{"gene":"VEZF1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1999,"finding":"Vezf1 encodes a zinc finger transcription factor (predicted 56 kDa, six zinc finger domains) whose expression is restricted to vascular endothelial cells and their precursors in the yolk sac blood islands during embryogenesis, established by retroviral entrapment and in situ hybridization.","method":"Retroviral entrapment vectors, cDNA isolation, in situ hybridization, sequence analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, gene isolation and expression mapping with in situ hybridization; no functional perturbation in this paper alone","pmids":["9986727"],"is_preprint":false},{"year":2001,"finding":"VEZF1/DB1 localizes to the nucleus and directly activates transcription driven by the human endothelin-1 (ET-1) promoter by binding a specific 6-bp element (ACCCCC) located 47 bp upstream of the ET-1 transcription start site; a 2-bp mutation in this element abolished responsiveness, and recombinant VEZF1 was shown to bind this sequence directly.","method":"Transient transfection reporter assays, deletion mutagenesis, electrophoretic mobility shift assay (EMSA), recombinant protein binding, antibody supershift in nuclear extracts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (reporter assay, mutagenesis, EMSA with recombinant protein, nuclear complex supershift) in a single focused study","pmids":["11504723"],"is_preprint":false},{"year":2005,"finding":"Targeted inactivation of Vezf1 in mice reveals dose-dependent roles in blood vascular and lymphatic development: homozygous null embryos display vascular remodeling defects, loss of vascular integrity, hemorrhaging, and defective endothelial cell adhesion and tight junction formation; heterozygous embryos show lymphatic hypervascularization and edema (cystic hygroma-like phenotype).","method":"Targeted gene knockout in mice, ultrastructural EM analysis, histological and immunohistochemical examination","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with defined cellular and structural phenotypes, ultrastructural validation, dose-dependent effects confirmed across genotypes","pmids":["15882861"],"is_preprint":false},{"year":2005,"finding":"Metallothionein 1 (MT1) is a downstream transcriptional target of VEZF1 in endothelial cells; knockdown of VEZF1 decreases MT1 expression while overexpression increases it, and MT1 is expressed at sites of angiogenesis in vivo.","method":"Northern blotting following VEZF1 knockdown/overexpression, microarray analysis, in vivo expression analysis","journal":"Endothelium : journal of endothelial cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, Northern blotting with gain- and loss-of-function, consistent with microarray data","pmids":["16162438"],"is_preprint":false},{"year":2008,"finding":"Deletion of both copies of Vezf1 in mouse embryonic stem cells causes genome-wide loss of DNA methylation at LINE1 elements, minor satellite repeats, imprinted genes, and CpG islands, associated with a substantial decrease in the de novo DNA methyltransferase Dnmt3b, establishing VEZF1 as an upstream regulator of Dnmt3b expression and global DNA methylation.","method":"Homozygous Vezf1 knockout in mouse ESCs, bisulfite sequencing, Southern blotting for methylation, RT-PCR/Western blot for Dnmt3b","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with multiple orthogonal readouts (bisulfite sequencing, Southern blot, Dnmt3b quantification), single lab","pmids":["18676812"],"is_preprint":false},{"year":1998,"finding":"The transcription factor DB1/VEZF1 physically interacts with prenylated RhoB (but weakly with RhoA and not with H-Ras); the RhoB-binding domain in DB1 is upstream and separable from the zinc finger DNA-binding domain; RhoB inhibits transcriptional activation by DB1, whereas RhoA and Ras have little or no effect; prenylated RhoB species were identified in the nuclear membrane and intranuclear laminar region where they can associate with DB1.","method":"Co-immunoprecipitation/interaction assays sensitive to prenylation state, subcellular fractionation, transcriptional reporter assays","journal":"Cell adhesion and communication","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional interaction validated by binding assay, subcellular localization, and transcriptional reporter with multiple Rho family comparators; single lab","pmids":["9865462"],"is_preprint":false},{"year":2010,"finding":"VEZF1 acts as a barrier element factor that protects gene promoters from de novo DNA methylation independently of histone acetylation or transcription; the methylation-protection activity of VEZF1 is separable from the CTCF-dependent enhancer-blocking and USF-dependent histone modification functions of the HS4 insulator; VEZF1 elements are sufficient to mediate demethylation and protection of the APRT CpG island promoter.","method":"Stable reporter gene system in cell culture, bisulfite sequencing, deletion and functional mutagenesis of HS4 insulator, protein purification identifying VEZF1 as the interacting factor","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (stable reporter assay, bisulfite sequencing, protein purification, functional dissection of insulator sub-elements), replication at APRT locus","pmids":["20062523"],"is_preprint":false},{"year":2010,"finding":"Vezf1-null ES cells fail to form organized vascular networks in embryoid bodies and show vascular sprouting defects; loss of Vezf1 results in reduced retinol/vitamin A signaling and aberrant extracellular matrix formation; Vezf1-null cells also display defects in hematopoietic differentiation.","method":"Targeted Vezf1-null ES cell lines, embryoid body differentiation model, in vivo teratocarcinoma model, immunohistochemistry, histological analysis","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model with multiple differentiation readouts, single lab","pmids":["20431070"],"is_preprint":false},{"year":2012,"finding":"Genome-wide, VEZF1 binding sites in HeLaS3 cells are strongly correlated with peaks of elongating Ser2-phosphorylated RNA Polymerase II, indicating VEZF1-dependent slowing of Pol II elongation; in Vezf1-null mouse ESCs, accumulation of elongating Pol II near Vezf1 binding sites in the Dnmt3b gene and other loci is significantly reduced; VEZF1 binding near cassette exons can influence alternative splicing; VEZF1 physically interacts with Mrg15/Mrgbp, a protein that recognizes H3K36 trimethylation.","method":"ChIP-seq (Vezf1, Ser2-P Pol II) in HeLaS3 and WT/KO mES cells, genome-wide correlation analysis, RT-PCR for alternative splicing, co-immunoprecipitation of VEZF1 with Mrg15/Mrgbp","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with genetic KO validation, Co-IP for interaction, multiple orthogonal methods in one study","pmids":["22308494"],"is_preprint":false},{"year":2013,"finding":"Nuclear RhoB-GTP controls distinct gene expression programs in blood versus lymphatic endothelial cells by regulating VEZF1-mediated transcription; loss of RhoB decreases angiogenesis but enhances lymphangiogenesis following injury; a small-molecule inhibitor of VEZF1-DNA interaction recapitulates RhoB loss in ischemic retinopathy.","method":"RhoB null mice, primary human blood and lymphatic endothelial cell assays, small-molecule inhibitor of VEZF1-DNA interaction, ischemic retinopathy model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model, primary cell experiments, pharmacological validation with VEZF1 inhibitor, multiple vascular endpoints","pmids":["24280686"],"is_preprint":false},{"year":2018,"finding":"In Vezf1-null mouse ESCs, expression of the antiangiogenic factor Cited2 is significantly increased; Vezf1-null ESCs show defective differentiation into endothelial cells with reduced activation of EC-specific genes and lower H3K27 acetylation at their promoters; shRNA depletion of Cited2 significantly rescues the angiogenic defects of Vezf1-null ECs; Vezf1 can block inappropriate promoter-enhancer interactions, preventing aberrant promoter activation.","method":"Vezf1 KO mouse ESCs, endothelial differentiation assay, tube formation assay, shRNA knockdown of Cited2, ChIP for H3K27ac","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with rescue experiment (shRNA Cited2), ChIP, and functional differentiation assay; multiple orthogonal methods","pmids":["29794136"],"is_preprint":false},{"year":2018,"finding":"A small molecule (T4, IC50 ~20 μM) that inhibits VEZF1 binding to its cognate DNA sequence was identified and shown to strongly inhibit endothelial network formation (tube formation assay) without affecting cell viability at or below IC50.","method":"Structure-based virtual screening of NCI Diversity Compound Library, EMSA for VEZF1-DNA binding inhibition, tube formation assay in murine endothelial cells","journal":"Molecules (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — EMSA and functional cell assay, single lab, computational model used for design","pmids":["29970794"],"is_preprint":false},{"year":2020,"finding":"VEZF1 binds directly to DNA guanine quadruplex (G4) structures both in vitro and in cells; VEZF1-G4 interaction modulates the ratio of VASH1A/VASH1B mRNA isoforms via alternative polyadenylation; disruption of VEZF1-G4 interaction (by VEZF1 depletion or G4-stabilizing small molecules) increases the long VASH1A isoform and elevates tubulin detyrosinase activity; loss of VEZF1-G4 interaction in HUVECs diminishes angiogenesis.","method":"In vitro G4-binding assays, cellular G4 interaction studies, genetic depletion of VEZF1, G4-stabilizing small molecules, RT-PCR for VASH1 isoforms, tubulin detyrosinase activity assay, tube formation assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro biochemical assay plus cell-based validation, genetic depletion and pharmacological perturbation, multiple orthogonal readouts","pmids":["33231681"],"is_preprint":false},{"year":2020,"finding":"Vezf1 regulates cardiac growth and cardiomyocyte contractile function in zebrafish; knockdown of Vezf1 reduces cardiac growth and impairs ventricular contractile response to β-adrenergic stimuli without dysregulating cardiomyocyte Ca2+ transient kinetics; Vezf1 transcriptionally regulates Myh7/β-MHC through an MCAT binding site in the Myh7 promoter; TEAD-1 is a binding partner of Vezf1.","method":"Zebrafish Vezf1 knockdown, cardiomyocyte contractile functional assays, β-adrenergic stimulation, Ca2+ transient measurement, gene ontology analysis, Myh7 promoter reporter assay, co-immunoprecipitation of Vezf1 with TEAD-1","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — zebrafish KD model, functional phenotyping, promoter reporter, Co-IP for TEAD-1 interaction; single lab","pmids":["31911272"],"is_preprint":false},{"year":2021,"finding":"TRIM29 promotes VEZF1 mRNA translation by recruiting RNA-binding protein BICC1 to the VEZF1 3'UTR; VEZF1 in turn transcriptionally activates SETBP1, driving the SETBP1/SET/PP2A axis in ovarian cancer stem cell-like maintenance.","method":"Global proteomics, luciferase reporter assay, ChIP, co-immunoprecipitation, RNA-seq, in vitro ubiquitination assay, RT-qPCR, ELISA","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, reporter assay, RNA-seq), single lab, mechanistic chain involves VEZF1 as transcriptional activator","pmids":["34973391"],"is_preprint":false},{"year":2022,"finding":"VEZF1 is a substrate for STUB1 (CHIP) E3 ubiquitin ligase-mediated ubiquitination and proteasomal degradation; VEZF1 transcriptionally activates PAQR4 to promote HCC proliferation and metastasis.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, luciferase reporter assay, gain- and loss-of-function in HCC cells in vitro and in vivo","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and in vitro ubiquitination assay for STUB1-VEZF1 interaction, reporter assay for PAQR4 transcription; single lab","pmids":["36241701"],"is_preprint":false},{"year":2023,"finding":"VEZF1 directly interacts with ETV2 (Ets variant 2) as demonstrated by yeast two-hybrid, co-immunoprecipitation, and GST pulldown; VEZF1 co-activates the Flt1 promoter together with ETV2, as shown by luciferase reporter and ChIP; Vezf1 knockout ESCs show downregulation of hematoendothelial marker genes during embryoid body differentiation, while VEZF1 overexpression induces hematoendothelial gene expression.","method":"Yeast two-hybrid, Co-immunoprecipitation, GST pulldown, Flt1 promoter-luciferase reporter assay, EMSA, ChIP, Vezf1 KO ESCs, embryoid body differentiation","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct interaction confirmed by three orthogonal binding assays (Y2H, Co-IP, GST pulldown) plus functional validation by reporter assay, EMSA, ChIP, and genetic KO rescue","pmids":["36923254"],"is_preprint":false},{"year":2023,"finding":"A heterozygous nonsense mutation in VEZF1 (p.Lys164*) segregates with autosomal-dominant dilated cardiomyopathy; the mutant VEZF1 protein fails to transactivate the promoters of MYH7 and ET1, two DCM-associated genes, in dual-luciferase reporter assays.","method":"Whole-exome sequencing, Sanger sequencing validation, dual-luciferase reporter assay with MYH7 and ET1 promoters","journal":"European journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional reporter assay demonstrating loss of transactivation, genetic segregation validated by sequencing; single lab, limited mechanistic depth","pmids":["36657711"],"is_preprint":false},{"year":2024,"finding":"VEZF1 directly activates SPOP transcription (shown by luciferase reporter and ChIP); VEZF1 overexpression suppresses STAT3 protein stability, reduces CCL2 secretion, and inhibits macrophage M2 polarization and IL-6 feedback in bladder cancer cells.","method":"Luciferase reporter assay, ChIP, co-immunoprecipitation, in vitro ubiquitination assay, RT-qPCR array, ELISA, co-culture system","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, reporter, Co-IP, functional co-culture), single lab","pmids":["39479456"],"is_preprint":false},{"year":2025,"finding":"O-GlcNAcylation at specific serine residues (Ser123 and Ser124) of VEZF1 attenuates its proteasomal degradation, stabilizing VEZF1 protein and promoting TNS1 transcription in hepatocellular carcinoma; GFAT1 drives this process through its enzymatic activity in the hexosamine biosynthetic pathway.","method":"4D label-free quantitative proteomics for O-GlcNAcylation profiling, site-specific mutagenesis of Ser123/Ser124, co-immunoprecipitation, in vitro/in vivo HCC models, VEZF1-derived peptide inhibitor","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-identified modification with site mutagenesis and functional validation in cell and animal models; single lab","pmids":["40858565"],"is_preprint":false},{"year":2025,"finding":"HIF1A knockdown increases O-GlcNAcylation of VEZF1, stabilizing VEZF1 protein; elevated VEZF1 drives endothelin-1 expression, which modulates FOXO1, leading to BAX transcription and granulosa cell apoptosis and follicular atresia.","method":"siRNA knockdown of HIF1A, 4D label-free quantitative proteomics for O-GlcNAcylation, western blot, ChIP (FOXO1 at BAX promoter), TUNEL assay in porcine granulosa cells","journal":"Journal of animal science and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-identified modification, ChIP, genetic KD; single lab, porcine model","pmids":["40973947"],"is_preprint":false}],"current_model":"VEZF1 (also known as DB1/ZNF161) is a nuclear Krüppel-like C2H2 zinc finger transcription factor expressed predominantly in vascular endothelial cells that activates target gene promoters (e.g., ET-1, Myh7, SPOP, PAQR4, Flt1) by binding G-rich motifs (ACCCCC) and DNA G-quadruplex structures, cooperates with partners including ETV2 and TEAD-1, regulates RNA Pol II elongation pausing and alternative splicing genome-wide, maintains DNA methylation by sustaining Dnmt3b expression, acts as a chromatin barrier element to prevent DNA methylation and inappropriate enhancer–promoter interactions, and whose protein stability is controlled by STUB1-mediated ubiquitination and by O-GlcNAcylation; in the nucleus it is also subject to sequestration by prenylated RhoB-GTP, linking small GTPase signaling to transcriptional output."},"narrative":{"mechanistic_narrative":"VEZF1 (DB1/ZNF161) is a Krüppel-like C2H2 zinc finger transcription factor first identified as an endothelial-restricted regulator of blood vascular and lymphatic development, where its dose-dependent loss causes vascular remodeling defects, loss of endothelial integrity, and lymphatic hypervascularization [PMID:9986727, PMID:15882861]. It functions as a sequence-specific activator, binding a G-rich element (ACCCCC) to drive endothelial promoters such as endothelin-1 [PMID:11504723], and cooperates with the endothelial transcription factors ETV2 to co-activate Flt1 and promote hematoendothelial gene expression [PMID:36923254]. Beyond classical promoter binding, VEZF1 directly recognizes DNA G-quadruplex structures, coupling this interaction to alternative polyadenylation of VASH1 isoforms and to angiogenic output [PMID:33231681]. VEZF1 shapes the chromatin and transcriptional landscape on multiple levels: it acts as a barrier element that protects promoters from de novo DNA methylation independently of CTCF-dependent enhancer blocking and histone modification [PMID:20062523], sustains global DNA methylation by maintaining Dnmt3b expression [PMID:18676812], blocks inappropriate enhancer–promoter interactions [PMID:29794136], and modulates RNA Pol II elongation pausing and alternative splicing genome-wide in concert with the H3K36me3 reader Mrg15/Mrgbp [PMID:22308494]. VEZF1 activity is gated post-translationally and by upstream signaling: prenylated nuclear RhoB-GTP binds VEZF1 through a domain separable from its zinc fingers and represses its transcriptional activation, linking small-GTPase signaling to distinct blood versus lymphatic gene programs [PMID:9865462, PMID:24280686], while protein abundance is controlled by STUB1/CHIP-mediated ubiquitination and proteasomal degradation [PMID:36241701] and stabilized by O-GlcNAcylation at Ser123/Ser124 [PMID:40858565]. In disease contexts, a heterozygous VEZF1 nonsense mutation (p.Lys164*) segregates with autosomal-dominant dilated cardiomyopathy and abolishes transactivation of the MYH7 and ET1 promoters [PMID:36657711], and VEZF1 acts as a transcriptional driver in multiple cancers through targets including PAQR4, SPOP, SETBP1, and TNS1 [PMID:34973391, PMID:36241701, PMID:39479456, PMID:40858565].","teleology":[{"year":1999,"claim":"Establishing VEZF1's identity and expression domain answered whether a dedicated endothelial transcription factor exists, anchoring it to the vascular lineage.","evidence":"Retroviral entrapment, cDNA isolation, and in situ hybridization in mouse embryos","pmids":["9986727"],"confidence":"Medium","gaps":["No functional perturbation or target genes defined","DNA-binding specificity not yet established"]},{"year":2001,"claim":"Identifying the ACCCCC element in the ET-1 promoter and direct VEZF1 binding answered how VEZF1 activates target genes at the sequence level.","evidence":"Reporter assays, deletion mutagenesis, EMSA with recombinant protein, and supershift in nuclear extracts","pmids":["11504723"],"confidence":"High","gaps":["Genome-wide binding repertoire unknown","Cofactors at the promoter not identified"]},{"year":1998,"claim":"Discovery of the prenylated RhoB–VEZF1 interaction answered how a small GTPase could gate VEZF1 transcriptional output independently of DNA binding.","evidence":"Prenylation-sensitive interaction assays, subcellular fractionation, and reporter assays comparing Rho family members","pmids":["9865462"],"confidence":"Medium","gaps":["Physiological context of nuclear RhoB regulation not addressed in this study","Structural basis of the interaction undefined"]},{"year":2005,"claim":"Targeted knockout in mice and identification of MT1 as a target answered what developmental processes VEZF1 controls and revealed dose-dependent vascular and lymphatic roles.","evidence":"Mouse gene knockout with EM and IHC; Northern blot with gain/loss-of-function for MT1","pmids":["15882861","16162438"],"confidence":"High","gaps":["Molecular mechanism linking VEZF1 loss to junction/adhesion defects unresolved","Whether MT1 mediates phenotypes untested"]},{"year":2008,"claim":"Linking VEZF1 to Dnmt3b maintenance answered how it influences the epigenome, extending its role from a promoter activator to a regulator of global DNA methylation.","evidence":"Vezf1-null mouse ESCs with bisulfite sequencing, Southern blot, and Dnmt3b quantification","pmids":["18676812"],"confidence":"High","gaps":["Direct binding to the Dnmt3b locus not fully mapped here","Causal chain from methylation loss to phenotype unclear"]},{"year":2010,"claim":"Defining VEZF1 as a methylation-protective barrier factor and dissecting it from CTCF/USF insulator functions answered how it maintains promoter activity epigenetically.","evidence":"Stable reporter system, bisulfite sequencing, insulator sub-element dissection, and protein purification at the HS4 and APRT loci","pmids":["20062523"],"confidence":"High","gaps":["Mechanism by which VEZF1 excludes DNMTs unknown","Endogenous genomic scope of barrier activity not mapped"]},{"year":2010,"claim":"ESC differentiation studies answered which downstream programs VEZF1 controls, implicating retinol/vitamin A signaling, ECM, and hematopoietic differentiation.","evidence":"Vezf1-null ESC embryoid body and teratocarcinoma models with histology and IHC","pmids":["20431070"],"confidence":"Medium","gaps":["Direct targets within these programs not defined","Single-lab differentiation readouts"]},{"year":2012,"claim":"Genome-wide ChIP-seq answered how VEZF1 acts co-transcriptionally, revealing a role in Pol II elongation pausing and splicing via the H3K36me3 reader Mrg15.","evidence":"VEZF1 and Ser2-P Pol II ChIP-seq in HeLaS3 and WT/KO mESCs, splicing RT-PCR, and Co-IP with Mrg15/Mrgbp","pmids":["22308494"],"confidence":"High","gaps":["Mechanism by which VEZF1 slows Pol II unknown","Functional consequences of altered splicing not catalogued"]},{"year":2013,"claim":"Showing nuclear RhoB-GTP regulates VEZF1-driven programs answered how the same factor produces opposite blood versus lymphatic outcomes and validated VEZF1 as a druggable node.","evidence":"RhoB-null mice, primary blood/lymphatic endothelial cells, VEZF1-DNA small-molecule inhibitor, and ischemic retinopathy model","pmids":["24280686"],"confidence":"High","gaps":["Lineage-specific target genes only partly defined","How RhoB switches VEZF1 between programs mechanistically unclear"]},{"year":2018,"claim":"Identifying Cited2 derepression and enhancer-promoter mis-regulation answered how VEZF1 loss impairs endothelial differentiation, with rescue establishing causality.","evidence":"Vezf1-KO ESC differentiation, tube formation, Cited2 shRNA rescue, and H3K27ac ChIP","pmids":["29794136"],"confidence":"High","gaps":["Direct vs indirect control of Cited2 not fully resolved","Generality of enhancer-blocking across loci untested"]},{"year":2018,"claim":"A structure-based inhibitor of VEZF1-DNA binding answered whether blocking VEZF1 occupancy alone suffices to impair angiogenesis.","evidence":"Virtual screening, EMSA, and tube formation assay in murine endothelial cells","pmids":["29970794"],"confidence":"Medium","gaps":["Modest IC50 and selectivity not established","In vivo efficacy not tested"]},{"year":2020,"claim":"Demonstrating direct G-quadruplex binding answered a new mode of DNA recognition, coupling VEZF1 to alternative polyadenylation of VASH1 and tubulin detyrosination in angiogenesis.","evidence":"In vitro and cellular G4-binding assays, VEZF1 depletion, G4-stabilizing compounds, VASH1 isoform RT-PCR, detyrosinase and tube formation assays","pmids":["33231681"],"confidence":"High","gaps":["Genome-wide scope of G4-dependent regulation unmapped","Relationship between G4 and ACCCCC binding modes unclear"]},{"year":2020,"claim":"Zebrafish studies answered whether VEZF1 acts beyond endothelium, revealing cardiomyocyte contractile control via Myh7 and a TEAD-1 partnership.","evidence":"Vezf1 knockdown, contractile and Ca2+ assays, Myh7 promoter reporter, and Co-IP with TEAD-1","pmids":["31911272"],"confidence":"Medium","gaps":["TEAD-1 interaction surface undefined","Cardiac role in mammals not confirmed here"]},{"year":2021,"claim":"Defining a TRIM29/BICC1 translational input and a SETBP1/SET/PP2A output answered how VEZF1 is regulated and acts in ovarian cancer stem-like cells.","evidence":"Proteomics, reporter assays, ChIP, Co-IP, RNA-seq, and ubiquitination assays","pmids":["34973391"],"confidence":"Medium","gaps":["Direct vs indirect SETBP1 regulation across contexts unclear","Single-lab cancer model"]},{"year":2022,"claim":"Identifying STUB1-mediated ubiquitination answered how VEZF1 protein abundance is controlled, linking its stability to PAQR4-driven HCC progression.","evidence":"Co-IP, in vitro ubiquitination, reporter assay, and HCC gain/loss-of-function in vitro and in vivo","pmids":["36241701"],"confidence":"Medium","gaps":["Degron and ubiquitination sites not mapped","Whether STUB1 acts on endothelial VEZF1 untested"]},{"year":2023,"claim":"Demonstrating direct ETV2 interaction and Flt1 co-activation answered how VEZF1 partners with a master endothelial factor to specify hematoendothelial fate.","evidence":"Y2H, Co-IP, GST pulldown, Flt1 reporter, EMSA, ChIP, and Vezf1-KO ESC differentiation","pmids":["36923254"],"confidence":"High","gaps":["Genome-wide co-occupancy with ETV2 not mapped","Interaction domains not finely resolved"]},{"year":2023,"claim":"A segregating nonsense mutation answered whether VEZF1 dysfunction causes human disease, linking loss of MYH7/ET1 transactivation to dilated cardiomyopathy.","evidence":"Whole-exome and Sanger sequencing with dual-luciferase reporter assays for MYH7 and ET1 promoters","pmids":["36657711"],"confidence":"Medium","gaps":["Single family, limited mechanistic depth","Haploinsufficiency vs dominant-negative mechanism not distinguished"]},{"year":2024,"claim":"Linking VEZF1 to SPOP transcription answered how it shapes the tumor immune microenvironment by suppressing STAT3 stability and macrophage M2 polarization.","evidence":"Reporter assay, ChIP, Co-IP, ubiquitination assay, ELISA, and macrophage co-culture in bladder cancer cells","pmids":["39479456"],"confidence":"Medium","gaps":["Direct SPOP promoter binding vs indirect effects partly resolved","Single-lab cancer context"]},{"year":2025,"claim":"Identifying O-GlcNAcylation at Ser123/Ser124 answered how nutrient/metabolic signaling stabilizes VEZF1, with branches into HCC (TNS1) and granulosa cell apoptosis (ET-1/FOXO1/BAX).","evidence":"4D label-free O-GlcNAc proteomics, site mutagenesis, Co-IP, ChIP, and HCC/porcine granulosa cell models","pmids":["40858565","40973947"],"confidence":"Medium","gaps":["Interplay between O-GlcNAcylation and STUB1 ubiquitination not integrated","Physiological triggers of the hexosamine pathway input incompletely defined"]},{"year":null,"claim":"How VEZF1 integrates its multiple regulatory modes — sequence-specific binding, G4 recognition, RhoB gating, and competing post-translational modifications — into context-specific transcriptional outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of VEZF1 on DNA or in complex with partners","Logic switching between blood/lymphatic and cardiac/cancer programs uncharacterized","Crosstalk among STUB1, O-GlcNAc, and RhoB inputs not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,16,17]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,6,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,8,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,7,16]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,6,8]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,12]}],"complexes":[],"partners":["ETV2","TEAD1","RHOB","MRGBP","STUB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14119","full_name":"Vascular endothelial zinc finger 1","aliases":["Putative transcription factor DB1","Zinc finger protein 161"],"length_aa":521,"mass_kda":56.9,"function":"Possible transcription factor. Specifically binds to the CT/GC-rich region of the interleukin-3 promoter and mediates tax transactivation of IL-3","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q14119/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VEZF1","classification":"Not Classified","n_dependent_lines":130,"n_total_lines":1208,"dependency_fraction":0.1076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VEZF1","total_profiled":1310},"omim":[{"mim_id":"620247","title":"CARDIOMYOPATHY, DILATED, 1OO; CMD1OO","url":"https://www.omim.org/entry/620247"},{"mim_id":"606747","title":"VASCULAR ENDOTHELIAL ZINC FINGER 1; VEZF1","url":"https://www.omim.org/entry/606747"},{"mim_id":"115200","title":"CARDIOMYOPATHY, DILATED, 1A; CMD1A","url":"https://www.omim.org/entry/115200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VEZF1"},"hgnc":{"alias_symbol":["DB1"],"prev_symbol":["ZNF161"]},"alphafold":{"accession":"Q14119","domains":[{"cath_id":"3.30.160.60","chopping":"180-256","consensus_level":"medium","plddt":82.6706,"start":180,"end":256},{"cath_id":"-","chopping":"262-317","consensus_level":"high","plddt":73.7871,"start":262,"end":317}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14119","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14119-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14119-F1-predicted_aligned_error_v6.png","plddt_mean":59.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VEZF1","jax_strain_url":"https://www.jax.org/strain/search?query=VEZF1"},"sequence":{"accession":"Q14119","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14119.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14119/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14119"}},"corpus_meta":[{"pmid":"21957497","id":"PMC_21957497","title":"Quantitative 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situ hybridization.\",\n      \"method\": \"Retroviral entrapment vectors, cDNA isolation, in situ hybridization, sequence analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, gene isolation and expression mapping with in situ hybridization; no functional perturbation in this paper alone\",\n      \"pmids\": [\"9986727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"VEZF1/DB1 localizes to the nucleus and directly activates transcription driven by the human endothelin-1 (ET-1) promoter by binding a specific 6-bp element (ACCCCC) located 47 bp upstream of the ET-1 transcription start site; a 2-bp mutation in this element abolished responsiveness, and recombinant VEZF1 was shown to bind this sequence directly.\",\n      \"method\": \"Transient transfection reporter assays, deletion mutagenesis, electrophoretic mobility shift assay (EMSA), recombinant protein binding, antibody supershift in nuclear extracts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (reporter assay, mutagenesis, EMSA with recombinant protein, nuclear complex supershift) in a single focused study\",\n      \"pmids\": [\"11504723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Targeted inactivation of Vezf1 in mice reveals dose-dependent roles in blood vascular and lymphatic development: homozygous null embryos display vascular remodeling defects, loss of vascular integrity, hemorrhaging, and defective endothelial cell adhesion and tight junction formation; heterozygous embryos show lymphatic hypervascularization and edema (cystic hygroma-like phenotype).\",\n      \"method\": \"Targeted gene knockout in mice, ultrastructural EM analysis, histological and immunohistochemical examination\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with defined cellular and structural phenotypes, ultrastructural validation, dose-dependent effects confirmed across genotypes\",\n      \"pmids\": [\"15882861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Metallothionein 1 (MT1) is a downstream transcriptional target of VEZF1 in endothelial cells; knockdown of VEZF1 decreases MT1 expression while overexpression increases it, and MT1 is expressed at sites of angiogenesis in vivo.\",\n      \"method\": \"Northern blotting following VEZF1 knockdown/overexpression, microarray analysis, in vivo expression analysis\",\n      \"journal\": \"Endothelium : journal of endothelial cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, Northern blotting with gain- and loss-of-function, consistent with microarray data\",\n      \"pmids\": [\"16162438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Deletion of both copies of Vezf1 in mouse embryonic stem cells causes genome-wide loss of DNA methylation at LINE1 elements, minor satellite repeats, imprinted genes, and CpG islands, associated with a substantial decrease in the de novo DNA methyltransferase Dnmt3b, establishing VEZF1 as an upstream regulator of Dnmt3b expression and global DNA methylation.\",\n      \"method\": \"Homozygous Vezf1 knockout in mouse ESCs, bisulfite sequencing, Southern blotting for methylation, RT-PCR/Western blot for Dnmt3b\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with multiple orthogonal readouts (bisulfite sequencing, Southern blot, Dnmt3b quantification), single lab\",\n      \"pmids\": [\"18676812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The transcription factor DB1/VEZF1 physically interacts with prenylated RhoB (but weakly with RhoA and not with H-Ras); the RhoB-binding domain in DB1 is upstream and separable from the zinc finger DNA-binding domain; RhoB inhibits transcriptional activation by DB1, whereas RhoA and Ras have little or no effect; prenylated RhoB species were identified in the nuclear membrane and intranuclear laminar region where they can associate with DB1.\",\n      \"method\": \"Co-immunoprecipitation/interaction assays sensitive to prenylation state, subcellular fractionation, transcriptional reporter assays\",\n      \"journal\": \"Cell adhesion and communication\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional interaction validated by binding assay, subcellular localization, and transcriptional reporter with multiple Rho family comparators; single lab\",\n      \"pmids\": [\"9865462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"VEZF1 acts as a barrier element factor that protects gene promoters from de novo DNA methylation independently of histone acetylation or transcription; the methylation-protection activity of VEZF1 is separable from the CTCF-dependent enhancer-blocking and USF-dependent histone modification functions of the HS4 insulator; VEZF1 elements are sufficient to mediate demethylation and protection of the APRT CpG island promoter.\",\n      \"method\": \"Stable reporter gene system in cell culture, bisulfite sequencing, deletion and functional mutagenesis of HS4 insulator, protein purification identifying VEZF1 as the interacting factor\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (stable reporter assay, bisulfite sequencing, protein purification, functional dissection of insulator sub-elements), replication at APRT locus\",\n      \"pmids\": [\"20062523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Vezf1-null ES cells fail to form organized vascular networks in embryoid bodies and show vascular sprouting defects; loss of Vezf1 results in reduced retinol/vitamin A signaling and aberrant extracellular matrix formation; Vezf1-null cells also display defects in hematopoietic differentiation.\",\n      \"method\": \"Targeted Vezf1-null ES cell lines, embryoid body differentiation model, in vivo teratocarcinoma model, immunohistochemistry, histological analysis\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model with multiple differentiation readouts, single lab\",\n      \"pmids\": [\"20431070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Genome-wide, VEZF1 binding sites in HeLaS3 cells are strongly correlated with peaks of elongating Ser2-phosphorylated RNA Polymerase II, indicating VEZF1-dependent slowing of Pol II elongation; in Vezf1-null mouse ESCs, accumulation of elongating Pol II near Vezf1 binding sites in the Dnmt3b gene and other loci is significantly reduced; VEZF1 binding near cassette exons can influence alternative splicing; VEZF1 physically interacts with Mrg15/Mrgbp, a protein that recognizes H3K36 trimethylation.\",\n      \"method\": \"ChIP-seq (Vezf1, Ser2-P Pol II) in HeLaS3 and WT/KO mES cells, genome-wide correlation analysis, RT-PCR for alternative splicing, co-immunoprecipitation of VEZF1 with Mrg15/Mrgbp\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with genetic KO validation, Co-IP for interaction, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22308494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nuclear RhoB-GTP controls distinct gene expression programs in blood versus lymphatic endothelial cells by regulating VEZF1-mediated transcription; loss of RhoB decreases angiogenesis but enhances lymphangiogenesis following injury; a small-molecule inhibitor of VEZF1-DNA interaction recapitulates RhoB loss in ischemic retinopathy.\",\n      \"method\": \"RhoB null mice, primary human blood and lymphatic endothelial cell assays, small-molecule inhibitor of VEZF1-DNA interaction, ischemic retinopathy model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model, primary cell experiments, pharmacological validation with VEZF1 inhibitor, multiple vascular endpoints\",\n      \"pmids\": [\"24280686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Vezf1-null mouse ESCs, expression of the antiangiogenic factor Cited2 is significantly increased; Vezf1-null ESCs show defective differentiation into endothelial cells with reduced activation of EC-specific genes and lower H3K27 acetylation at their promoters; shRNA depletion of Cited2 significantly rescues the angiogenic defects of Vezf1-null ECs; Vezf1 can block inappropriate promoter-enhancer interactions, preventing aberrant promoter activation.\",\n      \"method\": \"Vezf1 KO mouse ESCs, endothelial differentiation assay, tube formation assay, shRNA knockdown of Cited2, ChIP for H3K27ac\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with rescue experiment (shRNA Cited2), ChIP, and functional differentiation assay; multiple orthogonal methods\",\n      \"pmids\": [\"29794136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A small molecule (T4, IC50 ~20 μM) that inhibits VEZF1 binding to its cognate DNA sequence was identified and shown to strongly inhibit endothelial network formation (tube formation assay) without affecting cell viability at or below IC50.\",\n      \"method\": \"Structure-based virtual screening of NCI Diversity Compound Library, EMSA for VEZF1-DNA binding inhibition, tube formation assay in murine endothelial cells\",\n      \"journal\": \"Molecules (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — EMSA and functional cell assay, single lab, computational model used for design\",\n      \"pmids\": [\"29970794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VEZF1 binds directly to DNA guanine quadruplex (G4) structures both in vitro and in cells; VEZF1-G4 interaction modulates the ratio of VASH1A/VASH1B mRNA isoforms via alternative polyadenylation; disruption of VEZF1-G4 interaction (by VEZF1 depletion or G4-stabilizing small molecules) increases the long VASH1A isoform and elevates tubulin detyrosinase activity; loss of VEZF1-G4 interaction in HUVECs diminishes angiogenesis.\",\n      \"method\": \"In vitro G4-binding assays, cellular G4 interaction studies, genetic depletion of VEZF1, G4-stabilizing small molecules, RT-PCR for VASH1 isoforms, tubulin detyrosinase activity assay, tube formation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro biochemical assay plus cell-based validation, genetic depletion and pharmacological perturbation, multiple orthogonal readouts\",\n      \"pmids\": [\"33231681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Vezf1 regulates cardiac growth and cardiomyocyte contractile function in zebrafish; knockdown of Vezf1 reduces cardiac growth and impairs ventricular contractile response to β-adrenergic stimuli without dysregulating cardiomyocyte Ca2+ transient kinetics; Vezf1 transcriptionally regulates Myh7/β-MHC through an MCAT binding site in the Myh7 promoter; TEAD-1 is a binding partner of Vezf1.\",\n      \"method\": \"Zebrafish Vezf1 knockdown, cardiomyocyte contractile functional assays, β-adrenergic stimulation, Ca2+ transient measurement, gene ontology analysis, Myh7 promoter reporter assay, co-immunoprecipitation of Vezf1 with TEAD-1\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — zebrafish KD model, functional phenotyping, promoter reporter, Co-IP for TEAD-1 interaction; single lab\",\n      \"pmids\": [\"31911272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM29 promotes VEZF1 mRNA translation by recruiting RNA-binding protein BICC1 to the VEZF1 3'UTR; VEZF1 in turn transcriptionally activates SETBP1, driving the SETBP1/SET/PP2A axis in ovarian cancer stem cell-like maintenance.\",\n      \"method\": \"Global proteomics, luciferase reporter assay, ChIP, co-immunoprecipitation, RNA-seq, in vitro ubiquitination assay, RT-qPCR, ELISA\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, reporter assay, RNA-seq), single lab, mechanistic chain involves VEZF1 as transcriptional activator\",\n      \"pmids\": [\"34973391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VEZF1 is a substrate for STUB1 (CHIP) E3 ubiquitin ligase-mediated ubiquitination and proteasomal degradation; VEZF1 transcriptionally activates PAQR4 to promote HCC proliferation and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, luciferase reporter assay, gain- and loss-of-function in HCC cells in vitro and in vivo\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and in vitro ubiquitination assay for STUB1-VEZF1 interaction, reporter assay for PAQR4 transcription; single lab\",\n      \"pmids\": [\"36241701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VEZF1 directly interacts with ETV2 (Ets variant 2) as demonstrated by yeast two-hybrid, co-immunoprecipitation, and GST pulldown; VEZF1 co-activates the Flt1 promoter together with ETV2, as shown by luciferase reporter and ChIP; Vezf1 knockout ESCs show downregulation of hematoendothelial marker genes during embryoid body differentiation, while VEZF1 overexpression induces hematoendothelial gene expression.\",\n      \"method\": \"Yeast two-hybrid, Co-immunoprecipitation, GST pulldown, Flt1 promoter-luciferase reporter assay, EMSA, ChIP, Vezf1 KO ESCs, embryoid body differentiation\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct interaction confirmed by three orthogonal binding assays (Y2H, Co-IP, GST pulldown) plus functional validation by reporter assay, EMSA, ChIP, and genetic KO rescue\",\n      \"pmids\": [\"36923254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A heterozygous nonsense mutation in VEZF1 (p.Lys164*) segregates with autosomal-dominant dilated cardiomyopathy; the mutant VEZF1 protein fails to transactivate the promoters of MYH7 and ET1, two DCM-associated genes, in dual-luciferase reporter assays.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing validation, dual-luciferase reporter assay with MYH7 and ET1 promoters\",\n      \"journal\": \"European journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional reporter assay demonstrating loss of transactivation, genetic segregation validated by sequencing; single lab, limited mechanistic depth\",\n      \"pmids\": [\"36657711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VEZF1 directly activates SPOP transcription (shown by luciferase reporter and ChIP); VEZF1 overexpression suppresses STAT3 protein stability, reduces CCL2 secretion, and inhibits macrophage M2 polarization and IL-6 feedback in bladder cancer cells.\",\n      \"method\": \"Luciferase reporter assay, ChIP, co-immunoprecipitation, in vitro ubiquitination assay, RT-qPCR array, ELISA, co-culture system\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, reporter, Co-IP, functional co-culture), single lab\",\n      \"pmids\": [\"39479456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"O-GlcNAcylation at specific serine residues (Ser123 and Ser124) of VEZF1 attenuates its proteasomal degradation, stabilizing VEZF1 protein and promoting TNS1 transcription in hepatocellular carcinoma; GFAT1 drives this process through its enzymatic activity in the hexosamine biosynthetic pathway.\",\n      \"method\": \"4D label-free quantitative proteomics for O-GlcNAcylation profiling, site-specific mutagenesis of Ser123/Ser124, co-immunoprecipitation, in vitro/in vivo HCC models, VEZF1-derived peptide inhibitor\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified modification with site mutagenesis and functional validation in cell and animal models; single lab\",\n      \"pmids\": [\"40858565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIF1A knockdown increases O-GlcNAcylation of VEZF1, stabilizing VEZF1 protein; elevated VEZF1 drives endothelin-1 expression, which modulates FOXO1, leading to BAX transcription and granulosa cell apoptosis and follicular atresia.\",\n      \"method\": \"siRNA knockdown of HIF1A, 4D label-free quantitative proteomics for O-GlcNAcylation, western blot, ChIP (FOXO1 at BAX promoter), TUNEL assay in porcine granulosa cells\",\n      \"journal\": \"Journal of animal science and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified modification, ChIP, genetic KD; single lab, porcine model\",\n      \"pmids\": [\"40973947\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VEZF1 (also known as DB1/ZNF161) is a nuclear Krüppel-like C2H2 zinc finger transcription factor expressed predominantly in vascular endothelial cells that activates target gene promoters (e.g., ET-1, Myh7, SPOP, PAQR4, Flt1) by binding G-rich motifs (ACCCCC) and DNA G-quadruplex structures, cooperates with partners including ETV2 and TEAD-1, regulates RNA Pol II elongation pausing and alternative splicing genome-wide, maintains DNA methylation by sustaining Dnmt3b expression, acts as a chromatin barrier element to prevent DNA methylation and inappropriate enhancer–promoter interactions, and whose protein stability is controlled by STUB1-mediated ubiquitination and by O-GlcNAcylation; in the nucleus it is also subject to sequestration by prenylated RhoB-GTP, linking small GTPase signaling to transcriptional output.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VEZF1 (DB1/ZNF161) is a Krüppel-like C2H2 zinc finger transcription factor first identified as an endothelial-restricted regulator of blood vascular and lymphatic development, where its dose-dependent loss causes vascular remodeling defects, loss of endothelial integrity, and lymphatic hypervascularization [#0, #2]. It functions as a sequence-specific activator, binding a G-rich element (ACCCCC) to drive endothelial promoters such as endothelin-1 [#1], and cooperates with the endothelial transcription factors ETV2 to co-activate Flt1 and promote hematoendothelial gene expression [#16]. Beyond classical promoter binding, VEZF1 directly recognizes DNA G-quadruplex structures, coupling this interaction to alternative polyadenylation of VASH1 isoforms and to angiogenic output [#12]. VEZF1 shapes the chromatin and transcriptional landscape on multiple levels: it acts as a barrier element that protects promoters from de novo DNA methylation independently of CTCF-dependent enhancer blocking and histone modification [#6], sustains global DNA methylation by maintaining Dnmt3b expression [#4], blocks inappropriate enhancer–promoter interactions [#10], and modulates RNA Pol II elongation pausing and alternative splicing genome-wide in concert with the H3K36me3 reader Mrg15/Mrgbp [#8]. VEZF1 activity is gated post-translationally and by upstream signaling: prenylated nuclear RhoB-GTP binds VEZF1 through a domain separable from its zinc fingers and represses its transcriptional activation, linking small-GTPase signaling to distinct blood versus lymphatic gene programs [#5, #9], while protein abundance is controlled by STUB1/CHIP-mediated ubiquitination and proteasomal degradation [#15] and stabilized by O-GlcNAcylation at Ser123/Ser124 [#19]. In disease contexts, a heterozygous VEZF1 nonsense mutation (p.Lys164*) segregates with autosomal-dominant dilated cardiomyopathy and abolishes transactivation of the MYH7 and ET1 promoters [#17], and VEZF1 acts as a transcriptional driver in multiple cancers through targets including PAQR4, SPOP, SETBP1, and TNS1 [#14, #15, #18, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing VEZF1's identity and expression domain answered whether a dedicated endothelial transcription factor exists, anchoring it to the vascular lineage.\",\n      \"evidence\": \"Retroviral entrapment, cDNA isolation, and in situ hybridization in mouse embryos\",\n      \"pmids\": [\"9986727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional perturbation or target genes defined\", \"DNA-binding specificity not yet established\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying the ACCCCC element in the ET-1 promoter and direct VEZF1 binding answered how VEZF1 activates target genes at the sequence level.\",\n      \"evidence\": \"Reporter assays, deletion mutagenesis, EMSA with recombinant protein, and supershift in nuclear extracts\",\n      \"pmids\": [\"11504723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide binding repertoire unknown\", \"Cofactors at the promoter not identified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Discovery of the prenylated RhoB–VEZF1 interaction answered how a small GTPase could gate VEZF1 transcriptional output independently of DNA binding.\",\n      \"evidence\": \"Prenylation-sensitive interaction assays, subcellular fractionation, and reporter assays comparing Rho family members\",\n      \"pmids\": [\"9865462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of nuclear RhoB regulation not addressed in this study\", \"Structural basis of the interaction undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Targeted knockout in mice and identification of MT1 as a target answered what developmental processes VEZF1 controls and revealed dose-dependent vascular and lymphatic roles.\",\n      \"evidence\": \"Mouse gene knockout with EM and IHC; Northern blot with gain/loss-of-function for MT1\",\n      \"pmids\": [\"15882861\", \"16162438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking VEZF1 loss to junction/adhesion defects unresolved\", \"Whether MT1 mediates phenotypes untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking VEZF1 to Dnmt3b maintenance answered how it influences the epigenome, extending its role from a promoter activator to a regulator of global DNA methylation.\",\n      \"evidence\": \"Vezf1-null mouse ESCs with bisulfite sequencing, Southern blot, and Dnmt3b quantification\",\n      \"pmids\": [\"18676812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding to the Dnmt3b locus not fully mapped here\", \"Causal chain from methylation loss to phenotype unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining VEZF1 as a methylation-protective barrier factor and dissecting it from CTCF/USF insulator functions answered how it maintains promoter activity epigenetically.\",\n      \"evidence\": \"Stable reporter system, bisulfite sequencing, insulator sub-element dissection, and protein purification at the HS4 and APRT loci\",\n      \"pmids\": [\"20062523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which VEZF1 excludes DNMTs unknown\", \"Endogenous genomic scope of barrier activity not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"ESC differentiation studies answered which downstream programs VEZF1 controls, implicating retinol/vitamin A signaling, ECM, and hematopoietic differentiation.\",\n      \"evidence\": \"Vezf1-null ESC embryoid body and teratocarcinoma models with histology and IHC\",\n      \"pmids\": [\"20431070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct targets within these programs not defined\", \"Single-lab differentiation readouts\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genome-wide ChIP-seq answered how VEZF1 acts co-transcriptionally, revealing a role in Pol II elongation pausing and splicing via the H3K36me3 reader Mrg15.\",\n      \"evidence\": \"VEZF1 and Ser2-P Pol II ChIP-seq in HeLaS3 and WT/KO mESCs, splicing RT-PCR, and Co-IP with Mrg15/Mrgbp\",\n      \"pmids\": [\"22308494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which VEZF1 slows Pol II unknown\", \"Functional consequences of altered splicing not catalogued\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing nuclear RhoB-GTP regulates VEZF1-driven programs answered how the same factor produces opposite blood versus lymphatic outcomes and validated VEZF1 as a druggable node.\",\n      \"evidence\": \"RhoB-null mice, primary blood/lymphatic endothelial cells, VEZF1-DNA small-molecule inhibitor, and ischemic retinopathy model\",\n      \"pmids\": [\"24280686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lineage-specific target genes only partly defined\", \"How RhoB switches VEZF1 between programs mechanistically unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying Cited2 derepression and enhancer-promoter mis-regulation answered how VEZF1 loss impairs endothelial differentiation, with rescue establishing causality.\",\n      \"evidence\": \"Vezf1-KO ESC differentiation, tube formation, Cited2 shRNA rescue, and H3K27ac ChIP\",\n      \"pmids\": [\"29794136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect control of Cited2 not fully resolved\", \"Generality of enhancer-blocking across loci untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A structure-based inhibitor of VEZF1-DNA binding answered whether blocking VEZF1 occupancy alone suffices to impair angiogenesis.\",\n      \"evidence\": \"Virtual screening, EMSA, and tube formation assay in murine endothelial cells\",\n      \"pmids\": [\"29970794\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Modest IC50 and selectivity not established\", \"In vivo efficacy not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating direct G-quadruplex binding answered a new mode of DNA recognition, coupling VEZF1 to alternative polyadenylation of VASH1 and tubulin detyrosination in angiogenesis.\",\n      \"evidence\": \"In vitro and cellular G4-binding assays, VEZF1 depletion, G4-stabilizing compounds, VASH1 isoform RT-PCR, detyrosinase and tube formation assays\",\n      \"pmids\": [\"33231681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide scope of G4-dependent regulation unmapped\", \"Relationship between G4 and ACCCCC binding modes unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Zebrafish studies answered whether VEZF1 acts beyond endothelium, revealing cardiomyocyte contractile control via Myh7 and a TEAD-1 partnership.\",\n      \"evidence\": \"Vezf1 knockdown, contractile and Ca2+ assays, Myh7 promoter reporter, and Co-IP with TEAD-1\",\n      \"pmids\": [\"31911272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TEAD-1 interaction surface undefined\", \"Cardiac role in mammals not confirmed here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining a TRIM29/BICC1 translational input and a SETBP1/SET/PP2A output answered how VEZF1 is regulated and acts in ovarian cancer stem-like cells.\",\n      \"evidence\": \"Proteomics, reporter assays, ChIP, Co-IP, RNA-seq, and ubiquitination assays\",\n      \"pmids\": [\"34973391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect SETBP1 regulation across contexts unclear\", \"Single-lab cancer model\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying STUB1-mediated ubiquitination answered how VEZF1 protein abundance is controlled, linking its stability to PAQR4-driven HCC progression.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, reporter assay, and HCC gain/loss-of-function in vitro and in vivo\",\n      \"pmids\": [\"36241701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degron and ubiquitination sites not mapped\", \"Whether STUB1 acts on endothelial VEZF1 untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating direct ETV2 interaction and Flt1 co-activation answered how VEZF1 partners with a master endothelial factor to specify hematoendothelial fate.\",\n      \"evidence\": \"Y2H, Co-IP, GST pulldown, Flt1 reporter, EMSA, ChIP, and Vezf1-KO ESC differentiation\",\n      \"pmids\": [\"36923254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide co-occupancy with ETV2 not mapped\", \"Interaction domains not finely resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A segregating nonsense mutation answered whether VEZF1 dysfunction causes human disease, linking loss of MYH7/ET1 transactivation to dilated cardiomyopathy.\",\n      \"evidence\": \"Whole-exome and Sanger sequencing with dual-luciferase reporter assays for MYH7 and ET1 promoters\",\n      \"pmids\": [\"36657711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family, limited mechanistic depth\", \"Haploinsufficiency vs dominant-negative mechanism not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking VEZF1 to SPOP transcription answered how it shapes the tumor immune microenvironment by suppressing STAT3 stability and macrophage M2 polarization.\",\n      \"evidence\": \"Reporter assay, ChIP, Co-IP, ubiquitination assay, ELISA, and macrophage co-culture in bladder cancer cells\",\n      \"pmids\": [\"39479456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SPOP promoter binding vs indirect effects partly resolved\", \"Single-lab cancer context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying O-GlcNAcylation at Ser123/Ser124 answered how nutrient/metabolic signaling stabilizes VEZF1, with branches into HCC (TNS1) and granulosa cell apoptosis (ET-1/FOXO1/BAX).\",\n      \"evidence\": \"4D label-free O-GlcNAc proteomics, site mutagenesis, Co-IP, ChIP, and HCC/porcine granulosa cell models\",\n      \"pmids\": [\"40858565\", \"40973947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between O-GlcNAcylation and STUB1 ubiquitination not integrated\", \"Physiological triggers of the hexosamine pathway input incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VEZF1 integrates its multiple regulatory modes — sequence-specific binding, G4 recognition, RhoB gating, and competing post-translational modifications — into context-specific transcriptional outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of VEZF1 on DNA or in complex with partners\", \"Logic switching between blood/lymphatic and cardiac/cancer programs uncharacterized\", \"Crosstalk among STUB1, O-GlcNAc, and RhoB inputs not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 16, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 6, 12]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [1, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 8, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 7, 16]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 6, 8]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ETV2\", \"TEAD1\", \"RHOB\", \"MRGBP\", \"STUB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}