n      \"pmids\": [\"30042172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Transcriptional repression of ESRP1 under hypoxia is mediated by SLUG (downstream of TGF-β signaling) and by RBFOX2, which transcriptionally represses ESRP1 while interacting with SLUG; hypoxia-driven ESRP1 depletion causes skipping of hMENA exon 11a, producing a pro-metastatic hMENAΔ11a isoform.\",\n      \"method\": \"qRT-PCR, western blot, RNAi knockdown, chromatin immunoprecipitation for SLUG binding to ESRP1 promoter, RT-PCR isoform analysis\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP evidence for direct transcriptional repression plus splicing consequence, single lab\",\n      \"pmids\": [\"33089214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"E2F1 and CpG hydroxymethylation (mediated by TET3) at the E2F1 binding motif in the ESRP1 promoter conjointly induce ESRP1 expression in breast carcinoma; under hypoxia, reduced TET3 activity causes loss of hydroxymethylation and gain of methylation at these CpG sites, preventing E2F1 binding and reducing ESRP1 transcription.\",\n      \"method\": \"ChIP, dual luciferase reporter, bisulfite sequencing, western blot, RNAi knockdown\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays establishing transcriptional mechanism, single lab\",\n      \"pmids\": [\"34362878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ESRP1 upregulates ISG15 expression through CREB (with CREB enriched at the ISG15 promoter), and in turn ISG15 promotes ISGylation of ESRP1 protein, slowing its degradation and forming a positive feedback loop that jointly suppresses EMT in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation for ISGylation, chromatin immunoprecipitation for CREB at ISG15 promoter, dual luciferase reporter, western blot\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for ISGylation plus ChIP for transcriptional activation, single lab\",\n      \"pmids\": [\"32641707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ESRP1 regulates alternative splicing of CARM1 pre-mRNA to produce two transcripts (CARM1FL and CARM1ΔE15); the resulting CARM1 isoform ratio controls arginine methylation of Smad7, modulating TGF-β/Smad pathway activation and thereby influencing chemoresistance in small cell lung cancer.\",\n      \"method\": \"mRNA transcriptome sequencing, RT-PCR isoform analysis, overexpression/knockdown, western blot for Smad7 methylation\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with isoform validation and downstream pathway readout, single lab\",\n      \"pmids\": [\"33495408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of ESRP1 in mouse oocytes disrupts alternative splicing of maternal mRNA transcripts (528 aberrant AS events identified by single-cell RNA-seq), particularly in microtubule cytoskeletal genes including Rac1, Kif2c, Kif23, Ndel1, and Bora, leading to abnormal spindle organization, blocked first polar body extrusion, and female infertility.\",\n      \"method\": \"Esrp1 conditional knockout mice, single-cell RNA-seq, spindle assembly checkpoint analysis, oocyte meiosis assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with transcriptome analysis and defined cellular phenotype, single lab\",\n      \"pmids\": [\"33318146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"eCLIP mapping of ESRP1 binding sites in mouse epidermis revealed that ESRP1 functions in splicing through direct, position-dependent RNA binding to promote exon inclusion or skipping, and also binds widely to 3′ and 5′ UTRs of epithelial genes, indicating post-transcriptional regulatory functions beyond splicing.\",\n      \"method\": \"Enhanced CLIP-seq (eCLIP) in mouse epidermis, RNA-Seq of Esrp1/2-null epidermis, integration of binding and splicing data\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide direct binding map integrated with functional splicing data in vivo\",\n      \"pmids\": [\"36238894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ESRP1 regulates isoform switching of LRRFIP2 between epithelial (variant 2) and mesenchymal (variant 3) isoforms; the epithelial LRRFIP2 isoform inhibits oncogenic CARM1 function through direct protein–protein interaction, and CRISPR-mediated deletion of LRRFIP2 exon 7 causes isoform switch and suppresses liver metastasis of gastric cancer cells.\",\n      \"method\": \"Ectopic expression, CRISPR/Cas9 exon deletion, liver metastasis mouse model, co-immunoprecipitation for LRRFIP2-CARM1 interaction\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR isoform switch in vivo plus Co-IP mechanistic evidence, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36307405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ESRP1 controls biogenesis of the large circRNA circDOCK1(2-27) by binding GGU-containing repeat sequences in intron 1 of DOCK1 pre-mRNA, detaining splicing to enable back-splicing to exon 27. X-ray crystal structure of RNA-bound ESRP1 qRRM2 domain shows GGU motifs embedded in clamp-like aromatic pockets. CircDOCK1(2-27) represses cell motility both by diverting transcripts from DOCK1 mRNA production and by direct inhibition of migration.\",\n      \"method\": \"HITS-CLIP, CRISPR-mediated deletions, BioID proximity biotinylation, X-ray crystallography of qRRM2-RNA complex, cell motility assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus HITS-CLIP binding map plus CRISPR functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"38015468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ESRP1 overexpression in CRC cells enhances FGFR1/2 signaling and Akt activation in anchorage-independent conditions, and promotes macrometastasis formation in mouse livers, establishing a pro-oncogenic role for ESRP1 in colorectal cancer through enhanced growth factor receptor signaling.\",\n      \"method\": \"Gain- and loss-of-function in CRC cell lines, mouse liver metastasis model, western blot for FGFR/Akt signaling\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional studies with signaling pathway readout, single lab\",\n      \"pmids\": [\"28052020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ESRP1 binds to the GGUGGU sequence in the 3′UTR of cyclin A2 mRNA, decreasing its stability; ESRP1 overexpression increases CDC20 expression (promoting cyclin A2 protein degradation) and induces G1-phase cell cycle arrest in cervical cancer cells.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, overexpression, cell cycle analysis by flow cytometry, western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP binding to defined sequence motif plus functional mRNA stability and cell cycle readout, single lab\",\n      \"pmids\": [\"31362365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ESRP1 promotes exon 11 alternative splicing of CLSTN1 pre-mRNA; the resulting short CLSTN1 isoform stabilizes the E-cadherin/β-catenin complex and promotes β-catenin ubiquitination and degradation, thereby inhibiting gastric cancer cell migration and invasion.\",\n      \"method\": \"RNAi knockdown, overexpression, RT-PCR isoform analysis, co-immunoprecipitation, ubiquitination assay, in vitro/in vivo invasion assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splicing followed by mechanistic Co-IP and ubiquitination readout, single lab\",\n      \"pmids\": [\"38114495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Esrp1 overexpression in chicken stomach smooth muscle cells (SMCs) impairs SMC differentiation and switches FGFR2 splicing to the IIIb isoform; Esrp1 physically interacts with the RNA-binding protein RBPMS2 and RBPMS2-mediated SMC dedifferentiation requires Esrp1.\",\n      \"method\": \"Gain-of-function in chicken embryos, co-immunoprecipitation for ESRP1-RBPMS2 interaction, SMC differentiation assays, RT-PCR FGFR2 isoform analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo functional requirement established, single lab\",\n      \"pmids\": [\"27108394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Full-length APC expression in SW480 colorectal cancer cells increases ESRP1 expression, and ESRP1 depletion in SW480+APC cells reverts p120-catenin isoform switching (from isoform 3A back to isoform 1A) and reduces cell-cell adhesion, placing ESRP1 downstream of APC in the regulation of p120-catenin splicing and adhesion.\",\n      \"method\": \"APC re-expression, ESRP1 knockdown, RT-PCR p120-catenin isoform analysis, cell-cell adhesion assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (APC→ESRP1→p120-catenin isoform) with functional adhesion readout, single lab\",\n      \"pmids\": [\"33237836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Irf6 regulates the expression of esrp1 in zebrafish periderm and orofacial epithelium; genetic disruption of irf6 and esrp1/2 in zebrafish causes cleft of the anterior neurocranium through impaired chondrogenesis (not neural crest cell migration defects), and Irf6 heterozygosity reduces cleft severity in Esrp1/2 mutants, demonstrating genetic interaction.\",\n      \"method\": \"Zebrafish genetic mutants, compound mouse mutants (Irf6;Esrp1;Esrp2), cranial neural crest lineage tracing, in situ hybridization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with lineage tracing, single lab across two model organisms\",\n      \"pmids\": [\"33234718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cleft lip in Esrp1 knockout mice is associated with altered epithelial-mesenchymal crosstalk; transcriptomic analysis of ectoderm and mesenchyme in Esrp1 embryos identified altered expression of genes in multiple signaling pathways (including those previously implicated in cleft lip/palate).\",\n      \"method\": \"Esrp1 KO mouse models, transcriptomic analysis of separated ectoderm and mesenchyme, histological analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with tissue-specific transcriptomics, single lab\",\n      \"pmids\": [\"32253237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Decreased ESRP1 expression reduces MENA11a isoform expression by altering MENA alternative splicing; matrix stiffness decreases ESRP1 expression, triggering this splicing switch, which enhances cancer cell contractility via focal adhesion kinase activity and promotes intravasation.\",\n      \"method\": \"In vitro hydrogel stiffness systems, mouse model, western blot and RT-PCR, ESRP1 knockdown, intravasation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems (in vitro stiffness, mouse, patient specimens) with mechanistic pathway readout, single lab\",\n      \"pmids\": [\"37027295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ESRP1 binds to PHGDH mRNA at its 5′UTR and increases PHGDH mRNA stability in tamoxifen-resistant breast cancer cells; ESRP1 knockdown significantly decreases PHGDH mRNA stability in resistant cells.\",\n      \"method\": \"RNA-binding protein immunoprecipitation followed by microarray (RIP-Chip), immunoprecipitation-mass spectrometry, RNA EMSA, RIP-qRT-PCR, mRNA stability assay\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding validation methods (EMSA, RIP-qRT-PCR) plus mRNA stability functional assay, single lab\",\n      \"pmids\": [\"36925195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Snail transcription factor directly represses ESRP1 transcription by binding to the ESRP1 promoter in epithelial ovarian cancer cells, establishing ESRP1 as a downstream transcriptional target of Snail during EMT.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for Snail at ESRP1 promoter, luciferase reporter, RNAi\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay for direct transcriptional repression, single lab\",\n      \"pmids\": [\"29131012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In non-small cell lung cancer, Snail-mediated silencing of ESRP1 is required for anchorage-independent growth and metastatic behavior; ESRP1 loss is a critical event in Snail-dependent malignant transformation of pulmonary epithelial cells, acting in an ALDH+CD44+CD24− stem cell subset.\",\n      \"method\": \"RNAi knockdown/rescue, anchorage-independent growth assay, in vivo primary tumor and metastasis models, FACS for stem cell markers\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiment (Snail requires ESRP1 loss) validated in vivo, single lab\",\n      \"pmids\": [\"29431637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ESRP1 binds to pre-PTPN12 RNA and promotes the biogenesis of circPTPN12; circPTPN12 interacts with the PDZ domain of PDLIM2 and promotes PDLIM2-mediated ubiquitination of NF-κB p65, placing ESRP1 upstream of circPTPN12 in a circRNA biogenesis and NF-κB suppression axis in hepatocellular carcinoma.\",\n      \"method\": \"RNA immunoprecipitation, biotin-coupled probe pull-down, FISH, RNA sequencing, in vitro/in vivo functional assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding validation methods plus functional pathway readout, single lab\",\n      \"pmids\": [\"38992675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, Esrp1 and Esrp2 directly bind tmc1 and tmc2a mRNAs in sensory hair cells and regulate their stability; loss of esrp1/2 reduces tmc1/2a mRNA levels and impairs mechano-electrical transduction (MET) function of hair cells.\",\n      \"method\": \"Esrp1/2 double knockout zebrafish, RNA-sequencing, RNA binding assay for tmc1/tmc2a mRNA, electrophysiological MET assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding plus in vivo functional KO with electrophysiological readout, single lab\",\n      \"pmids\": [\"40086870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Overexpression of CTNND1 (p120-catenin) is sufficient to rescue morphogenesis of epithelial-derived structures in esrp1/2 zebrafish mutants, placing Ctnnd1 as a key downstream effector of Esrp1-regulated splicing in palatogenesis.\",\n      \"method\": \"esrp1/2 zebrafish mutants, CTNND1 overexpression rescue experiments, RT-PCR for Ctnnd1 isoforms\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment establishing epistasis in vivo, single lab\",\n      \"pmids\": [\"39179789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Lactylation of ESRP1 at lysine 43 (K43) stabilizes ESRP1 protein; glycolytic lactate promotes this modification. ESRP1 regulates biogenesis of circPHGDH, and circPHGDH knockdown suppresses ESRP1 lactylation, forming a positive feedback loop driving prostate cancer progression.\",\n      \"method\": \"RNA immunoprecipitation, immunoprecipitation, western blot for lactylation, site-directed mutagenesis (K43), luciferase reporter, RNA pull-down\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic evidence for lactylation is Co-IP/western blot only, no structural validation\",\n      \"pmids\": [\"41760734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ESRP1 interacts with DHCR7 protein and upregulates DHCR7 expression, enhancing ferroptosis susceptibility in diffuse-type gastric cancer cells; both in vitro and in vivo models confirm ESRP1 inhibits DGC malignant progression through this mechanism.\",\n      \"method\": \"Co-immunoprecipitation for ESRP1-DHCR7 interaction, overexpression/knockdown, xenograft mouse model, ferroptosis assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus functional assay, single lab\",\n      \"pmids\": [\"40528239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ESRP1 overexpression in alveolar epithelial cells promotes EMT via activation of the Epac-Rap1a signaling axis; Co-IP demonstrated direct interaction between ESRP1, Epac, and Rap1a. Silencing of Epac or Rap1a did not alter ESRP1 expression, confirming ESRP1 is upstream.\",\n      \"method\": \"Single-cell RNA-seq, co-immunoprecipitation, lentiviral overexpression, siRNA knockdown, TGF-β1-induced EMT model\",\n      \"journal\": \"Frontiers in medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with epistasis test by knockdown, single lab\",\n      \"pmids\": [\"41728622\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ESRP1 is an epithelial cell-type-specific RNA-binding protein (containing three RNA recognition motifs including a structurally characterized qRRM2 domain that recognizes GGU motifs) that coordinates a global epithelial alternative splicing program by binding pre-mRNA in a position-dependent manner—promoting exon inclusion or skipping—and also stabilizes or represses target mRNAs via 3′/5′ UTR binding; its key substrates include FGFR2 (IIIb/IIIc switch), CD44 (variant/standard switch), ENAH/MENA (exon 11a), CTNND1, LRRFIP2, CLSTN1, CARM1, and others that collectively regulate actin cytoskeleton dynamics, cell adhesion, polarity, and migration, and it is transcriptionally repressed by Snail and RBFOX2 (downstream of TGF-β/hypoxia) and transcriptionally induced by E2F1/TET3-mediated promoter hydroxymethylation, while its own protein stability is regulated by ISGylation; loss of Esrp1 in mice causes cleft lip/palate, hearing loss, kidney branching defects, skin barrier failure, oocyte meiosis failure, and widespread developmental abnormalities, establishing ESRP1 as an essential post-transcriptional regulator of epithelial cell identity and organogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ESRP1 is an epithelial cell-type-specific RNA-binding protein that coordinates a global epithelial post-transcriptional program, regulating >100 alternative splicing events in transcripts governing actin cytoskeleton organization, cell-cell adhesion, polarity, and migration [#0, #1]. Reciprocal gain- and loss-of-function established its defining activity as a regulator of mutually exclusive FGFR2 IIIb/IIIc splicing and of CD44, CTNND1, and ENAH/MENA isoform choice [#0, #2]. eCLIP in epidermis showed that ESRP1 acts through direct, position-dependent binding that promotes exon inclusion or skipping, and also binds widely to 3\\u2032 and 5\\u2032 UTRs, extending its role beyond splicing to mRNA stability control [#17]; a crystal structure of its qRRM2 domain bound to GGU motifs embedded in aromatic clamp-like pockets provides the molecular basis for sequence-specific recognition [#19]. Through its UTR-binding activity ESRP1 stabilizes target mRNAs such as PHGDH and destabilizes others including cyclin A2, and it drives back-splicing of circular RNAs (circDOCK1, circPTPN12) by detaining splicing at GGU-rich introns [#19, #21, #28, #31]. The splicing program it controls converges on epithelial morphogenesis: Esrp1 knockout mice develop fully penetrant cleft lip and palate, skin barrier failure, hearing loss through aberrant Fgfr2 splicing that mis-routes FGF9 signaling, and oocyte meiotic spindle defects [#4, #5, #16], and CTNND1 (p120-catenin) is a key downstream effector whose overexpression rescues epithelial morphogenesis in esrp1/2 mutants [#33]. ESRP1 is transcriptionally repressed by Snail/SLUG and RBFOX2 during EMT and induced by E2F1 together with TET3-mediated promoter hydroxymethylation [#12, #13, #29], and its protein level is further controlled by ISGylation [#14]. Direct evidence links ESRP1 mutations to human sensorineural hearing loss via disrupted target splicing [#5].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established ESRP1's foundational identity by showing an epithelial-specific RNA-binding protein directly controls the FGFR2 IIIb/IIIc splicing switch, defining the molecular determinant of an epithelial splicing program.\",\n      \"evidence\": \"cDNA expression screen with reciprocal ectopic expression and RNAi in epithelial/mesenchymal cell lines, RT-PCR isoform analysis\",\n      \"pmids\": [\"19285943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA binding sites not yet mapped\", \"Did not distinguish direct splicing targets from indirect effects\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the scope of ESRP1 as a master splicing regulator by genome-wide profiling, showing it controls a coordinated program of >100 events in cytoskeleton, adhesion, polarity, and migration genes.\",\n      \"evidence\": \"Exon ST1.0 splicing array after ESRP1/2 RNAi with RT-PCR validation of 38 targets\",\n      \"pmids\": [\"19829082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Array does not resolve direct vs indirect targets\", \"No binding map to assign mechanism per exon\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected ESRP1 splicing activity to disease phenotype by showing CD44v/CD44s isoform control governs xCT surface stability and metastatic lung colonization.\",\n      \"evidence\": \"RNAi knockdown, RT-PCR, orthotopic transplantation mouse model\",\n      \"pmids\": [\"22673910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CD44v stabilizing xCT not fully resolved\", \"Generalizability beyond breast cancer model unaddressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed ESRP1 functions beyond splicing as a translational regulator and nuclear-speckle partner, binding Oct4/Sox2 mRNAs to limit pluripotency and associating with PNN.\",\n      \"evidence\": \"RIP and polysome fractionation in ES cells; co-IP and co-localization with PNN in corneal epithelium\",\n      \"pmids\": [\"24015231\", \"23299472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PNN co-IP not reciprocally validated for direct contact\", \"Translational repression mechanism on Oct4/Sox2 not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated in vivo essentiality by showing germline Esrp1 loss causes fully penetrant cleft lip/palate and epidermal Esrp loss disrupts skin barrier, establishing ESRP-dependent splicing as required for epithelial organogenesis.\",\n      \"evidence\": \"Conditional and germline knockout mice with RNA-Seq of epidermis and phenotypic analysis\",\n      \"pmids\": [\"26371508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific splicing changes drive each phenotype not isolated\", \"Esrp1 vs Esrp2 contributions partially redundant\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked ESRP1 to human Mendelian disease and resolved a signaling epistasis, showing mutations cause sensorineural hearing loss via aberrant Fgfr2 splicing that mis-routes FGF9 ligand usage.\",\n      \"evidence\": \"Whole-exome sequencing of patients, iPSC allele repair, Esrp1-KO cochlear RNA-Seq, Fgf9 genetic rescue\",\n      \"pmids\": [\"29107558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full target set underlying stria vascularis defect not enumerated\", \"Penetrance and allelic spectrum in humans limited\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed ESRP1 itself is autoregulated and spatially partitioned, with exon 12 alternative splicing producing nuclear versus cytoplasmic isoforms in a conserved manner.\",\n      \"evidence\": \"RT-PCR isoform characterization, subcellular fractionation, microscopy, Drosophila ortholog comparison\",\n      \"pmids\": [\"28634384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of isoform localization difference not tested\", \"Regulation of exon 12 choice unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed ESRP1 within a competitive splicing-factor network by showing it acts antagonistically to hnRNPM at shared GU-rich cis-elements, and is transcriptionally silenced by Snail during EMT.\",\n      \"evidence\": \"Comparative knockdown splicing analysis with motif enrichment; ChIP and reporter assays for Snail at ESRP1 promoter\",\n      \"pmids\": [\"30042172\", \"29131012\", \"29431637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct competition at individual exons not biochemically reconstituted\", \"Snail-ESRP1 axis context-dependence across tissues unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the transcriptional and post-translational control of ESRP1, showing SLUG/RBFOX2 repress it under hypoxia while ISGylation stabilizes its protein in a CREB-ISG15 feedback loop.\",\n      \"evidence\": \"ChIP, RNAi, co-IP for ISGylation, reporter assays in cancer cell lines\",\n      \"pmids\": [\"33089214\", \"32641707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ISGylation site on ESRP1 not mapped\", \"Crosstalk between transcriptional and ISGylation control not integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established the E2F1/TET3 hydroxymethylation axis as the inductive arm of ESRP1 regulation and extended ESRP1 phenotypes to oocyte meiosis through splicing of microtubule cytoskeletal genes.\",\n      \"evidence\": \"ChIP, bisulfite sequencing, reporter assays; Esrp1 conditional KO mice with single-cell RNA-seq of oocytes\",\n      \"pmids\": [\"34362878\", \"33318146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct splicing targets causing spindle defects not validated individually\", \"TET3-E2F1 mechanism shown in one cancer context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the first in vivo direct binding map and showed ESRP1 binds UTRs as well as splice sites, mechanistically unifying its splicing and mRNA-fate functions.\",\n      \"evidence\": \"eCLIP in mouse epidermis integrated with Esrp1/2-null RNA-Seq\",\n      \"pmids\": [\"36238894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"UTR-binding consequences (stability/translation) not assayed transcriptome-wide\", \"Position rules derived from epidermis only\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Delivered the structural basis of sequence recognition and a novel function in circRNA biogenesis, showing the qRRM2 domain clamps GGU motifs to detain splicing and drive back-splicing of circDOCK1.\",\n      \"evidence\": \"HITS-CLIP, X-ray crystallography of qRRM2-RNA complex, CRISPR deletions, motility assays\",\n      \"pmids\": [\"38015468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of GGU-clamp recognition across all targets not demonstrated\", \"Contribution of the other two RRMs unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ESRP1's position-dependent binding code, UTR-mediated stability control, and circRNA biogenesis activity are integrated into a single tissue-specific regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking splice-site vs UTR binding outcomes\", \"Roles of the three RRMs and isoform localization in target selection undefined\", \"Lactylation and other PTMs reported only at Low confidence\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 17, 19, 21, 28]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 17, 19]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [8, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 17, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5, 25, 26, 33]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PNN\", \"RBPMS2\", \"hnRNPM\", \"RBFOX2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}