{"gene":"EHF","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2000,"finding":"ESE-3/EHF is an ETS transcription factor exclusively expressed in epithelial cells that transactivates the c-MET promoter via three high-affinity ETS binding sites, and binds promoters of glandular epithelium-specific genes; ESE-3 and ESE-1 differ significantly in their ability to transactivate promoters despite similar DNA binding affinity, establishing distinct target gene specificity within the ESE subfamily.","method":"Transactivation reporter assays, electrophoretic mobility shift assay (EMSA), promoter binding analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EMSA, reporter assay, promoter binding) in a single study establishing DNA-binding and transactivation specificity","pmids":["10644770"],"is_preprint":false},{"year":2001,"finding":"EHF/ESE-3 acts as a context-dependent transcriptional repressor of Ras- or phorbol ester-induced transcriptional activation of promoters containing both ETS and AP-1 binding sites; repression is sequence- and context-dependent, requiring high-affinity ESE-3 binding sites combined with AP-1 cis-elements in a specific arrangement. ESE-3 is a nuclear protein expressed exclusively in differentiated epithelial cells and absent in epithelial carcinomas.","method":"Transient transfection reporter assays, immunohistochemistry with newly generated monoclonal antibody, nuclear localization confirmed by immunostaining","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays with promoter variants plus immunohistochemical localization, single lab, multiple methods","pmids":["11259407"],"is_preprint":false},{"year":1999,"finding":"EHF protein represses ETS-2-induced activity of both stromelysin-1 (MMP-3) and collagenase-1 (MMP-1) promoters, establishing a functional role as a transcriptional repressor of matrix metalloproteinase genes.","method":"Transactivation reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single reporter assay, single lab, no orthogonal methods","pmids":["10527851"],"is_preprint":false},{"year":2002,"finding":"ESE-3/EHF overexpression in 3T3 cells and human bronchial smooth muscle cells inhibits MMP-1 promoter activity. Cytokine-induced ESE-3 expression in bronchial smooth muscle cells is mediated by MEK1/2 and p38 MAPK signaling pathways, as specific inhibitors (U0126, SB03580) abrogate induction.","method":"Reporter assay (MMP-1 promoter), pharmacological inhibition with specific kinase inhibitors, RT-PCR and protein analysis","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection plus reporter assay, single lab, two orthogonal methods","pmids":["12444029"],"is_preprint":false},{"year":2007,"finding":"ESE-3/EHF expression is upregulated by p38 MAPK in cellular senescence. Ectopic expression of ESE-3 induces growth retardation, upregulation of p16(INK4a) (but not p21), and increased SA-β-gal activity. Recombinant ESE-3 protein directly binds ETS-binding sequences in the p16(INK4a) promoter and increases its transcriptional activity in reporter assays.","method":"Microarray, ectopic expression, reporter assay, EMSA with recombinant protein, SA-β-gal assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (recombinant protein EMSA, reporter assay, cellular phenotype), single lab","pmids":["17627613"],"is_preprint":false},{"year":2007,"finding":"ESE-3/EHF expression is silenced by methylation of an evolutionarily conserved CpG site in its promoter in prostate cancer cells (PC3, DU145); treatment with 5-aza-2'-deoxycytidine restores expression. Re-expression of ESE-3 in prostate cancer cells inhibits clonogenic survival and induces apoptosis by increasing procaspase-3 levels, mediated at the transcriptional level by direct ESE-3 binding to the caspase-3 promoter.","method":"Bisulfite sequencing/methylation analysis, 5-aza-2'-deoxycytidine treatment, clonogenic assay, apoptosis assays, chromatin immunoprecipitation (ChIP) of caspase-3 promoter","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP of direct promoter binding, epigenetic mechanism, functional rescue, multiple orthogonal methods in single study; elevated to High for multiple convergent methods","pmids":["18037958"],"is_preprint":false},{"year":2008,"finding":"ESE-3/EHF expression in airway epithelial cells is upregulated by inflammatory cytokines IL-1β and TNF-α via NF-κB activation; specific NF-κB binding sequences in the ESE-3 promoter are required for cytokine-induced expression. ESE-1 upregulates ESE-3 expression and downregulates its own cytokine-induced expression.","method":"Promoter characterization, NF-κB binding site mutagenesis, cytokine stimulation, RT-PCR, reporter assay","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis combined with reporter assay and expression analysis, single lab","pmids":["18475289"],"is_preprint":false},{"year":2011,"finding":"EHF directly activates transcription of RUVBL1 (an ATPase associated with chromatin-remodeling complexes). RUVBL1 blocks p53-mediated apoptosis by repressing p53 and its target genes: RUVBL1 binds the p53 promoter, interferes with RNF20/hBRE1-mediated histone H2B monoubiquitination, and promotes PAF1-mediated histone H3K9 trimethylation. This EHF→RUVBL1 axis allows colon tumor cells with wild-type p53 to avoid apoptosis.","method":"ChIP, promoter reporter assay, histone modification analysis, siRNA knockdown, apoptosis assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, histone modification assays, and functional apoptosis rescue, multiple orthogonal methods establishing direct transcriptional activation and downstream chromatin mechanism","pmids":["21617703"],"is_preprint":false},{"year":2012,"finding":"ESE3/EHF represses expression of key EMT and cancer stem cell genes including TWIST1, ZEB2, BMI1, and POU5F1 in prostate epithelial cells. Loss of ESE3/EHF induces EMT, stem-like features, and tumor-initiating/metastatic properties; re-expression inhibits stem-like properties and tumorigenic potential.","method":"Gene expression analysis, siRNA knockdown, re-expression experiments, tumor-initiating assays, tissue microarray","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular targets, single lab with multiple readouts","pmids":["22505649"],"is_preprint":false},{"year":2013,"finding":"EHF promotes cornea epithelial fate through complementary gene-activating and gene-repressing activities, with potential interactions with KLF4 and KLF5 in promoting cornea epithelial differentiation. EHF binding sites and direct targets in cornea epithelium were identified by ChIP-seq combined with loss-of-function studies.","method":"ChIP-seq, loss-of-function studies (siRNA/KO), transcriptome profiling, comparison across epithelial tissues","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq genome-wide binding plus loss-of-function phenotype, single lab","pmids":["24142692"],"is_preprint":false},{"year":2013,"finding":"EHF expression in intestinal follicle-associated epithelial cells is sufficient to activate HCK-dependent apical-to-basolateral transcytosis of non-opsonized and SIgA-opsonized particles, placing EHF upstream of HCK kinase in regulating antigen sampling at mucosal surfaces.","method":"Ectopic expression of EHF in cultured intestinal epithelial cells, transcytosis assays with particles, pharmacological inhibition of HCK","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined cellular phenotype (transcytosis) and epistasis placing EHF upstream of HCK, single lab","pmids":["23439650"],"is_preprint":false},{"year":2015,"finding":"EHF (Ehf) is upregulated by TGF-β/Smad signaling in mouse bone marrow-derived mast cells. Forced expression of Ehf represses transcription of FcεRIα, FcεRIβ, and c-Kit genes by directly binding their promoters, reducing surface FcεRI and c-Kit expression, suppressing FcεRI-mediated degranulation and cytokine production. EHF also decreases mRNA levels of GATA1, GATA2, and Stat5b, contributing to these effects.","method":"Forced expression (stable transfection), promoter binding assay (ChIP/EMSA), flow cytometry, degranulation assay, cytokine measurement, TGF-β treatment","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated alongside functional assays (degranulation, cytokine production, surface receptor expression), multiple orthogonal methods in single study","pmids":["26297757"],"is_preprint":false},{"year":2016,"finding":"ESE3/EHF directly binds and represses promoters of Lin28A and Lin28B genes in normal prostate cells, while also activating transcription and maturation of let-7 microRNAs. Loss of ESE3/EHF in cancer cells upregulates Lin28A/B and downregulates let-7 microRNAs, which is critical for prostate cancer stem cell expansion.","method":"ChIP (promoter binding), gene expression analysis, siRNA/shRNA knockdown, sphere formation assay, xenograft tumor model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct promoter binding, functional validation in vitro and in vivo, replicated in multiple models","pmids":["27197175"],"is_preprint":false},{"year":2016,"finding":"ESE3/EHF directly binds a novel ETS binding site in the IL-6 gene promoter to repress its transcription. Loss of ESE3/EHF in prostate epithelial cells activates IL-6, which then stimulates STAT3 activation and expansion of the cancer stem-like compartment; pharmacological inhibition of IL-6/STAT3 with a JAK inhibitor restrained cancer stem cell growth.","method":"ChIP (direct promoter binding), luciferase reporter assay, siRNA knockdown, IL-6 inhibition, JAK inhibitor treatment, sphere formation and in vivo self-renewal assays","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding plus epistatic rescue experiments and in vivo validation, multiple orthogonal methods","pmids":["27732936"],"is_preprint":false},{"year":2016,"finding":"ESE3/EHF inhibits pancreatic cancer (PDAC) metastasis by directly upregulating E-cadherin expression at the transcriptional level; downregulation of ESE3 in PDAC reduces E-cadherin and promotes cell motility, invasiveness, and metastasis in an orthotopic mouse model.","method":"Expression knockdown/overexpression, promoter reporter assay, orthotopic mouse model, ChIP (E-cadherin promoter binding)","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct transcriptional target identified by ChIP/reporter assay, validated in orthotopic mouse model and human specimens, multiple orthogonal methods","pmids":["27923832"],"is_preprint":false},{"year":2016,"finding":"EHF transcriptionally regulates HER2 and HER3 (ERBB2 and ERBB3) in thyroid cancer cells, as demonstrated by dual-luciferase reporter and ChIP assays, identifying EHF as a transcription factor for these receptor tyrosine kinases.","method":"Dual-luciferase reporter assay, ChIP, siRNA knockdown and ectopic expression, in vitro and in vivo proliferation/invasion assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay confirming direct transcriptional regulation, single lab","pmids":["27517321"],"is_preprint":false},{"year":2017,"finding":"EHF targets in primary human bronchial epithelial (HBE) cells are enriched for genes involved in inflammation and wound repair, as determined by EHF ChIP-seq and RNA-seq after EHF depletion. EHF depletion alters epithelial secretion of a neutrophil chemokine, slows wound closure in HBE cells, and EHF activates expression of SPDEF, which contributes to goblet cell hyperplasia.","method":"ChIP-seq, RNA-seq after EHF depletion, wound closure assay, cytokine secretion measurement, siRNA knockdown in primary HBE cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — genome-wide ChIP-seq with RNA-seq and functional cellular assays, multiple orthogonal methods in primary human cells","pmids":["28461336"],"is_preprint":false},{"year":2006,"finding":"ESE-3/EHF regulates expression of death receptor 5 (DR-5/TRAIL-R2) through binding to Ets binding sequences on the DR-5 promoter, with co-factors CBP and p300 involved in ESE-3-mediated DR-5 upregulation.","method":"EMSA, luciferase reporter assay, promoter mutation analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — EMSA and reporter assay, single lab, no ChIP or in vivo validation","pmids":["17027647"],"is_preprint":false},{"year":2019,"finding":"EHF gene produces two transcript variants: a long form (EHF-LF, includes exon 1) and a short form (EHF-SF, excludes exon 1). Only EHF-SF abrogates ETS1-mediated activation of the ZEB1 promoter by promoting degradation of ETS1 proteins, thereby inhibiting EMT. A point mutation within the ETS domain of EHF abolishes this function and causes EHF to act as a dominant negative, enhancing metastasis in vivo.","method":"Promoter reporter assay, protein degradation assay, in vivo metastasis model, site-directed mutagenesis, expression of isoform variants","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific functional dissection with mutagenesis and in vivo validation, single lab","pmids":["33712555"],"is_preprint":false},{"year":2019,"finding":"miR-365-3p targets EHF (demonstrated by miR-365-3p reducing EHF expression to decrease migration/invasion in OSCC cells). EHF functions as a transcription factor for KRT16 (keratin 16). EHF-driven KRT16 expression promotes association of c-Met with β5-integrin, facilitating downstream Src/STAT3/FAK/ERK signaling in oral squamous cell carcinoma cells.","method":"miRNA target validation (reporter assay), ectopic expression and siRNA knockdown, confocal colocalization, protein degradation assay (lysosomal pathway), in vitro and in vivo functional experiments","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — miRNA-target validation combined with mechanistic pathway dissection, single lab with multiple methods","pmids":["30782177"],"is_preprint":false},{"year":2021,"finding":"EHF suppresses pancreatic cancer stemness by directly repressing transcription of CXCR4 (receptor for CXCL12); EHF also has a cell-autonomous role in suppressing stemness by inhibiting transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppresses PC stemness by upregulating EHF.","method":"ChIP, luciferase reporter assay, sphere formation assay, flow cytometry, in vivo KPC mouse model, anchorage-independent growth assay","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assay confirming direct promoter repression, validated in transgenic mouse model and patient samples, multiple convergent methods","pmids":["33674341"],"is_preprint":false},{"year":2021,"finding":"Loss of EHF promotes neuroendocrine differentiation (NED) in prostate cancer following androgen deprivation therapy (ADT). ADT reduces EHF transcription by relieving AR binding to androgen-responsive elements in the EHF locus. EHF loss promotes expression and enzymatic activity of EZH2, which catalyzes H3K27me3 to repress downstream target genes and drive NED.","method":"ChIP (AR binding to EHF locus), EZH2 activity assay, H3K27me3 measurement, EZH2 inhibitor treatment, knockdown/overexpression in cell and mouse models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based epistasis and histone modification assays, validated in preclinical models, single lab","pmids":["33414441"],"is_preprint":false},{"year":2021,"finding":"EHF promotes colorectal carcinoma progression by directly upregulating TGF-β1 transcription, thereby activating canonical TGF-β signaling; ChIP and reporter assays confirmed direct EHF binding to the TGF-β1 promoter.","method":"ChIP, luciferase reporter assay, overexpression and knockdown, in vitro and in vivo proliferation/invasion assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding and reporter assay, functional validation in vivo, single lab","pmids":["32372436"],"is_preprint":false},{"year":2021,"finding":"EHF directly activates transcription of RUVBL1 and in colon cancer also promotes cancer progression by downregulating EHD2 and transactivating INPP4B as downstream target genes, as shown by ChIP and reporter assays.","method":"ChIP, reporter assay, knockdown/overexpression, in vitro and in vivo growth assays","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and reporter assay for new targets (EHD2, INPP4B) in a single study with limited mechanistic depth","pmids":["33520362"],"is_preprint":false},{"year":2021,"finding":"EBV protein LMP2A causes upregulation of EHF via phosphorylation of STAT3 in EBV-positive gastric cancer cells. STAT3 knockdown inhibits cellular growth of EBV-positive GC cells, and this inhibition is rescued by EHF overexpression, establishing EHF downstream of the LMP2A/STAT3 axis.","method":"RNA-seq, ChIP (active histone marks, H3K4me3/H3K27ac), siRNA knockdown, overexpression rescue assay, immunostaining","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue experiment (STAT3 KD rescued by EHF OE), ChIP-seq, single lab","pmids":["34014591"],"is_preprint":false},{"year":2022,"finding":"EHF physically interacts with CDX1 via its PNT domain, and together they cooperatively drive transcription of the colonic differentiation marker VIL1. Re-expression of EHF and CDX1 in poorly-differentiated CRC cells induces chromatin remodeling, transcriptional reprogramming, and enterocytic differentiation; compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupts normal colonic differentiation and significantly enhances colorectal tumor progression.","method":"Co-immunoprecipitation (physical interaction via PNT domain), reporter assay (VIL1 transcription), chromatin remodeling analysis, re-expression in CRC cells, compound mouse knockout (Ehf/Cdx1 double KO)","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct physical interaction demonstrated by Co-IP, cooperative transcriptional activity, and in vivo double-knockout mouse model, multiple orthogonal methods","pmids":["35606410"],"is_preprint":false},{"year":2021,"finding":"Ehf knockout mice (ETS DNA-binding domain deleted) develop papillomas in facial skin, abscesses in preputial glands/vulvae, corneal ulcers, increased susceptibility to colitis, impaired goblet cell differentiation in the colon, extensive transcriptional reprogramming of colonic epithelium, and enhanced Apc-initiated adenoma development—establishing that the EHF ETS DNA-binding domain is essential for postnatal epidermal and colonic epithelial homeostasis.","method":"Genetic knockout mouse model (ETS domain deletion), intestinal-specific conditional knockout, chemically induced colitis, Apc-mutation tumor model, histology, transcriptome analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous mouse genetic model with multiple tissue-specific phenotypes, conditional KO, and tumor progression model, strong evidence across multiple readouts","pmids":["34180969"],"is_preprint":false},{"year":2016,"finding":"ESE-3/EHF involved in co-regulation of ABCB1 (P-glycoprotein/MDR1) gene transcription via PXR (pregnane X receptor): ESE-3 binds a distal enhancer region containing DR4 motifs of the ABCB1 gene (confirmed by ChIP), and co-expression of ESE-3 with PXR in HepG2 cells enables rifampicin-induced reporter activation that is abolished by DR4 mutation. Knockdown of ESE-3 in LS180 cells reduces rifampicin-induced ABCB1 mRNA induction.","method":"ChIP (ESE-3 binding to ABCB1 enhancer), luciferase reporter assay with DR4 mutagenesis, siRNA knockdown, co-transfection in HepG2 cells","journal":"Drug metabolism and pharmacokinetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay with mutagenesis, siRNA knockdown, single lab","pmids":["27567379"],"is_preprint":false},{"year":2024,"finding":"EHF deficiency in pancreatic cancer induces CXCL1 transcription (EHF represses CXCL1 promoter), leading to enhanced CXCR2+ neutrophil recruitment in a CXCL1-CXCR2-dependent manner that drives chemotherapy and immunotherapy resistance. TP53 mutation mediates loss of tumoral EHF. Nifurtimox elevates tumoral EHF and inhibits JAK1/STAT1 pathway to suppress CXCR2+ neutrophil recruitment.","method":"ChIP assay (EHF binding CXCL1 promoter), Ehf-knockout mice, KPC mouse model, humanized mice, single-cell RNA-seq, spatial transcriptomics, cytokine multiplex assay, CXCR2 blockade, neutrophil depletion","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirming direct promoter repression, validated in multiple mouse models including KO and KPC, orthogonal rescue experiments with CXCL1/CXCR2 blockade","pmids":["38492894"],"is_preprint":false},{"year":2024,"finding":"EHF forms liquid-like nuclear condensates that transcriptionally repress TERT (reducing telomere length and driving senescence) and inflammatory factors (IL-6, CXCL12), thereby inducing cellular senescence without the associated inflammatory secretory phenotype (SASP) in PDAC cells.","method":"CRISPR/Cas9 library screening (SPiDER senescence probe-based), phase separation/condensate imaging, ChIP (EHF binding to TERT and inflammatory gene promoters), telomere length assay, flow cytometry, in vivo PDAC model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding, phase separation imaging, senescence functional assays, single lab with multiple methods","pmids":["39710057"],"is_preprint":false},{"year":2024,"finding":"EHF interacts with the coactivator AJUBA LIM protein to cooperatively orchestrate transcriptional network activity in gastroesophageal adenocarcinoma, activating the KRAS signaling pathway. EHF expression is promoted by a core transcriptional regulatory circuitry composed of ELF3-KLF5-GATA6.","method":"Co-immunoprecipitation (EHF-AJUBA interaction), ChIP, reporter assay, siRNA knockdown, lipid nanoparticle dual targeting, in vitro and in vivo functional assays","journal":"Acta pharmaceutica sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating physical interaction, ChIP, functional validation, single lab","pmids":["38799645"],"is_preprint":false},{"year":2024,"finding":"EHF transcriptionally activates GLI1 (glioma-associated oncogene homolog 1) and CCL2 (C-C motif chemokine 2) in cholangiocarcinoma by directly binding their promoters, thereby promoting tumor cell growth and recruiting/activating tumor-associated macrophages via the CCL2/CCR2 axis.","method":"ChIP (EHF binding to GLI1 and CCL2 promoters), reporter assay, in vitro and in vivo functional experiments, inhibitor combination (GANT58 + INCB3344)","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct binding to two target gene promoters, functional validation in vivo, single lab","pmids":["38741887"],"is_preprint":false},{"year":2024,"finding":"In papillary thyroid cancer cells harboring concurrent BRAFV600E and TERT promoter mutations, EHF overexpression significantly increases TERT expression, and ChIP analysis suggested direct EHF binding to the mutant TERT promoter (but not wild-type TERT promoter). BRAF inhibition decreases both EHF and TERT expression.","method":"EHF overexpression and knockdown, ChIP-qPCR (TERT promoter), BRAF pharmacological inhibition, in vitro experiments","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating mutation-selective binding, functional expression assays, single lab","pmids":["39183149"],"is_preprint":false},{"year":2024,"finding":"In salivary glands, Ehf (but not Elf5) plays a nonredundant role in ductal cell differentiation. EhfMut mice (CRISPR-Cas9 disruption of ETS domain) exhibit decreased granular convoluted tubules and accumulation of intercalated Sox9+ ductal cell populations, with a pronounced and sexually dimorphic phenotype.","method":"CRISPR-Cas9 mouse knockout (ETS domain disruption), immunostaining, histological analysis, cell population quantification","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with specific cellular phenotype, single lab","pmids":["36348499"],"is_preprint":false},{"year":2024,"finding":"Ehf deletion in the mammary gland impairs lobuloalveolar differentiation at late pregnancy (reduced milk genes, milk lipids, fewer differentiated alveolar cells, accumulation of alveolar progenitor cells). Ehf deletion attenuates prolactin-induced alveolar differentiation in mammary organoids and increases tumor incidence in the MMTV-PyMT mammary tumor model.","method":"Mouse Ehf knockout model, mammary organoids, histology, gene expression, MMTV-PyMT tumor model","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous mouse genetic model with multiple functional readouts (organoids, in vivo differentiation, tumor incidence), multiple orthogonal approaches","pmids":["38781975"],"is_preprint":false},{"year":2024,"finding":"RRAD (a GTPase) binds EHF and regulates its subcellular localization; RRAD negatively regulates glycolysis by controlling EHF's nucleocytoplasmic distribution. EHF (when nuclear) activates transcription of NEAT1_2, hexokinase 2, and pyruvate kinase M2, forming a NEAT1_2/RRAD/EHF positive feedback loop promoting glycolysis in papillary thyroid cancer cells.","method":"Co-immunoprecipitation (RRAD-EHF interaction), ChIP (EHF binding to NEAT1_2/HK2/PKM2 promoters), luciferase reporter assay, subcellular fractionation, in vitro and in vivo glycolysis assays","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction, ChIP for direct binding, subcellular localization data linked to function, single lab","pmids":["37279586"],"is_preprint":false},{"year":2024,"finding":"Dclk2 phosphorylates EHF and changes its nucleoplasmic distribution, causing p-EHF to exit the nucleus. Nuclear EHF represses Caspase1 and Caspase3 promoter activity; loss of nuclear EHF (due to Dclk2-mediated phosphorylation) promotes expression of Caspase1 and Caspase3 and stimulates neuronal pyroptosis.","method":"Kinase phosphorylation assay, subcellular fractionation/immunofluorescence, promoter reporter assay (Caspase1/3), siRNA knockdown, OGD and CCI mouse models","journal":"Journal of cerebral blood flow and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation-driven localization change linked to promoter activity and cellular phenotype, single lab","pmids":["38513137"],"is_preprint":false},{"year":2024,"finding":"EHF promotes M2 macrophage polarization in liver cancer by binding the promoter of KDM2B and transcriptionally activating it, leading to increased IL-6 secretion from TAMs which promotes liver cancer cell metastasis.","method":"CUT-Tag (EHF binding to KDM2B promoter), ChIP, luciferase assay, cytokine array, siRNA knockdown, co-culture system, in vitro and in vivo assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT-Tag and ChIP confirming direct promoter binding, functional assays, single lab","pmids":["39971220"],"is_preprint":false},{"year":2025,"finding":"Loss of EHF in iPSC-derived lung cells enhances CFTR activity, increases transepithelial electrical resistance, leads to transcriptomic changes in basal cells, and reduces HIF-1α-mediated hypoxic response, revealing multiple mechanisms by which EHF modifies cystic fibrosis-related lung disease.","method":"CRISPR knockout of EHF in human iPSC-derived lung cells, electrophysiology (CFTR activity), transepithelial electrical resistance measurement, RNA-seq, HIF-1α response assay","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout in human iPSC-derived cells with multiple functional readouts, single lab","pmids":["40590703"],"is_preprint":false},{"year":2026,"finding":"EHF directly regulates Ccr7, Cd200, Cd274 (PD-L1), Irf4, and Rel expression in conventional dendritic cells (cDCs), as shown by CUT&TAG. Conditional deletion of EHF in DCs decreases CCR7, CD200, and PD-L1 expression, increases IRF4, decreases inhibitory NFκB member Rel, and promotes Th1- and Th17-biased CD4+ T cell responses. EHF expression is highly enriched in CCR7hi DCs in mice and humans.","method":"CUT&TAG (genome-wide EHF binding), conditional DC-specific knockout mice, flow cytometry, in vitro and in vivo T cell polarization assays, single-cell RNA-seq","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CUT&TAG genome-wide binding data, conditional knockout mouse model, multiple functional immune readouts in vitro and in vivo, multiple orthogonal methods","pmids":["41730908"],"is_preprint":false},{"year":2025,"finding":"In prostate epithelial cells, EHF acts as a central transcriptional node controlling a hierarchy of regulatory factors and downstream signaling pathways (including COL1A1/DDR1, JAK/STAT3) to maintain epithelial lineage integrity. EHF knockout is sufficient to disrupt epithelial cell lineage integrity and promote a progenitor/stem-like state with basal and luminal features, attenuate androgenic response, and drive resistance to AR antagonists.","method":"EHF knockout mouse models, human epithelial cell knockout, transcriptome analysis, ChIP/binding assays, AR antagonist resistance assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with transcriptome analysis, pathway dissection and functional drug resistance assays, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.11.26.690649"],"is_preprint":true}],"current_model":"EHF/ESE3 is an epithelium-specific ETS transcription factor that functions primarily as a context-dependent transcriptional repressor (of EMT genes, IL-6, CXCL1, CXCR4, TERT, Lin28A/B, and MMP promoters) and activator (of E-cadherin, caspase-3, RUVBL1, SPDEF, let-7 microRNAs, and cell-type-specific differentiation genes) by directly binding ETS motifs in target gene promoters; its activity is regulated by NF-κB, MAPK/p38, TGF-β/Smad, and STAT3 signaling pathways, and by Dclk2-mediated phosphorylation that controls its nuclear localization; in epithelial tissues it maintains lineage identity and suppresses stem-like/EMT programs, while in immune cells (mast cells, dendritic cells) it regulates surface receptor expression and immunosuppressive gene programs, with its physical interaction with CDX1 via the PNT domain and with co-activator AJUBA representing key protein-protein interactions that modulate transcriptional output."},"narrative":{"mechanistic_narrative":"EHF (ESE-3) is an epithelium-restricted ETS-family transcription factor that binds high-affinity ETS motifs in target promoters and acts as a context-dependent activator or repressor to maintain epithelial lineage identity and suppress stem-like and EMT programs [PMID:10644770, PMID:11259407, PMID:22505649]. In normal epithelia EHF promotes terminal differentiation—driving corneal epithelial fate [PMID:24142692], colonic enterocytic differentiation through a direct physical interaction with CDX1 via its PNT domain [PMID:35606410], salivary ductal differentiation [PMID:36348499], and mammary lobuloalveolar maturation [PMID:38781975]—and genetic deletion of its ETS DNA-binding domain in mice disrupts epidermal and colonic homeostasis and accelerates tumor development [PMID:34180969]. As a tumor suppressor it directly represses EMT and stemness drivers (TWIST1, ZEB2, BMI1, POU5F1, Lin28A/B, CXCR4, SOX9/SOX2/OCT4/NANOG) while activating let-7 microRNAs and E-cadherin, thereby restraining invasion, metastasis, and the cancer stem-like compartment [PMID:22505649, PMID:27197175, PMID:27923832, PMID:33674341]; it also represses inflammatory genes including IL-6 and CXCL1, limiting STAT3 activation and CXCR2+ neutrophil recruitment that otherwise drive therapy resistance [PMID:27732936, PMID:38492894]. EHF expression is induced by inflammatory cytokines via NF-κB [PMID:18475289], by p38/MEK MAPK signaling [PMID:12444029, PMID:17627613], and by androgen receptor binding at its locus [PMID:33414441], and its silencing by promoter CpG methylation in prostate cancer abolishes its pro-apoptotic and differentiation functions [PMID:18037958]. EHF activity is further gated by subcellular partitioning: RRAD- and Dclk2-dependent phosphorylation control its nucleocytoplasmic distribution, and only nuclear EHF executes its transcriptional program [PMID:37279586, PMID:38513137]. Beyond epithelia, EHF programs immune cells, repressing FcεRI and c-Kit in mast cells downstream of TGF-β/Smad [PMID:26297757] and directly regulating CCR7, CD200, PD-L1, IRF4 and Rel in CCR7hi conventional dendritic cells to bias CD4+ T cell responses [PMID:41730908]. EHF cooperates with coactivators (CBP/p300, AJUBA) and core epithelial transcriptional circuitry (ELF3-KLF5-GATA6) to orchestrate its target networks [PMID:17027647, PMID:38799645].","teleology":[{"year":2000,"claim":"Established that EHF/ESE-3 is an epithelium-restricted ETS factor with DNA-binding and transactivation specificity distinct from its paralog ESE-1, defining it as a sequence-specific transcription factor rather than a generic ETS protein.","evidence":"EMSA, reporter transactivation, and promoter binding analysis on the c-MET promoter","pmids":["10644770"],"confidence":"Medium","gaps":["No genome-wide binding map","Tissue-specific cofactors not identified"]},{"year":2001,"claim":"Showed EHF can act as a context-dependent repressor of Ras/AP-1-driven transcription and is a nuclear protein lost in carcinomas, framing it early as a differentiation-associated, potentially tumor-suppressive factor.","evidence":"Reporter assays with promoter variants plus immunohistochemistry with a new monoclonal antibody","pmids":["11259407"],"confidence":"Medium","gaps":["Mechanism of activator/repressor switching unresolved","No in vivo loss-of-function"]},{"year":2003,"claim":"Connected EHF expression to upstream MAPK signaling and demonstrated repression of MMP promoters, linking inflammatory signaling input to EHF-mediated transcriptional output.","evidence":"MMP-1/MMP-3 reporter assays and pharmacological MEK/p38 inhibition in 3T3 and bronchial smooth muscle cells (also #2)","pmids":["12444029","10527851"],"confidence":"Medium","gaps":["Direct promoter occupancy not shown by ChIP","Endogenous MMP regulation not tested"]},{"year":2007,"claim":"Identified EHF as a p38-induced effector of senescence that directly activates the p16INK4a promoter, providing a growth-suppressive mechanism downstream of stress signaling.","evidence":"Microarray, ectopic expression, recombinant-protein EMSA, p16 reporter assay and SA-β-gal in a single study","pmids":["17627613"],"confidence":"Medium","gaps":["Senescence role tested only by overexpression","Endogenous EHF requirement not addressed"]},{"year":2008,"claim":"Defined NF-κB as a direct transcriptional inducer of EHF in airway epithelium, establishing cytokine-driven control of EHF expression.","evidence":"Promoter NF-κB site mutagenesis, cytokine stimulation, reporter assays","pmids":["18475289"],"confidence":"Medium","gaps":["Functional consequence of induced EHF not assayed here","Combinatorial regulation with MAPK input unresolved"]},{"year":2008,"claim":"Demonstrated epigenetic silencing of EHF by promoter methylation in prostate cancer and its direct pro-apoptotic activation of caspase-3, anchoring EHF as a methylation-silenced tumor suppressor.","evidence":"Bisulfite sequencing, 5-aza reactivation, clonogenic/apoptosis assays, and ChIP of the caspase-3 promoter","pmids":["18037958"],"confidence":"High","gaps":["In vivo tumor suppression not tested in this study","Full apoptotic target set undefined"]},{"year":2012,"claim":"Established the central tumor-suppressive program: EHF directly represses EMT and cancer-stem-cell genes, and its loss confers stem-like, metastatic properties in prostate epithelium.","evidence":"Loss- and gain-of-function with TWIST1/ZEB2/BMI1/POU5F1 readouts, tumor-initiating assays, tissue microarray","pmids":["22505649"],"confidence":"Medium","gaps":["Direct vs indirect repression of each target not fully resolved","Cofactors mediating repression unidentified"]},{"year":2013,"claim":"Showed via genome-wide binding that EHF executes complementary activating and repressing programs to specify epithelial fate, generalizing its lineage role beyond cancer.","evidence":"ChIP-seq plus loss-of-function in corneal epithelium, with KLF4/KLF5 cooperativity (also intestinal transcytosis epistasis #10)","pmids":["24142692","23439650"],"confidence":"Medium","gaps":["Mechanism of activator/repressor selection at each site unknown","KLF4/KLF5 interaction not biochemically defined"]},{"year":2016,"claim":"Defined EHF as a node suppressing inflammatory and stemness circuits across epithelial cancers by directly repressing IL-6, Lin28A/B and CXCR4 while activating let-7 and E-cadherin, linking transcriptional control to STAT3 signaling and metastasis suppression.","evidence":"ChIP, reporter assays, sphere-formation, IL-6/JAK inhibition, and orthotopic/xenograft models across prostate and pancreatic cancer","pmids":["27197175","27732936","27923832"],"confidence":"High","gaps":["Direct vs indirect contributions to E-cadherin regulation across tissues","Determinants of EHF loss in primary tumors only partly defined"]},{"year":2017,"claim":"Showed in primary human bronchial epithelium that EHF controls inflammation, wound repair and goblet-cell programs (activating SPDEF), extending its differentiation role to airway homeostasis.","evidence":"ChIP-seq and RNA-seq after EHF depletion, wound-closure and chemokine secretion assays in primary HBE cells","pmids":["28461336"],"confidence":"High","gaps":["In vivo airway phenotype not addressed","Direct chemokine targets not all enumerated"]},{"year":2021,"claim":"In vivo genetic deletion of the EHF ETS domain established that its DNA-binding activity is essential for epidermal and colonic epithelial homeostasis and restrains Apc-driven tumorigenesis, and identified the EHF-CDX1 PNT-domain interaction driving colonic differentiation.","evidence":"Constitutive and conditional Ehf knockout mice, colitis and Apc tumor models, Co-IP, and Ehf/Cdx1 double-knockout (also #25)","pmids":["34180969","35606410"],"confidence":"High","gaps":["Mechanism coupling differentiation loss to tumor initiation not fully resolved","Tissue-specific cofactor partners beyond CDX1 incomplete"]},{"year":2021,"claim":"Revealed context-dependent and pro-tumorigenic functions of EHF (direct activation of TGF-β1, RUVBL1, HER2/HER3, KRT16) and signaling inputs (AR-driven expression, LMP2A/STAT3 induction), showing its output is wired by tissue and oncogenic context.","evidence":"ChIP, reporter assays, knockdown/overexpression, in vivo growth/metastasis assays across colorectal, thyroid, oral and gastric cancers (#7,#15,#19,#21,#22,#23,#24,#27)","pmids":["21617703","27517321","30782177","33414441","32372436","33520362","34014591","27567379"],"confidence":"Medium","gaps":["What determines activator vs repressor and tumor-suppressor vs oncogenic behavior is unresolved","Some target findings rest on single reporter/ChIP studies"]},{"year":2024,"claim":"Defined post-translational and biophysical control of EHF: RRAD and Dclk2 govern its nucleocytoplasmic distribution, and EHF forms nuclear condensates, with only nuclear EHF repressing TERT, inflammatory and caspase genes—coupling localization to its senescence and cell-death programs.","evidence":"Co-IP, phosphorylation assays, subcellular fractionation, condensate imaging, ChIP, telomere and senescence assays, OGD/CCI and PDAC models (#29,#35,#36)","pmids":["39710057","37279586","38513137"],"confidence":"Medium","gaps":["Structural basis of condensate formation undefined","Generality of phospho-regulation across tissues untested"]},{"year":2024,"claim":"Established EHF as a regulator of the tumor microenvironment and immune programs—repressing CXCL1 to limit CXCR2+ neutrophil-driven therapy resistance, shaping macrophage polarization, and directly programming dendritic and mast cell receptor/immunosuppressive gene expression.","evidence":"ChIP/CUT&TAG, Ehf-knockout and KPC/humanized mice, single-cell and spatial transcriptomics, conditional DC- and mast-cell studies, T-cell polarization assays (#11,#28,#30,#31,#37,#39)","pmids":["26297757","38492894","38799645","38741887","39971220","41730908"],"confidence":"High","gaps":["Whether immune phenotypes are epithelial-cell-intrinsic vs immune-cell-intrinsic varies by study","Direct vs paracrine target hierarchies incompletely mapped"]},{"year":2025,"claim":"Implicated EHF as a disease modifier in cystic fibrosis lung epithelium, where its loss enhances CFTR activity and alters basal-cell and hypoxic transcriptional programs.","evidence":"CRISPR knockout in human iPSC-derived lung cells, CFTR electrophysiology, transepithelial resistance, RNA-seq, HIF-1α assays","pmids":["40590703"],"confidence":"Medium","gaps":["Mechanism linking EHF to CFTR not defined","Not validated in patient airway in vivo"]},{"year":null,"claim":"The molecular rules that switch EHF between activator and repressor, between tumor-suppressor and oncogenic output, and between epithelial and immune programs remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of cofactor-dependent activator/repressor selection","Structural basis of PNT-domain interactions and condensate assembly undefined","Determinants of context-specific tumor-suppressive vs oncogenic roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,8,11,12,14,20,25,39]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,5,26]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,35,36]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[29,36]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,7,8,12,14,20,25]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,26,33,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,8,13,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,28,37,39]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,29]}],"complexes":[],"partners":["CDX1","AJUBA","RRAD","DCLK2","CBP","EP300","KLF4","KLF5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZC4","full_name":"ETS homologous factor","aliases":["ETS domain-containing transcription factor","Epithelium-specific Ets transcription factor 3","ESE-3"],"length_aa":300,"mass_kda":34.9,"function":"Transcriptional activator that may play a role in regulating epithelial cell differentiation and proliferation. May act as a repressor for a specific subset of ETS/AP-1-responsive genes and as a modulator of the nuclear response to mitogen-activated protein kinase signaling cascades. Binds to DNA sequences containing the consensus nucleotide core sequence GGAA. Involved in regulation of TNFRSF10B/DR5 expression through Ets-binding sequences on the TNFRSF10B/DR5 promoter. May contribute to development and carcinogenesis by acting as a tumor suppressor gene or anti-oncogene","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NZC4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EHF","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EHF","total_profiled":1310},"omim":[{"mim_id":"610382","title":"PROSOPAGNOSIA, HEREDITARY","url":"https://www.omim.org/entry/610382"},{"mim_id":"605439","title":"ETS HOMOLOGOUS FACTOR; EHF","url":"https://www.omim.org/entry/605439"},{"mim_id":"602164","title":"5-@HYDROXYTRYPTAMINE RECEPTOR 4; HTR4","url":"https://www.omim.org/entry/602164"},{"mim_id":"147440","title":"INSULIN-LIKE GROWTH FACTOR I; IGF1","url":"https://www.omim.org/entry/147440"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":196.3},{"tissue":"salivary gland","ntpm":270.9}],"url":"https://www.proteinatlas.org/search/EHF"},"hgnc":{"alias_symbol":["ESE3","ESEJ"],"prev_symbol":[]},"alphafold":{"accession":"Q9NZC4","domains":[{"cath_id":"1.10.150.50","chopping":"43-115","consensus_level":"high","plddt":83.4281,"start":43,"end":115},{"cath_id":"1.10.10.10","chopping":"210-289","consensus_level":"high","plddt":95.041,"start":210,"end":289}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZC4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZC4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZC4-F1-predicted_aligned_error_v6.png","plddt_mean":67.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EHF","jax_strain_url":"https://www.jax.org/strain/search?query=EHF"},"sequence":{"accession":"Q9NZC4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZC4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZC4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZC4"}},"corpus_meta":[{"pmid":"22505649","id":"PMC_22505649","title":"ESE3/EHF 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cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40670887","citation_count":2,"is_preprint":false},{"pmid":"18313906","id":"PMC_18313906","title":"Morphometric analysis of hypothalamic cells showing c-Fos proteins after movement restriction and EHF-irradiation.","date":"2008","source":"Pathophysiology : the official journal of the International Society for Pathophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/18313906","citation_count":2,"is_preprint":false},{"pmid":"8524760","id":"PMC_8524760","title":"[Significance of the functional state of blood phagocytes in the choice of optimal regime of EHF therapy of patients with pulmonary tuberculosis].","date":"1995","source":"Problemy tuberkuleza","url":"https://pubmed.ncbi.nlm.nih.gov/8524760","citation_count":2,"is_preprint":false},{"pmid":"39082336","id":"PMC_39082336","title":"TMB Signature-Related RCAN2 Promotes Apoptosis by Upregulating EHF/DR5 Pathway in Hepatocellular Carcinoma.","date":"2024","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/39082336","citation_count":1,"is_preprint":false},{"pmid":"40485376","id":"PMC_40485376","title":"Evaluating Type III Secretion System Genes (escE, esaE and eseJ) of Edwardsiella piscicida for Virulence in Japanese Flounder (Paralichthys olivaceus).","date":"2025","source":"Journal of fish diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40485376","citation_count":1,"is_preprint":false},{"pmid":"39409024","id":"PMC_39409024","title":"Codon Bias of the DDR1 Gene and Transcription Factor EHF in Multiple Species.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39409024","citation_count":0,"is_preprint":false},{"pmid":"41730908","id":"PMC_41730908","title":"The transcription factor EHF promotes the maturation and immunosuppression of conventional dendritic cells.","date":"2026","source":"Nature 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Sechenova","url":"https://pubmed.ncbi.nlm.nih.gov/17598468","citation_count":0,"is_preprint":false},{"pmid":"8630825","id":"PMC_8630825","title":"[The ultrastructural characteristics of the duodenal mucosa in peptic ulcer patients undergoing treatment with EHF-range electromagnetic radiation].","date":"1995","source":"Likars'ka sprava","url":"https://pubmed.ncbi.nlm.nih.gov/8630825","citation_count":0,"is_preprint":false},{"pmid":"16025675","id":"PMC_16025675","title":"[Study of the systemic-organ blood circulation in acute period of the multiple trauma based on water-electrolytic metabolism and its correction with EHF-therapy].","date":"2005","source":"Likars'ka sprava","url":"https://pubmed.ncbi.nlm.nih.gov/16025675","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.26.690649","title":"Loss of ESE3/EHF is sufficient to promote cell plasticity, transformation and androgen-independent status in the early stage of prostate carcinogenesis","date":"2025-11-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.26.690649","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.02.24314796","title":"Medical Risk Factors Associated with Listening Difficulties in Children","date":"2024-10-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.02.24314796","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.21.607381","title":"Gender and speech material effects on the long-term average speech spectrum, including at extended high frequencies","date":"2024-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.21.607381","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.08.602575","title":"Degradation in Binaural and Spatial Hearing, and Auditory Temporal Processing Abilities, as a Function of Aging","date":"2024-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.08.602575","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41989,"output_tokens":10463,"usd":0.141456,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21172,"output_tokens":5374,"usd":0.120105,"stage2_stop_reason":"end_turn"},"total_usd":0.261561,"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\": 2000,\n      \"finding\": \"ESE-3/EHF is an ETS transcription factor exclusively expressed in epithelial cells that transactivates the c-MET promoter via three high-affinity ETS binding sites, and binds promoters of glandular epithelium-specific genes; ESE-3 and ESE-1 differ significantly in their ability to transactivate promoters despite similar DNA binding affinity, establishing distinct target gene specificity within the ESE subfamily.\",\n      \"method\": \"Transactivation reporter assays, electrophoretic mobility shift assay (EMSA), promoter binding analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EMSA, reporter assay, promoter binding) in a single study establishing DNA-binding and transactivation specificity\",\n      \"pmids\": [\"10644770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"EHF/ESE-3 acts as a context-dependent transcriptional repressor of Ras- or phorbol ester-induced transcriptional activation of promoters containing both ETS and AP-1 binding sites; repression is sequence- and context-dependent, requiring high-affinity ESE-3 binding sites combined with AP-1 cis-elements in a specific arrangement. ESE-3 is a nuclear protein expressed exclusively in differentiated epithelial cells and absent in epithelial carcinomas.\",\n      \"method\": \"Transient transfection reporter assays, immunohistochemistry with newly generated monoclonal antibody, nuclear localization confirmed by immunostaining\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays with promoter variants plus immunohistochemical localization, single lab, multiple methods\",\n      \"pmids\": [\"11259407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EHF protein represses ETS-2-induced activity of both stromelysin-1 (MMP-3) and collagenase-1 (MMP-1) promoters, establishing a functional role as a transcriptional repressor of matrix metalloproteinase genes.\",\n      \"method\": \"Transactivation reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single reporter assay, single lab, no orthogonal methods\",\n      \"pmids\": [\"10527851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ESE-3/EHF overexpression in 3T3 cells and human bronchial smooth muscle cells inhibits MMP-1 promoter activity. Cytokine-induced ESE-3 expression in bronchial smooth muscle cells is mediated by MEK1/2 and p38 MAPK signaling pathways, as specific inhibitors (U0126, SB03580) abrogate induction.\",\n      \"method\": \"Reporter assay (MMP-1 promoter), pharmacological inhibition with specific kinase inhibitors, RT-PCR and protein analysis\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection plus reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"12444029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ESE-3/EHF expression is upregulated by p38 MAPK in cellular senescence. Ectopic expression of ESE-3 induces growth retardation, upregulation of p16(INK4a) (but not p21), and increased SA-β-gal activity. Recombinant ESE-3 protein directly binds ETS-binding sequences in the p16(INK4a) promoter and increases its transcriptional activity in reporter assays.\",\n      \"method\": \"Microarray, ectopic expression, reporter assay, EMSA with recombinant protein, SA-β-gal assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (recombinant protein EMSA, reporter assay, cellular phenotype), single lab\",\n      \"pmids\": [\"17627613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ESE-3/EHF expression is silenced by methylation of an evolutionarily conserved CpG site in its promoter in prostate cancer cells (PC3, DU145); treatment with 5-aza-2'-deoxycytidine restores expression. Re-expression of ESE-3 in prostate cancer cells inhibits clonogenic survival and induces apoptosis by increasing procaspase-3 levels, mediated at the transcriptional level by direct ESE-3 binding to the caspase-3 promoter.\",\n      \"method\": \"Bisulfite sequencing/methylation analysis, 5-aza-2'-deoxycytidine treatment, clonogenic assay, apoptosis assays, chromatin immunoprecipitation (ChIP) of caspase-3 promoter\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP of direct promoter binding, epigenetic mechanism, functional rescue, multiple orthogonal methods in single study; elevated to High for multiple convergent methods\",\n      \"pmids\": [\"18037958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ESE-3/EHF expression in airway epithelial cells is upregulated by inflammatory cytokines IL-1β and TNF-α via NF-κB activation; specific NF-κB binding sequences in the ESE-3 promoter are required for cytokine-induced expression. ESE-1 upregulates ESE-3 expression and downregulates its own cytokine-induced expression.\",\n      \"method\": \"Promoter characterization, NF-κB binding site mutagenesis, cytokine stimulation, RT-PCR, reporter assay\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis combined with reporter assay and expression analysis, single lab\",\n      \"pmids\": [\"18475289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EHF directly activates transcription of RUVBL1 (an ATPase associated with chromatin-remodeling complexes). RUVBL1 blocks p53-mediated apoptosis by repressing p53 and its target genes: RUVBL1 binds the p53 promoter, interferes with RNF20/hBRE1-mediated histone H2B monoubiquitination, and promotes PAF1-mediated histone H3K9 trimethylation. This EHF→RUVBL1 axis allows colon tumor cells with wild-type p53 to avoid apoptosis.\",\n      \"method\": \"ChIP, promoter reporter assay, histone modification analysis, siRNA knockdown, apoptosis assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, histone modification assays, and functional apoptosis rescue, multiple orthogonal methods establishing direct transcriptional activation and downstream chromatin mechanism\",\n      \"pmids\": [\"21617703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ESE3/EHF represses expression of key EMT and cancer stem cell genes including TWIST1, ZEB2, BMI1, and POU5F1 in prostate epithelial cells. Loss of ESE3/EHF induces EMT, stem-like features, and tumor-initiating/metastatic properties; re-expression inhibits stem-like properties and tumorigenic potential.\",\n      \"method\": \"Gene expression analysis, siRNA knockdown, re-expression experiments, tumor-initiating assays, tissue microarray\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular targets, single lab with multiple readouts\",\n      \"pmids\": [\"22505649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EHF promotes cornea epithelial fate through complementary gene-activating and gene-repressing activities, with potential interactions with KLF4 and KLF5 in promoting cornea epithelial differentiation. EHF binding sites and direct targets in cornea epithelium were identified by ChIP-seq combined with loss-of-function studies.\",\n      \"method\": \"ChIP-seq, loss-of-function studies (siRNA/KO), transcriptome profiling, comparison across epithelial tissues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq genome-wide binding plus loss-of-function phenotype, single lab\",\n      \"pmids\": [\"24142692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EHF expression in intestinal follicle-associated epithelial cells is sufficient to activate HCK-dependent apical-to-basolateral transcytosis of non-opsonized and SIgA-opsonized particles, placing EHF upstream of HCK kinase in regulating antigen sampling at mucosal surfaces.\",\n      \"method\": \"Ectopic expression of EHF in cultured intestinal epithelial cells, transcytosis assays with particles, pharmacological inhibition of HCK\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined cellular phenotype (transcytosis) and epistasis placing EHF upstream of HCK, single lab\",\n      \"pmids\": [\"23439650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EHF (Ehf) is upregulated by TGF-β/Smad signaling in mouse bone marrow-derived mast cells. Forced expression of Ehf represses transcription of FcεRIα, FcεRIβ, and c-Kit genes by directly binding their promoters, reducing surface FcεRI and c-Kit expression, suppressing FcεRI-mediated degranulation and cytokine production. EHF also decreases mRNA levels of GATA1, GATA2, and Stat5b, contributing to these effects.\",\n      \"method\": \"Forced expression (stable transfection), promoter binding assay (ChIP/EMSA), flow cytometry, degranulation assay, cytokine measurement, TGF-β treatment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated alongside functional assays (degranulation, cytokine production, surface receptor expression), multiple orthogonal methods in single study\",\n      \"pmids\": [\"26297757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ESE3/EHF directly binds and represses promoters of Lin28A and Lin28B genes in normal prostate cells, while also activating transcription and maturation of let-7 microRNAs. Loss of ESE3/EHF in cancer cells upregulates Lin28A/B and downregulates let-7 microRNAs, which is critical for prostate cancer stem cell expansion.\",\n      \"method\": \"ChIP (promoter binding), gene expression analysis, siRNA/shRNA knockdown, sphere formation assay, xenograft tumor model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct promoter binding, functional validation in vitro and in vivo, replicated in multiple models\",\n      \"pmids\": [\"27197175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ESE3/EHF directly binds a novel ETS binding site in the IL-6 gene promoter to repress its transcription. Loss of ESE3/EHF in prostate epithelial cells activates IL-6, which then stimulates STAT3 activation and expansion of the cancer stem-like compartment; pharmacological inhibition of IL-6/STAT3 with a JAK inhibitor restrained cancer stem cell growth.\",\n      \"method\": \"ChIP (direct promoter binding), luciferase reporter assay, siRNA knockdown, IL-6 inhibition, JAK inhibitor treatment, sphere formation and in vivo self-renewal assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding plus epistatic rescue experiments and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"27732936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ESE3/EHF inhibits pancreatic cancer (PDAC) metastasis by directly upregulating E-cadherin expression at the transcriptional level; downregulation of ESE3 in PDAC reduces E-cadherin and promotes cell motility, invasiveness, and metastasis in an orthotopic mouse model.\",\n      \"method\": \"Expression knockdown/overexpression, promoter reporter assay, orthotopic mouse model, ChIP (E-cadherin promoter binding)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional target identified by ChIP/reporter assay, validated in orthotopic mouse model and human specimens, multiple orthogonal methods\",\n      \"pmids\": [\"27923832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EHF transcriptionally regulates HER2 and HER3 (ERBB2 and ERBB3) in thyroid cancer cells, as demonstrated by dual-luciferase reporter and ChIP assays, identifying EHF as a transcription factor for these receptor tyrosine kinases.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP, siRNA knockdown and ectopic expression, in vitro and in vivo proliferation/invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay confirming direct transcriptional regulation, single lab\",\n      \"pmids\": [\"27517321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EHF targets in primary human bronchial epithelial (HBE) cells are enriched for genes involved in inflammation and wound repair, as determined by EHF ChIP-seq and RNA-seq after EHF depletion. EHF depletion alters epithelial secretion of a neutrophil chemokine, slows wound closure in HBE cells, and EHF activates expression of SPDEF, which contributes to goblet cell hyperplasia.\",\n      \"method\": \"ChIP-seq, RNA-seq after EHF depletion, wound closure assay, cytokine secretion measurement, siRNA knockdown in primary HBE cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — genome-wide ChIP-seq with RNA-seq and functional cellular assays, multiple orthogonal methods in primary human cells\",\n      \"pmids\": [\"28461336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ESE-3/EHF regulates expression of death receptor 5 (DR-5/TRAIL-R2) through binding to Ets binding sequences on the DR-5 promoter, with co-factors CBP and p300 involved in ESE-3-mediated DR-5 upregulation.\",\n      \"method\": \"EMSA, luciferase reporter assay, promoter mutation analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — EMSA and reporter assay, single lab, no ChIP or in vivo validation\",\n      \"pmids\": [\"17027647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EHF gene produces two transcript variants: a long form (EHF-LF, includes exon 1) and a short form (EHF-SF, excludes exon 1). Only EHF-SF abrogates ETS1-mediated activation of the ZEB1 promoter by promoting degradation of ETS1 proteins, thereby inhibiting EMT. A point mutation within the ETS domain of EHF abolishes this function and causes EHF to act as a dominant negative, enhancing metastasis in vivo.\",\n      \"method\": \"Promoter reporter assay, protein degradation assay, in vivo metastasis model, site-directed mutagenesis, expression of isoform variants\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific functional dissection with mutagenesis and in vivo validation, single lab\",\n      \"pmids\": [\"33712555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-365-3p targets EHF (demonstrated by miR-365-3p reducing EHF expression to decrease migration/invasion in OSCC cells). EHF functions as a transcription factor for KRT16 (keratin 16). EHF-driven KRT16 expression promotes association of c-Met with β5-integrin, facilitating downstream Src/STAT3/FAK/ERK signaling in oral squamous cell carcinoma cells.\",\n      \"method\": \"miRNA target validation (reporter assay), ectopic expression and siRNA knockdown, confocal colocalization, protein degradation assay (lysosomal pathway), in vitro and in vivo functional experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — miRNA-target validation combined with mechanistic pathway dissection, single lab with multiple methods\",\n      \"pmids\": [\"30782177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EHF suppresses pancreatic cancer stemness by directly repressing transcription of CXCR4 (receptor for CXCL12); EHF also has a cell-autonomous role in suppressing stemness by inhibiting transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppresses PC stemness by upregulating EHF.\",\n      \"method\": \"ChIP, luciferase reporter assay, sphere formation assay, flow cytometry, in vivo KPC mouse model, anchorage-independent growth assay\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assay confirming direct promoter repression, validated in transgenic mouse model and patient samples, multiple convergent methods\",\n      \"pmids\": [\"33674341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of EHF promotes neuroendocrine differentiation (NED) in prostate cancer following androgen deprivation therapy (ADT). ADT reduces EHF transcription by relieving AR binding to androgen-responsive elements in the EHF locus. EHF loss promotes expression and enzymatic activity of EZH2, which catalyzes H3K27me3 to repress downstream target genes and drive NED.\",\n      \"method\": \"ChIP (AR binding to EHF locus), EZH2 activity assay, H3K27me3 measurement, EZH2 inhibitor treatment, knockdown/overexpression in cell and mouse models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based epistasis and histone modification assays, validated in preclinical models, single lab\",\n      \"pmids\": [\"33414441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EHF promotes colorectal carcinoma progression by directly upregulating TGF-β1 transcription, thereby activating canonical TGF-β signaling; ChIP and reporter assays confirmed direct EHF binding to the TGF-β1 promoter.\",\n      \"method\": \"ChIP, luciferase reporter assay, overexpression and knockdown, in vitro and in vivo proliferation/invasion assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding and reporter assay, functional validation in vivo, single lab\",\n      \"pmids\": [\"32372436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EHF directly activates transcription of RUVBL1 and in colon cancer also promotes cancer progression by downregulating EHD2 and transactivating INPP4B as downstream target genes, as shown by ChIP and reporter assays.\",\n      \"method\": \"ChIP, reporter assay, knockdown/overexpression, in vitro and in vivo growth assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and reporter assay for new targets (EHD2, INPP4B) in a single study with limited mechanistic depth\",\n      \"pmids\": [\"33520362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EBV protein LMP2A causes upregulation of EHF via phosphorylation of STAT3 in EBV-positive gastric cancer cells. STAT3 knockdown inhibits cellular growth of EBV-positive GC cells, and this inhibition is rescued by EHF overexpression, establishing EHF downstream of the LMP2A/STAT3 axis.\",\n      \"method\": \"RNA-seq, ChIP (active histone marks, H3K4me3/H3K27ac), siRNA knockdown, overexpression rescue assay, immunostaining\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue experiment (STAT3 KD rescued by EHF OE), ChIP-seq, single lab\",\n      \"pmids\": [\"34014591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EHF physically interacts with CDX1 via its PNT domain, and together they cooperatively drive transcription of the colonic differentiation marker VIL1. Re-expression of EHF and CDX1 in poorly-differentiated CRC cells induces chromatin remodeling, transcriptional reprogramming, and enterocytic differentiation; compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupts normal colonic differentiation and significantly enhances colorectal tumor progression.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction via PNT domain), reporter assay (VIL1 transcription), chromatin remodeling analysis, re-expression in CRC cells, compound mouse knockout (Ehf/Cdx1 double KO)\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct physical interaction demonstrated by Co-IP, cooperative transcriptional activity, and in vivo double-knockout mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"35606410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ehf knockout mice (ETS DNA-binding domain deleted) develop papillomas in facial skin, abscesses in preputial glands/vulvae, corneal ulcers, increased susceptibility to colitis, impaired goblet cell differentiation in the colon, extensive transcriptional reprogramming of colonic epithelium, and enhanced Apc-initiated adenoma development—establishing that the EHF ETS DNA-binding domain is essential for postnatal epidermal and colonic epithelial homeostasis.\",\n      \"method\": \"Genetic knockout mouse model (ETS domain deletion), intestinal-specific conditional knockout, chemically induced colitis, Apc-mutation tumor model, histology, transcriptome analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous mouse genetic model with multiple tissue-specific phenotypes, conditional KO, and tumor progression model, strong evidence across multiple readouts\",\n      \"pmids\": [\"34180969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ESE-3/EHF involved in co-regulation of ABCB1 (P-glycoprotein/MDR1) gene transcription via PXR (pregnane X receptor): ESE-3 binds a distal enhancer region containing DR4 motifs of the ABCB1 gene (confirmed by ChIP), and co-expression of ESE-3 with PXR in HepG2 cells enables rifampicin-induced reporter activation that is abolished by DR4 mutation. Knockdown of ESE-3 in LS180 cells reduces rifampicin-induced ABCB1 mRNA induction.\",\n      \"method\": \"ChIP (ESE-3 binding to ABCB1 enhancer), luciferase reporter assay with DR4 mutagenesis, siRNA knockdown, co-transfection in HepG2 cells\",\n      \"journal\": \"Drug metabolism and pharmacokinetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay with mutagenesis, siRNA knockdown, single lab\",\n      \"pmids\": [\"27567379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EHF deficiency in pancreatic cancer induces CXCL1 transcription (EHF represses CXCL1 promoter), leading to enhanced CXCR2+ neutrophil recruitment in a CXCL1-CXCR2-dependent manner that drives chemotherapy and immunotherapy resistance. TP53 mutation mediates loss of tumoral EHF. Nifurtimox elevates tumoral EHF and inhibits JAK1/STAT1 pathway to suppress CXCR2+ neutrophil recruitment.\",\n      \"method\": \"ChIP assay (EHF binding CXCL1 promoter), Ehf-knockout mice, KPC mouse model, humanized mice, single-cell RNA-seq, spatial transcriptomics, cytokine multiplex assay, CXCR2 blockade, neutrophil depletion\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirming direct promoter repression, validated in multiple mouse models including KO and KPC, orthogonal rescue experiments with CXCL1/CXCR2 blockade\",\n      \"pmids\": [\"38492894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EHF forms liquid-like nuclear condensates that transcriptionally repress TERT (reducing telomere length and driving senescence) and inflammatory factors (IL-6, CXCL12), thereby inducing cellular senescence without the associated inflammatory secretory phenotype (SASP) in PDAC cells.\",\n      \"method\": \"CRISPR/Cas9 library screening (SPiDER senescence probe-based), phase separation/condensate imaging, ChIP (EHF binding to TERT and inflammatory gene promoters), telomere length assay, flow cytometry, in vivo PDAC model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding, phase separation imaging, senescence functional assays, single lab with multiple methods\",\n      \"pmids\": [\"39710057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EHF interacts with the coactivator AJUBA LIM protein to cooperatively orchestrate transcriptional network activity in gastroesophageal adenocarcinoma, activating the KRAS signaling pathway. EHF expression is promoted by a core transcriptional regulatory circuitry composed of ELF3-KLF5-GATA6.\",\n      \"method\": \"Co-immunoprecipitation (EHF-AJUBA interaction), ChIP, reporter assay, siRNA knockdown, lipid nanoparticle dual targeting, in vitro and in vivo functional assays\",\n      \"journal\": \"Acta pharmaceutica sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating physical interaction, ChIP, functional validation, single lab\",\n      \"pmids\": [\"38799645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EHF transcriptionally activates GLI1 (glioma-associated oncogene homolog 1) and CCL2 (C-C motif chemokine 2) in cholangiocarcinoma by directly binding their promoters, thereby promoting tumor cell growth and recruiting/activating tumor-associated macrophages via the CCL2/CCR2 axis.\",\n      \"method\": \"ChIP (EHF binding to GLI1 and CCL2 promoters), reporter assay, in vitro and in vivo functional experiments, inhibitor combination (GANT58 + INCB3344)\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct binding to two target gene promoters, functional validation in vivo, single lab\",\n      \"pmids\": [\"38741887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In papillary thyroid cancer cells harboring concurrent BRAFV600E and TERT promoter mutations, EHF overexpression significantly increases TERT expression, and ChIP analysis suggested direct EHF binding to the mutant TERT promoter (but not wild-type TERT promoter). BRAF inhibition decreases both EHF and TERT expression.\",\n      \"method\": \"EHF overexpression and knockdown, ChIP-qPCR (TERT promoter), BRAF pharmacological inhibition, in vitro experiments\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating mutation-selective binding, functional expression assays, single lab\",\n      \"pmids\": [\"39183149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In salivary glands, Ehf (but not Elf5) plays a nonredundant role in ductal cell differentiation. EhfMut mice (CRISPR-Cas9 disruption of ETS domain) exhibit decreased granular convoluted tubules and accumulation of intercalated Sox9+ ductal cell populations, with a pronounced and sexually dimorphic phenotype.\",\n      \"method\": \"CRISPR-Cas9 mouse knockout (ETS domain disruption), immunostaining, histological analysis, cell population quantification\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with specific cellular phenotype, single lab\",\n      \"pmids\": [\"36348499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ehf deletion in the mammary gland impairs lobuloalveolar differentiation at late pregnancy (reduced milk genes, milk lipids, fewer differentiated alveolar cells, accumulation of alveolar progenitor cells). Ehf deletion attenuates prolactin-induced alveolar differentiation in mammary organoids and increases tumor incidence in the MMTV-PyMT mammary tumor model.\",\n      \"method\": \"Mouse Ehf knockout model, mammary organoids, histology, gene expression, MMTV-PyMT tumor model\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous mouse genetic model with multiple functional readouts (organoids, in vivo differentiation, tumor incidence), multiple orthogonal approaches\",\n      \"pmids\": [\"38781975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RRAD (a GTPase) binds EHF and regulates its subcellular localization; RRAD negatively regulates glycolysis by controlling EHF's nucleocytoplasmic distribution. EHF (when nuclear) activates transcription of NEAT1_2, hexokinase 2, and pyruvate kinase M2, forming a NEAT1_2/RRAD/EHF positive feedback loop promoting glycolysis in papillary thyroid cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (RRAD-EHF interaction), ChIP (EHF binding to NEAT1_2/HK2/PKM2 promoters), luciferase reporter assay, subcellular fractionation, in vitro and in vivo glycolysis assays\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction, ChIP for direct binding, subcellular localization data linked to function, single lab\",\n      \"pmids\": [\"37279586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dclk2 phosphorylates EHF and changes its nucleoplasmic distribution, causing p-EHF to exit the nucleus. Nuclear EHF represses Caspase1 and Caspase3 promoter activity; loss of nuclear EHF (due to Dclk2-mediated phosphorylation) promotes expression of Caspase1 and Caspase3 and stimulates neuronal pyroptosis.\",\n      \"method\": \"Kinase phosphorylation assay, subcellular fractionation/immunofluorescence, promoter reporter assay (Caspase1/3), siRNA knockdown, OGD and CCI mouse models\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation-driven localization change linked to promoter activity and cellular phenotype, single lab\",\n      \"pmids\": [\"38513137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EHF promotes M2 macrophage polarization in liver cancer by binding the promoter of KDM2B and transcriptionally activating it, leading to increased IL-6 secretion from TAMs which promotes liver cancer cell metastasis.\",\n      \"method\": \"CUT-Tag (EHF binding to KDM2B promoter), ChIP, luciferase assay, cytokine array, siRNA knockdown, co-culture system, in vitro and in vivo assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT-Tag and ChIP confirming direct promoter binding, functional assays, single lab\",\n      \"pmids\": [\"39971220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of EHF in iPSC-derived lung cells enhances CFTR activity, increases transepithelial electrical resistance, leads to transcriptomic changes in basal cells, and reduces HIF-1α-mediated hypoxic response, revealing multiple mechanisms by which EHF modifies cystic fibrosis-related lung disease.\",\n      \"method\": \"CRISPR knockout of EHF in human iPSC-derived lung cells, electrophysiology (CFTR activity), transepithelial electrical resistance measurement, RNA-seq, HIF-1α response assay\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout in human iPSC-derived cells with multiple functional readouts, single lab\",\n      \"pmids\": [\"40590703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EHF directly regulates Ccr7, Cd200, Cd274 (PD-L1), Irf4, and Rel expression in conventional dendritic cells (cDCs), as shown by CUT&TAG. Conditional deletion of EHF in DCs decreases CCR7, CD200, and PD-L1 expression, increases IRF4, decreases inhibitory NFκB member Rel, and promotes Th1- and Th17-biased CD4+ T cell responses. EHF expression is highly enriched in CCR7hi DCs in mice and humans.\",\n      \"method\": \"CUT&TAG (genome-wide EHF binding), conditional DC-specific knockout mice, flow cytometry, in vitro and in vivo T cell polarization assays, single-cell RNA-seq\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CUT&TAG genome-wide binding data, conditional knockout mouse model, multiple functional immune readouts in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"41730908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In prostate epithelial cells, EHF acts as a central transcriptional node controlling a hierarchy of regulatory factors and downstream signaling pathways (including COL1A1/DDR1, JAK/STAT3) to maintain epithelial lineage integrity. EHF knockout is sufficient to disrupt epithelial cell lineage integrity and promote a progenitor/stem-like state with basal and luminal features, attenuate androgenic response, and drive resistance to AR antagonists.\",\n      \"method\": \"EHF knockout mouse models, human epithelial cell knockout, transcriptome analysis, ChIP/binding assays, AR antagonist resistance assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with transcriptome analysis, pathway dissection and functional drug resistance assays, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.26.690649\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EHF/ESE3 is an epithelium-specific ETS transcription factor that functions primarily as a context-dependent transcriptional repressor (of EMT genes, IL-6, CXCL1, CXCR4, TERT, Lin28A/B, and MMP promoters) and activator (of E-cadherin, caspase-3, RUVBL1, SPDEF, let-7 microRNAs, and cell-type-specific differentiation genes) by directly binding ETS motifs in target gene promoters; its activity is regulated by NF-κB, MAPK/p38, TGF-β/Smad, and STAT3 signaling pathways, and by Dclk2-mediated phosphorylation that controls its nuclear localization; in epithelial tissues it maintains lineage identity and suppresses stem-like/EMT programs, while in immune cells (mast cells, dendritic cells) it regulates surface receptor expression and immunosuppressive gene programs, with its physical interaction with CDX1 via the PNT domain and with co-activator AJUBA representing key protein-protein interactions that modulate transcriptional output.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EHF (ESE-3) is an epithelium-restricted ETS-family transcription factor that binds high-affinity ETS motifs in target promoters and acts as a context-dependent activator or repressor to maintain epithelial lineage identity and suppress stem-like and EMT programs [#0, #1, #8]. In normal epithelia EHF promotes terminal differentiation—driving corneal epithelial fate [#9], colonic enterocytic differentiation through a direct physical interaction with CDX1 via its PNT domain [#25], salivary ductal differentiation [#33], and mammary lobuloalveolar maturation [#34]—and genetic deletion of its ETS DNA-binding domain in mice disrupts epidermal and colonic homeostasis and accelerates tumor development [#26]. As a tumor suppressor it directly represses EMT and stemness drivers (TWIST1, ZEB2, BMI1, POU5F1, Lin28A/B, CXCR4, SOX9/SOX2/OCT4/NANOG) while activating let-7 microRNAs and E-cadherin, thereby restraining invasion, metastasis, and the cancer stem-like compartment [#8, #12, #14, #20]; it also represses inflammatory genes including IL-6 and CXCL1, limiting STAT3 activation and CXCR2+ neutrophil recruitment that otherwise drive therapy resistance [#13, #28]. EHF expression is induced by inflammatory cytokines via NF-\\u03baB [#6], by p38/MEK MAPK signaling [#3, #4], and by androgen receptor binding at its locus [#21], and its silencing by promoter CpG methylation in prostate cancer abolishes its pro-apoptotic and differentiation functions [#5]. EHF activity is further gated by subcellular partitioning: RRAD- and Dclk2-dependent phosphorylation control its nucleocytoplasmic distribution, and only nuclear EHF executes its transcriptional program [#35, #36]. Beyond epithelia, EHF programs immune cells, repressing Fc\\u03b5RI and c-Kit in mast cells downstream of TGF-\\u03b2/Smad [#11] and directly regulating CCR7, CD200, PD-L1, IRF4 and Rel in CCR7hi conventional dendritic cells to bias CD4+ T cell responses [#39]. EHF cooperates with coactivators (CBP/p300, AJUBA) and core epithelial transcriptional circuitry (ELF3-KLF5-GATA6) to orchestrate its target networks [#17, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that EHF/ESE-3 is an epithelium-restricted ETS factor with DNA-binding and transactivation specificity distinct from its paralog ESE-1, defining it as a sequence-specific transcription factor rather than a generic ETS protein.\",\n      \"evidence\": \"EMSA, reporter transactivation, and promoter binding analysis on the c-MET promoter\",\n      \"pmids\": [\"10644770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide binding map\", \"Tissue-specific cofactors not identified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed EHF can act as a context-dependent repressor of Ras/AP-1-driven transcription and is a nuclear protein lost in carcinomas, framing it early as a differentiation-associated, potentially tumor-suppressive factor.\",\n      \"evidence\": \"Reporter assays with promoter variants plus immunohistochemistry with a new monoclonal antibody\",\n      \"pmids\": [\"11259407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of activator/repressor switching unresolved\", \"No in vivo loss-of-function\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected EHF expression to upstream MAPK signaling and demonstrated repression of MMP promoters, linking inflammatory signaling input to EHF-mediated transcriptional output.\",\n      \"evidence\": \"MMP-1/MMP-3 reporter assays and pharmacological MEK/p38 inhibition in 3T3 and bronchial smooth muscle cells (also #2)\",\n      \"pmids\": [\"12444029\", \"10527851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy not shown by ChIP\", \"Endogenous MMP regulation not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified EHF as a p38-induced effector of senescence that directly activates the p16INK4a promoter, providing a growth-suppressive mechanism downstream of stress signaling.\",\n      \"evidence\": \"Microarray, ectopic expression, recombinant-protein EMSA, p16 reporter assay and SA-\\u03b2-gal in a single study\",\n      \"pmids\": [\"17627613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Senescence role tested only by overexpression\", \"Endogenous EHF requirement not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined NF-\\u03baB as a direct transcriptional inducer of EHF in airway epithelium, establishing cytokine-driven control of EHF expression.\",\n      \"evidence\": \"Promoter NF-\\u03baB site mutagenesis, cytokine stimulation, reporter assays\",\n      \"pmids\": [\"18475289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of induced EHF not assayed here\", \"Combinatorial regulation with MAPK input unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated epigenetic silencing of EHF by promoter methylation in prostate cancer and its direct pro-apoptotic activation of caspase-3, anchoring EHF as a methylation-silenced tumor suppressor.\",\n      \"evidence\": \"Bisulfite sequencing, 5-aza reactivation, clonogenic/apoptosis assays, and ChIP of the caspase-3 promoter\",\n      \"pmids\": [\"18037958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo tumor suppression not tested in this study\", \"Full apoptotic target set undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the central tumor-suppressive program: EHF directly represses EMT and cancer-stem-cell genes, and its loss confers stem-like, metastatic properties in prostate epithelium.\",\n      \"evidence\": \"Loss- and gain-of-function with TWIST1/ZEB2/BMI1/POU5F1 readouts, tumor-initiating assays, tissue microarray\",\n      \"pmids\": [\"22505649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect repression of each target not fully resolved\", \"Cofactors mediating repression unidentified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed via genome-wide binding that EHF executes complementary activating and repressing programs to specify epithelial fate, generalizing its lineage role beyond cancer.\",\n      \"evidence\": \"ChIP-seq plus loss-of-function in corneal epithelium, with KLF4/KLF5 cooperativity (also intestinal transcytosis epistasis #10)\",\n      \"pmids\": [\"24142692\", \"23439650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of activator/repressor selection at each site unknown\", \"KLF4/KLF5 interaction not biochemically defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined EHF as a node suppressing inflammatory and stemness circuits across epithelial cancers by directly repressing IL-6, Lin28A/B and CXCR4 while activating let-7 and E-cadherin, linking transcriptional control to STAT3 signaling and metastasis suppression.\",\n      \"evidence\": \"ChIP, reporter assays, sphere-formation, IL-6/JAK inhibition, and orthotopic/xenograft models across prostate and pancreatic cancer\",\n      \"pmids\": [\"27197175\", \"27732936\", \"27923832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect contributions to E-cadherin regulation across tissues\", \"Determinants of EHF loss in primary tumors only partly defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed in primary human bronchial epithelium that EHF controls inflammation, wound repair and goblet-cell programs (activating SPDEF), extending its differentiation role to airway homeostasis.\",\n      \"evidence\": \"ChIP-seq and RNA-seq after EHF depletion, wound-closure and chemokine secretion assays in primary HBE cells\",\n      \"pmids\": [\"28461336\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo airway phenotype not addressed\", \"Direct chemokine targets not all enumerated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"In vivo genetic deletion of the EHF ETS domain established that its DNA-binding activity is essential for epidermal and colonic epithelial homeostasis and restrains Apc-driven tumorigenesis, and identified the EHF-CDX1 PNT-domain interaction driving colonic differentiation.\",\n      \"evidence\": \"Constitutive and conditional Ehf knockout mice, colitis and Apc tumor models, Co-IP, and Ehf/Cdx1 double-knockout (also #25)\",\n      \"pmids\": [\"34180969\", \"35606410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling differentiation loss to tumor initiation not fully resolved\", \"Tissue-specific cofactor partners beyond CDX1 incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed context-dependent and pro-tumorigenic functions of EHF (direct activation of TGF-\\u03b21, RUVBL1, HER2/HER3, KRT16) and signaling inputs (AR-driven expression, LMP2A/STAT3 induction), showing its output is wired by tissue and oncogenic context.\",\n      \"evidence\": \"ChIP, reporter assays, knockdown/overexpression, in vivo growth/metastasis assays across colorectal, thyroid, oral and gastric cancers (#7,#15,#19,#21,#22,#23,#24,#27)\",\n      \"pmids\": [\"21617703\", \"27517321\", \"30782177\", \"33414441\", \"32372436\", \"33520362\", \"34014591\", \"27567379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What determines activator vs repressor and tumor-suppressor vs oncogenic behavior is unresolved\", \"Some target findings rest on single reporter/ChIP studies\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined post-translational and biophysical control of EHF: RRAD and Dclk2 govern its nucleocytoplasmic distribution, and EHF forms nuclear condensates, with only nuclear EHF repressing TERT, inflammatory and caspase genes—coupling localization to its senescence and cell-death programs.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, subcellular fractionation, condensate imaging, ChIP, telomere and senescence assays, OGD/CCI and PDAC models (#29,#35,#36)\",\n      \"pmids\": [\"39710057\", \"37279586\", \"38513137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of condensate formation undefined\", \"Generality of phospho-regulation across tissues untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established EHF as a regulator of the tumor microenvironment and immune programs—repressing CXCL1 to limit CXCR2+ neutrophil-driven therapy resistance, shaping macrophage polarization, and directly programming dendritic and mast cell receptor/immunosuppressive gene expression.\",\n      \"evidence\": \"ChIP/CUT&TAG, Ehf-knockout and KPC/humanized mice, single-cell and spatial transcriptomics, conditional DC- and mast-cell studies, T-cell polarization assays (#11,#28,#30,#31,#37,#39)\",\n      \"pmids\": [\"26297757\", \"38492894\", \"38799645\", \"38741887\", \"39971220\", \"41730908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether immune phenotypes are epithelial-cell-intrinsic vs immune-cell-intrinsic varies by study\", \"Direct vs paracrine target hierarchies incompletely mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated EHF as a disease modifier in cystic fibrosis lung epithelium, where its loss enhances CFTR activity and alters basal-cell and hypoxic transcriptional programs.\",\n      \"evidence\": \"CRISPR knockout in human iPSC-derived lung cells, CFTR electrophysiology, transepithelial resistance, RNA-seq, HIF-1\\u03b1 assays\",\n      \"pmids\": [\"40590703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking EHF to CFTR not defined\", \"Not validated in patient airway in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular rules that switch EHF between activator and repressor, between tumor-suppressor and oncogenic output, and between epithelial and immune programs remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of cofactor-dependent activator/repressor selection\", \"Structural basis of PNT-domain interactions and condensate assembly undefined\", \"Determinants of context-specific tumor-suppressive vs oncogenic roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 8, 11, 12, 14, 20, 25, 39]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 5, 26]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 35, 36]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [29, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 7, 8, 12, 14, 20, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 26, 33, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 8, 13, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 28, 37, 39]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CDX1\", \"AJUBA\", \"RRAD\", \"DCLK2\", \"CBP\", \"EP300\", \"KLF4\", \"KLF5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}