{"gene":"VGLL4","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2014,"finding":"VGLL4 directly competes with YAP for binding to TEAD transcription factors via its tandem Tondu (TDU) domains, which are both necessary and sufficient for its inhibitory activity toward YAP. A peptide mimicking VGLL4's TDU domains potently suppresses tumor growth in vitro and in vivo.","method":"Co-IP, competitive binding assays, domain deletion/mutagenesis, in vitro and in vivo tumor suppression assays with VGLL4-mimicking peptide","journal":"Cancer Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal binding assays with domain mutagenesis, functional rescue, in vivo validation, replicated across multiple studies","pmids":["24525233"],"is_preprint":false},{"year":2014,"finding":"VGLL4 inhibits formation of the YAP-TEAD transcriptional complex in lung cancer by directly competing with YAP for TEAD binding, acting through two TDU domains.","method":"Co-IP, competitive binding assays, ectopic expression in lung cancer cells, de novo mouse lung cancer model","journal":"Cell Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, in vivo mouse model, independent replication of binding competition mechanism","pmids":["24458094"],"is_preprint":false},{"year":2017,"finding":"VGLL4 targets a TEAD4-TCF4 transcriptional complex to simultaneously suppress both Hippo-YAP and Wnt/β-catenin signaling; TEAD4 and TCF4 physically associate and co-bind target gene promoters, and VGLL4 disrupts this complex to suppress TCF4 transactivation.","method":"Co-IP, chromatin immunoprecipitation, reporter assays, knockdown experiments, de novo mouse CRC model","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP showing TEAD4-TCF4 complex, ChIP confirming co-binding, functional reporter assays, in vivo mouse model, single lab","pmids":["28051067"],"is_preprint":false},{"year":2016,"finding":"VGLL4 is acetylated at lysine 225, and this acetylation negatively regulates its binding to TEAD1. VGLL4 inhibits cardiomyocyte proliferation by inhibiting TEAD1-YAP interaction and by targeting TEAD1 for proteasomal degradation. An acetylation-refractory VGLL4 mutant (K225R) shows enhanced TEAD1 degradation and limits neonatal CM proliferation.","method":"Mass spectrometry identification of acetylation site, acetylation-refractory mutant overexpression, Co-IP, in vivo neonatal mouse heart experiments","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS-identified PTM with mutagenesis validation, Co-IP, in vivo cardiac phenotype, multiple orthogonal methods in single study","pmids":["27720608"],"is_preprint":false},{"year":2016,"finding":"USP11 (ubiquitin-specific protease 11) interacts with VGLL4 via its USP domain binding to the N-terminal region of VGLL4, and stabilizes VGLL4 protein by promoting its deubiquitination. Knockdown of USP11 promotes cell growth in a YAP-dependent manner.","method":"Co-IP, domain mapping, deubiquitination assay, USP11 knockdown with phenotypic rescue","journal":"American Journal of Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, deubiquitination assay, functional knockdown, single lab with two orthogonal methods","pmids":["28042509"],"is_preprint":false},{"year":2017,"finding":"CDK1 phosphorylates VGLL4 during mitosis at Ser-58, Ser-155, Thr-159, and Ser-280. The non-phosphorylatable mutant VGLL4-4A (S58A/S155A/T159A/S280A) shows higher binding affinity to TEAD1 than wild-type VGLL4 and suppresses tumorigenesis more potently, indicating that mitotic CDK1 phosphorylation inhibits VGLL4's tumor-suppressive activity.","method":"In vitro kinase assay, site-directed mutagenesis, phosphomutant expression in pancreatic cancer cells, TEAD1 binding assay, in vitro and in vivo tumor suppression assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus mutagenesis, binding affinity measurement, in vivo xenograft, multiple orthogonal methods in single study","pmids":["28739871"],"is_preprint":false},{"year":2018,"finding":"VGLL4 acts as an adaptor protein forming a ternary complex with TEAD4 and CtBP2 to repress adipogenesis; VGLL4 enhances the interaction between TEAD4 and CtBP2. This TEAD4-VGLL4-CtBP2 complex dynamically exists at the early stage of adipogenesis and directly represses PPARγ and Adipoq promoters.","method":"Co-IP, knockdown of TEAD1-4 in 3T3-L1 preadipocytes, ChIP on PPARγ/Adipoq promoters, ternary complex characterization","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP demonstrating ternary complex, ChIP confirmation of target promoter binding, multiple orthogonal methods, single lab","pmids":["30209132"],"is_preprint":false},{"year":2018,"finding":"Loss of VGLL4 reduces PD-L1 expression in tumor cells. VGLL4 interacts with IRF2BP2 and promotes its protein stability by inhibiting proteasome-mediated degradation of IRF2BP2. Loss of IRF2BP2 leads to persistent binding of IRF2 (a transcriptional repressor) to the PD-L1 promoter, thereby reducing PD-L1. Additionally, YAP inhibits IFNγ-inducible PD-L1 expression partly by suppressing VGLL4 and IRF1 via miR-130a.","method":"Co-IP, proteasome inhibitor experiments, syngeneic mouse tumor models with Vgll4 knockout, promoter binding assays","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP for VGLL4-IRF2BP2 interaction, proteasome assay, in vivo syngeneic models, multiple orthogonal methods","pmids":["30396996"],"is_preprint":false},{"year":2019,"finding":"VGLL4 interacts with STAT3 and suppresses STAT3 phosphorylation/activation, leading to inactivation of STAT3 downstream transcription in triple-negative breast cancer cells.","method":"Co-IP, VGLL4 overexpression/knockdown, STAT3 reporter assays, in vivo nude mouse tumor model","journal":"Experimental & Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP demonstrating interaction, reporter assay for functional consequence, in vivo validation, single lab","pmids":["31748508"],"is_preprint":false},{"year":2019,"finding":"VGLL4 expressed in endothelial cell lineage is required for heart valve development; tissue-specific knockout of VGLL4 in endothelial cells leads to valve malformation with expanded expression of YAP targets. Genetic semi-knockout of YAP in VGLL4-ablated hearts significantly constrains hyper-proliferation of arterial valve interstitial cells, placing VGLL4 upstream of YAP targets in valve development.","method":"Tissue-specific conditional knockout in mice, genetic epistasis (semi-knockout of YAP in VGLL4-null background), histology, immunostaining","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined phenotype plus genetic epistasis experiment, in vivo mouse model","pmids":["30789911"],"is_preprint":false},{"year":2019,"finding":"VGLL4 plays dual roles in muscle regeneration: (1) as a conventional repressor of YAP during the proliferation stage; (2) as a co-activator of TEAD4 to promote MyoG transactivation in a YAP-independent manner during differentiation. VGLL4 stabilizes protein-protein interactions between MyoD and TEAD4 to achieve efficient MyoG transactivation.","method":"VGLL4 knockout in mice, Co-IP for MyoD-TEAD4 interaction, reporter assays, in vivo muscle regeneration phenotype analysis","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — VGLL4 KO mouse, Co-IP for ternary complex, reporter assay, in vivo regeneration phenotype, multiple orthogonal methods","pmids":["31328806"],"is_preprint":false},{"year":2022,"finding":"Genetic inactivation of Vgll4 bypasses the requirement for YAP in liver and lung development (striking antagonistic epistasis), establishing that the major physiological function of YAP is to antagonize VGLL4. Vgll4 inactivation dramatically enhanced intrahepatic cholangiocarcinoma in Nf2-deficient livers and ameliorated CCl4-induced liver damage.","method":"Genetic epistasis in mice: Vgll4 knockout rescuing YAP-null developmental lethality; Nf2/Vgll4 double knockout tumor model; CCl4 liver injury model","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in multiple in vivo contexts, double-mutant rescue of essential developmental function, replicated across tissue types","pmids":["36522128"],"is_preprint":false},{"year":2021,"finding":"Biochemical characterization shows that full-length VGLL4 and Drosophila Tgi are intrinsically disordered proteins. VGLL4 has two TEAD4-binding sites with one high-affinity site (100-fold tighter than the low-affinity site). In solution, VGLL4 predominantly forms dimeric complexes with TEAD4 via the high-affinity site; at high concentrations or when TEAD4 is immobilized/bound to DNA, one VGLL4 molecule can bridge two TEAD molecules, potentially enhancing repression at DNA-bound TEADs.","method":"Surface plasmon resonance (SPR) binding assays, size exclusion chromatography, biophysical characterization of intrinsic disorder","journal":"Protein Science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted SPR binding assays with quantitative affinity measurement, SEC complex analysis, multiple biophysical methods in single study","pmids":["34075638"],"is_preprint":false},{"year":2023,"finding":"VGLL4 and MENIN function as TEAD1 co-repressors in pancreatic β cells; both proteins bind TEAD1 and repress expression of target genes FZD7 and CCN2, leading to inhibition of β cell proliferation. β cell-specific deletion of YAP/TAZ does not affect proliferation, whereas TEAD1 deletion increases proliferation, implicating VGLL4/MENIN as the relevant TEAD1 co-repressors.","method":"β cell-specific TEAD1/YAP/TAZ knockout mice, split-GFP system and yeast two-hybrid for VGLL4/MENIN-TEAD1 interaction, reporter assays for FZD7/CCN2","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO epistasis, two independent protein-interaction platforms (split-GFP and Y2H), target gene reporter assays","pmids":["36662616"],"is_preprint":false},{"year":2019,"finding":"In zebrafish, VGLL4 (vgll4b) sequesters IRF2BP2 via its TDU1 domain interacting with IRF2BP2's ring finger domain, thereby preventing IRF2BP2 from repressing alas2 expression and heme biosynthesis. This places VGLL4 downstream of NOTCH1/HIF1α in an oxygen-sensing pathway controlling erythroid terminal differentiation.","method":"CRISPR/Cas9 vgll4b knockout zebrafish, domain mapping (TDU1 and IRF2BP2 ring finger), rescue experiments with irf2bp2 depletion, heme/erythroid phenotype analysis","journal":"Redox Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO zebrafish with defined phenotype, domain-level interaction mapping, genetic rescue epistasis, single lab","pmids":["31539803"],"is_preprint":false},{"year":2023,"finding":"VGLL4 promotes vascular smooth muscle cell (VSMC) differentiation from hESCs by interacting with TEAD1; the VGLL4-TEAD1 complex directly activates TET2 (a DNA dioxygenase) expression, which in turn demethylates VSMC marker genes to facilitate their expression.","method":"CRISPR/Cas9 VGLL4 knockdown hESCs, PiggyBac VGLL4 overexpression, Co-IP for VGLL4-TEAD1 interaction, luciferase reporter assay for TET2 promoter, VSMC differentiation assay","journal":"Journal of Molecular and Cellular Cardiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus luciferase reporter identifying TET2 as target, CRISPR KD and OE in stem cells, single lab","pmids":["36657637"],"is_preprint":false},{"year":2023,"finding":"VGLL4 promotes vascular endothelial cell specification from hESCs by binding TEAD1 and facilitating expression of endothelial master transcription factor FLI1; TEAD1 overexpression rescues the inhibitory effects of VGLL4 knockdown on endothelial differentiation.","method":"Co-IP for VGLL4-TEAD1 interaction, inducible VGLL4 overexpression (PiggyBac), VGLL4 heterozygous knockout (CRISPR), 3D vascular organoids and 2D endothelial differentiation assays","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, gain- and loss-of-function, genetic rescue with TEAD1, single lab","pmids":["37468661"],"is_preprint":false},{"year":2025,"finding":"VGLL4 forms a complex with TEAD4 and SMAD3 in chondrocytes to maintain extracellular matrix homeostasis; structural analysis defined that TEAD4 residues E263/D266/Q269/H427 bind SMAD3 residues K81/F260 via hydrogen bonds and hydrophobic contacts, while VGLL4 residues H240/F241 engage TEAD4 residues F337/F373 via π-stacking. VGLL4 deficiency causes ECM disorganization and osteoarthritis; interaction-deficient mutants lose therapeutic efficacy.","method":"Conditional KO mice (Col2-CreERT2;Vgll4fl/fl), structural interaction analysis, Co-IP, AAV-mediated gene delivery rescue, interaction-deficient mutants","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — structural interaction mapping with specific residues, conditional KO with defined phenotype, mutant rescue, AAV functional validation, multiple orthogonal methods","pmids":["41125571"],"is_preprint":false},{"year":2024,"finding":"VGLL4 drives TEAD4 multimerization, which increases TEAD4 DNA residence time and promotes YAP recruitment to DNA-bound TEAD4. At low VGLL4:TEAD4 ratios, VGLL4 enhances YAP recruitment to DNA-bound TEAD4 multimers; at high VGLL4:TEAD4 ratios, VGLL4 inhibits YAP recruitment. Both YAP and VGLL4 can promote TEAD4 multimerization.","method":"Fluorescence-combined optical tweezers, single-molecule DNA binding assays, stoichiometry-dependent co-factor recruitment experiments","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted single-molecule optical tweezers assay with precise stoichiometric control, novel mechanistic finding with rigorous biophysical method","pmids":["41965334"],"is_preprint":false},{"year":2026,"finding":"In zebrafish, Vgll4 restricts Tead-dependent transcription through two co-existing mechanisms: (1) competition with Yap1 for Tead binding (Yap1-dependent repression) and (2) Tead-dependent repression independent of Yap1. Loss- and gain-of-function epistasis experiments and transcriptional reporters confirmed both mechanisms operate in vivo.","method":"Loss- and gain-of-function in zebrafish posterior lateral line, genetic epistasis experiments, transcriptional reporter quantification, pharmacological treatments","journal":"Communications Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo epistasis in zebrafish with reporters, gain- and loss-of-function, pharmacological validation, multiple orthogonal approaches","pmids":["42032219"],"is_preprint":false},{"year":2026,"finding":"SAMD4A/B RNA-binding proteins destabilize VGLL4 mRNA and repress its translation, thereby activating TEAD-dependent transcription. Inhibiting SAMD4A/B elevates VGLL4 mRNA levels, suppresses TEAD activity, and inhibits cancer progression. Liver-specific SAMD4B transgenic mice show accelerated intrahepatic cholangiocarcinoma development in Nf2-deficient background.","method":"Whole-genome siRNA screen, SAMD4A/B knockdown, RNA stability and translation assays, SAMD4B liver-specific transgenic mice with Nf2 knockout","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen identification, RNA stability assay, in vivo transgenic mouse model, single lab","pmids":["42014888"],"is_preprint":false},{"year":2026,"finding":"VGLL4 forms a complex with TEAD4 and ATOH1 to stimulate GFI1 expression and promote Paneth cell differentiation; separately, VGLL4 forms a complex with TEAD4 and TCF4 to induce defensin expression, thereby maintaining intestinal microbiota composition and intestinal homeostasis.","method":"Intestinal epithelium-specific VGLL4 knockout mice, Co-IP for VGLL4-TEAD4-ATOH1 and VGLL4-TEAD4-TCF4 complexes, gene expression analysis, Paneth cell number quantification","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with defined phenotype, Co-IP for two distinct complexes, single lab","pmids":["41629625"],"is_preprint":false},{"year":2023,"finding":"VGLL4 inhibits ubiquitination and proteasomal degradation of LDHA, increasing LDHA protein levels and lactate production in response to hypoxia. This neuroprotective mechanism reduces APP amyloidogenic processing. Sodium oxamate (LDHA inhibitor) blocks this neuroprotective function of VGLL4.","method":"VGLL4 overexpression in AD model cells, ubiquitination assay for LDHA, pharmacological inhibition with sodium oxamate, APP processing assay","journal":"FASEB Journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method for LDHA ubiquitination, limited mechanistic follow-up on interaction mechanism","pmids":["37921465"],"is_preprint":false},{"year":2024,"finding":"USP15 deubiquitinates VGLL4 via K48-linked ubiquitin chains, stabilizing VGLL4 protein. This USP15-mediated VGLL4 stabilization suppresses STAT3 activation and PD-L1 transcription. SART3 regulates VGLL4 stability by influencing the nuclear translocation of USP15.","method":"Co-IP, deubiquitination assay (K48-linkage specificity), STAT3 reporter, PD-L1 expression analysis, CD8+ T cell infiltration assays","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, K48-specific deubiquitination assay, functional downstream read-outs, single lab","pmids":["38431034"],"is_preprint":false},{"year":2024,"finding":"Select sulfonamide TEAD lipid-pocket-binding small molecules promote TEAD interaction with VGLL4 (a cofactor switch from YAP to VGLL4), inducing chemically-driven VGLL4-TEAD complexes that repress pro-growth gene networks. Genetic deletion of VGLL4 causes resistance to these compounds in vitro and in vivo, demonstrating that VGLL4 is required for their anti-proliferative activity.","method":"Co-IP after compound treatment, chromatin assays, VGLL4 genetic deletion with compound resistance phenotype, in vitro and in vivo proliferation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic deletion resistance assay, in vivo validation, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2024,"finding":"VGLL4 containing intact TDU domains regulates classical brown adipose tissue (BAT) adipogenesis; deletion of TDU domains causes perinatal lethality and paucity of interscapular BAT. AAV-mediated brown adipocyte-specific VGLL4 overexpression increases BAT volume. Genomic studies indicate the VGLL4/TEAD1 complex directly regulates myogenic and adipogenic gene expression programs in BAT.","method":"TDU-domain deletion mouse mutant, histology, MRI, AAV-mediated overexpression, genomic/ChIP studies of VGLL4/TEAD1 complex","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific KO with defined phenotype, AAV rescue, ChIP genomic evidence, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2013,"finding":"VGLL4 overexpression in human embryonic stem cells significantly decreases cell death in response to dissociation stress, enhances colony formation from single cells, and decreases activity of initiator and effector caspases. An interaction between VGLL4 and the Rho/ROCK pathway was identified in hESC survival context.","method":"Gain-of-function ORF screen, caspase activity assays, colony formation assays, Rho/ROCK pathway interaction experiments","journal":"Stem Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab gain-of-function screen, caspase assay and colony formation, Rho/ROCK interaction not fully characterized mechanistically","pmids":["23765749"],"is_preprint":false},{"year":2021,"finding":"KDM6B (JMJD3) demethylase activity promotes VGLL4 expression in the hippocampus during LPS-induced neuroinflammation; KDM6B inhibition with GSK-J4 attenuates LPS-induced VGLL4, STAT3, IL-1β, and microglial activation. VGLL4 knockdown prevents LPS-induced anxiety-like behavior and STAT3/IL-1β upregulation, placing VGLL4 downstream of KDM6B in a neuroinflammatory pathway.","method":"KDM6B inhibitor (GSK-J4), adeno-associated virus-mediated Vgll4 shRNA knockdown, behavioral assays, western blotting","journal":"Behavioural Brain Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological inhibitor and AAV knockdown without direct biochemical KDM6B-VGLL4 promoter interaction validated","pmids":["33865886"],"is_preprint":false},{"year":2021,"finding":"VGLL4 knockdown attenuates hypoxia-induced pulmonary hypertension and STAT3 signaling in mice; VGLL4 acetylation is enhanced by chronic normobaric hypoxia and increases interaction with ac-H3K9 and p-STAT3. Abrogation of VGLL4 acetylation reverses hypoxia-induced pulmonary arterial remodeling and suppresses STAT3 signaling.","method":"AAV-mediated VGLL4 knockdown/overexpression in mice, VGLL4 acetylation mutant, Co-IP for ac-H3K9/VGLL4/STAT3 interaction, immunoprecipitation, pulmonary hypertension model","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — acetylation mutant phenotype in vivo, Co-IP, in vivo mouse model, single lab","pmids":["34314061"],"is_preprint":false},{"year":2023,"finding":"ACSL4 reduces VGLL4 expression to promote NF-κB signal transduction in microglia; ACSL4 knockdown increases VGLL4 levels and decreases proinflammatory cytokine production, placing VGLL4 downstream of ACSL4 as a negative regulator of NF-κB signaling in microglial neuroinflammation.","method":"ACSL4 knockdown in microglia, VGLL4 expression measurement, NF-κB signaling assays, in vivo LPS and MPTP mouse models","journal":"Brain, Behavior, and Immunity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ACSL4 knockdown with indirect VGLL4 regulation inferred, no direct ACSL4-VGLL4 biochemical interaction shown","pmids":["36791893"],"is_preprint":false},{"year":2024,"finding":"VGLL4 suppresses cardiomyocyte maturational hypertrophy by inhibiting the YAP/TAZ-TEAD complex and its downstream activation of the PI3K-AKT pathway; disrupting VGLL4-TEAD interaction abolishes this inhibition of PI3K-AKT.","method":"VGLL4 activation in neonatal rat ventricular myocytes and postnatal mouse heart, PI3K-AKT pathway measurements, VGLL4 interaction-disrupting mutant","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — interaction-disrupting mutant identifying PI3K-AKT as downstream pathway, in vitro and in vivo cardiac phenotype, single lab","pmids":["39195232"],"is_preprint":false},{"year":2026,"finding":"FTO (m6A demethylase) reduces m6A modification levels on VGLL4 mRNA, leading to decreased VGLL4 expression and consequent activation of STAT3 signaling in triple-negative breast cancer. MeRIP assay confirmed VGLL4 as the target of FTO-mediated m6A modification.","method":"MeRIP (m6A-RNA immunoprecipitation), RNA immunoprecipitation, RNA stability assay, FTO overexpression/knockdown, STAT3 signaling readout","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP directly confirming m6A on VGLL4 mRNA, RNA stability assay, functional STAT3 readout, single lab","pmids":["42264087"],"is_preprint":false},{"year":2024,"finding":"TEAD4 directly binds RUNX2 to repress RUNX2-driven osteogenesis, and VGLL4 antagonizes this repression by disrupting TEAD4-RUNX2 interactions; Co-IP confirmed VGLL4 reduces TEAD4-RUNX2 binding, and VGLL4 knockdown diminishes osteoblast differentiation.","method":"Co-IP and proximity ligation assay (PLA) for TEAD4-RUNX2 interaction, VGLL4 knockdown in BMSCs, osteogenic differentiation assays, OVX rat model","journal":"Journal of Ethnopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and PLA for interaction disruption, single lab, indirect pharmacological context","pmids":["39142621"],"is_preprint":false}],"current_model":"VGLL4 is an intrinsically disordered transcriptional co-repressor that primarily acts by directly competing with YAP for binding to TEAD1-4 transcription factors via its tandem Tondu (TDU) domains, thereby suppressing YAP-TEAD target gene transcription; it also functions as a co-activator or adaptor in multi-protein complexes (e.g., TEAD4-VGLL4-CtBP2, VGLL4-TEAD1-MENIN, VGLL4-TEAD4-SMAD3, VGLL4-TEAD4-TCF4) that regulate adipogenesis, β-cell proliferation, cartilage homeostasis, and Wnt signaling, while its activity is post-translationally regulated by CDK1-mediated phosphorylation (inhibitory), acetylation at K225 (inhibitory for TEAD binding), and deubiquitination by USP11/USP15 (stabilizing), with SAMD4A/B and FTO acting as upstream regulators of VGLL4 mRNA stability and m6A modification respectively."},"narrative":{"mechanistic_narrative":"VGLL4 is an intrinsically disordered transcriptional co-factor that governs TEAD-dependent transcription, acting principally as a repressor by competing with YAP for binding to TEAD1-4 through its tandem Tondu (TDU) domains, which are necessary and sufficient for its inhibitory activity and which form the basis of a peptide that suppresses tumor growth [PMID:24525233, PMID:24458094, PMID:34075638]. Biophysical reconstitution shows VGLL4 carries two TEAD-binding sites of differing affinity and forms dimeric complexes with TEAD4, and that its action is stoichiometry-dependent: by driving TEAD4 multimerization VGLL4 enhances YAP recruitment to DNA-bound TEAD at low VGLL4:TEAD ratios but inhibits it at high ratios [PMID:34075638, PMID:41965334]. Genetic epistasis establishes that the major physiological role of YAP is to antagonize VGLL4, since Vgll4 inactivation bypasses the requirement for YAP in liver and lung development [PMID:36522128]. Beyond simple competition, VGLL4 nucleates distinct TEAD4-containing multiprotein complexes that repress or activate specific programs — a TEAD4-VGLL4-CtBP2 complex represses adipogenic PPARγ/Adipoq promoters [PMID:30209132], a TEAD4-VGLL4-SMAD3 complex maintains chondrocyte extracellular matrix homeostasis with osteoarthritis arising upon loss [PMID:41125571], a VGLL4-TEAD1-MENIN complex restrains β-cell proliferation [PMID:36662616], and VGLL4-TEAD4-ATOH1 and VGLL4-TEAD4-TCF4 complexes drive Paneth cell differentiation and defensin expression in the intestine [PMID:41629625]; it can also act as a TEAD4 co-activator, stabilizing MyoD-TEAD4 to promote MyoG transactivation during muscle differentiation [PMID:31328806]. VGLL4 additionally suppresses Wnt/β-catenin signaling by disrupting a TEAD4-TCF4 complex [PMID:28051067] and is required for heart valve and cardiomyocyte development through restraint of YAP targets [PMID:30789911, PMID:27720608]. VGLL4 abundance and activity are tightly controlled: CDK1 phosphorylation and K225 acetylation inhibit TEAD binding [PMID:28739871, PMID:27720608], deubiquitination by USP11 and USP15 stabilizes the protein [PMID:28042509, PMID:38431034], and SAMD4A/B and FTO regulate VGLL4 mRNA stability and m6A modification [PMID:42014888, PMID:42264087].","teleology":[{"year":2014,"claim":"Establishing how VGLL4 opposes YAP defined the core mechanism: it answered whether VGLL4 is a passive bystander or an active competitor for the oncogenic transcriptional output of the Hippo pathway.","evidence":"Co-IP, competitive binding assays, domain deletion/mutagenesis, and a TDU-mimicking peptide tested in tumor models","pmids":["24525233","24458094"],"confidence":"High","gaps":["Did not resolve binding stoichiometry or affinity differences between the two TDU sites","Did not address VGLL4's roles outside competition"]},{"year":2016,"claim":"Identification of inhibitory acetylation at K225 and TEAD1 destabilization showed VGLL4 activity is post-translationally tuned and that it can deplete TEAD1 protein, not only block its complex.","evidence":"Mass spectrometry PTM mapping, K225R acetylation-refractory mutant, Co-IP, and neonatal mouse heart proliferation assays","pmids":["27720608"],"confidence":"High","gaps":["Acetyltransferase/deacetylase responsible for K225 not identified","Mechanism linking VGLL4 to TEAD1 proteasomal degradation unresolved"]},{"year":2016,"claim":"USP11-mediated deubiquitination revealed that VGLL4 protein levels are set by regulated turnover, linking its tumor-suppressive dosage to the ubiquitin system.","evidence":"Co-IP, domain mapping, deubiquitination assay, and USP11 knockdown with YAP-dependent growth rescue","pmids":["28042509"],"confidence":"Medium","gaps":["E3 ligase that ubiquitinates VGLL4 not identified","Single lab, ubiquitin linkage type not defined"]},{"year":2017,"claim":"Discovery that VGLL4 disrupts a TEAD4-TCF4 complex and that CDK1 phosphorylates VGLL4 broadened its reach beyond YAP, coupling it to Wnt signaling and to mitotic kinase control.","evidence":"Co-IP, ChIP, reporter assays, mouse CRC model (TCF4); in vitro kinase assay and phosphomutant VGLL4-4A binding/tumor assays (CDK1)","pmids":["28051067","28739871"],"confidence":"High","gaps":["Whether the same VGLL4 pool simultaneously engages TEAD-YAP and TEAD-TCF4 is unclear","Physiological trigger for CDK1 phosphorylation of VGLL4 outside mitosis not addressed"]},{"year":2018,"claim":"VGLL4 was shown to act as a positive adaptor in defined ternary complexes (TEAD4-CtBP2) and to stabilize partner proteins (IRF2BP2), redefining it as more than a competitive repressor.","evidence":"Reciprocal Co-IP, ChIP on PPARγ/Adipoq promoters in preadipocytes; Co-IP, proteasome inhibition, and Vgll4-knockout syngeneic tumor/PD-L1 models","pmids":["30209132","30396996"],"confidence":"High","gaps":["How VGLL4 switches between repressive competition and adaptor/stabilizer roles unresolved","Direct structural basis of the ternary complexes not defined here"]},{"year":2019,"claim":"In vivo conditional knockouts and dual-role analyses placed VGLL4 upstream of YAP targets in tissue development and revealed YAP-independent co-activator functions.","evidence":"Endothelial-specific Vgll4 KO with YAP genetic epistasis in valve development; Vgll4 KO with MyoD-TEAD4 Co-IP in muscle regeneration; CRISPR zebrafish vgll4b KO mapping IRF2BP2 sequestration","pmids":["30789911","31328806","31539803"],"confidence":"High","gaps":["Determinants that select repressive versus co-activator outcome in different tissues not defined","Mechanism of context-specific partner choice unclear"]},{"year":2021,"claim":"Biophysical reconstitution established VGLL4 as an intrinsically disordered protein with two TEAD-binding sites of distinct affinity, providing a physical model for dimeric and bridging modes of engagement.","evidence":"Surface plasmon resonance, size-exclusion chromatography, and intrinsic disorder characterization of full-length VGLL4 and Drosophila Tgi","pmids":["34075638"],"confidence":"High","gaps":["In-cell relevance of the bridging mode not established","How disorder relates to PTM-based regulation not addressed"]},{"year":2022,"claim":"Antagonistic genetic epistasis demonstrated that VGLL4 is the principal physiological effector opposed by YAP, since Vgll4 loss rescues YAP-null lethality in liver and lung.","evidence":"Vgll4 KO rescue of YAP-null developmental lethality, Nf2/Vgll4 double-knockout tumor model, CCl4 liver injury in mice","pmids":["36522128"],"confidence":"High","gaps":["Tissues where VGLL4 is not the dominant TEAD repressor not delineated","Quantitative contribution of competition versus other complexes in vivo unresolved"]},{"year":2023,"claim":"Multiple studies expanded VGLL4's TEAD-partnered complexes (MENIN, TET2, FLI1) and identified additional regulatory inputs (USP15 deubiquitination), connecting it to β-cell proliferation, vascular cell specification, and immune evasion.","evidence":"β-cell-specific KO with split-GFP/Y2H interaction assays; 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tissue","date":"2024-07-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.09.602788","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.26.605344","title":"Whole genome sequencing of 76 Mexican Indigenous reveals recent selection signatures linked to pathogens and diet adaptation","date":"2024-07-29","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.26.605344","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.03.615022","title":"An improved TEAD dominant-negative protein inhibitor to study Hippo YAP1/TAZ-dependent transcription","date":"2024-10-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.03.615022","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.08.652796","title":"Vgll4 Proteins limit Organ Size in Zebrafish through Yap1-Dependent and -Independent Mechanisms","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.08.652796","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34364,"output_tokens":8841,"usd":0.117853,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18587,"output_tokens":4833,"usd":0.10688,"stage2_stop_reason":"end_turn"},"total_usd":0.224733,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"VGLL4 directly competes with YAP for binding to TEAD transcription factors via its tandem Tondu (TDU) domains, which are both necessary and sufficient for its inhibitory activity toward YAP. A peptide mimicking VGLL4's TDU domains potently suppresses tumor growth in vitro and in vivo.\",\n      \"method\": \"Co-IP, competitive binding assays, domain deletion/mutagenesis, in vitro and in vivo tumor suppression assays with VGLL4-mimicking peptide\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal binding assays with domain mutagenesis, functional rescue, in vivo validation, replicated across multiple studies\",\n      \"pmids\": [\"24525233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VGLL4 inhibits formation of the YAP-TEAD transcriptional complex in lung cancer by directly competing with YAP for TEAD binding, acting through two TDU domains.\",\n      \"method\": \"Co-IP, competitive binding assays, ectopic expression in lung cancer cells, de novo mouse lung cancer model\",\n      \"journal\": \"Cell Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, in vivo mouse model, independent replication of binding competition mechanism\",\n      \"pmids\": [\"24458094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VGLL4 targets a TEAD4-TCF4 transcriptional complex to simultaneously suppress both Hippo-YAP and Wnt/β-catenin signaling; TEAD4 and TCF4 physically associate and co-bind target gene promoters, and VGLL4 disrupts this complex to suppress TCF4 transactivation.\",\n      \"method\": \"Co-IP, chromatin immunoprecipitation, reporter assays, knockdown experiments, de novo mouse CRC model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP showing TEAD4-TCF4 complex, ChIP confirming co-binding, functional reporter assays, in vivo mouse model, single lab\",\n      \"pmids\": [\"28051067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"VGLL4 is acetylated at lysine 225, and this acetylation negatively regulates its binding to TEAD1. VGLL4 inhibits cardiomyocyte proliferation by inhibiting TEAD1-YAP interaction and by targeting TEAD1 for proteasomal degradation. An acetylation-refractory VGLL4 mutant (K225R) shows enhanced TEAD1 degradation and limits neonatal CM proliferation.\",\n      \"method\": \"Mass spectrometry identification of acetylation site, acetylation-refractory mutant overexpression, Co-IP, in vivo neonatal mouse heart experiments\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-identified PTM with mutagenesis validation, Co-IP, in vivo cardiac phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"27720608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"USP11 (ubiquitin-specific protease 11) interacts with VGLL4 via its USP domain binding to the N-terminal region of VGLL4, and stabilizes VGLL4 protein by promoting its deubiquitination. Knockdown of USP11 promotes cell growth in a YAP-dependent manner.\",\n      \"method\": \"Co-IP, domain mapping, deubiquitination assay, USP11 knockdown with phenotypic rescue\",\n      \"journal\": \"American Journal of Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, deubiquitination assay, functional knockdown, single lab with two orthogonal methods\",\n      \"pmids\": [\"28042509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CDK1 phosphorylates VGLL4 during mitosis at Ser-58, Ser-155, Thr-159, and Ser-280. The non-phosphorylatable mutant VGLL4-4A (S58A/S155A/T159A/S280A) shows higher binding affinity to TEAD1 than wild-type VGLL4 and suppresses tumorigenesis more potently, indicating that mitotic CDK1 phosphorylation inhibits VGLL4's tumor-suppressive activity.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, phosphomutant expression in pancreatic cancer cells, TEAD1 binding assay, in vitro and in vivo tumor suppression assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus mutagenesis, binding affinity measurement, in vivo xenograft, multiple orthogonal methods in single study\",\n      \"pmids\": [\"28739871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VGLL4 acts as an adaptor protein forming a ternary complex with TEAD4 and CtBP2 to repress adipogenesis; VGLL4 enhances the interaction between TEAD4 and CtBP2. This TEAD4-VGLL4-CtBP2 complex dynamically exists at the early stage of adipogenesis and directly represses PPARγ and Adipoq promoters.\",\n      \"method\": \"Co-IP, knockdown of TEAD1-4 in 3T3-L1 preadipocytes, ChIP on PPARγ/Adipoq promoters, ternary complex characterization\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP demonstrating ternary complex, ChIP confirmation of target promoter binding, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30209132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of VGLL4 reduces PD-L1 expression in tumor cells. VGLL4 interacts with IRF2BP2 and promotes its protein stability by inhibiting proteasome-mediated degradation of IRF2BP2. Loss of IRF2BP2 leads to persistent binding of IRF2 (a transcriptional repressor) to the PD-L1 promoter, thereby reducing PD-L1. Additionally, YAP inhibits IFNγ-inducible PD-L1 expression partly by suppressing VGLL4 and IRF1 via miR-130a.\",\n      \"method\": \"Co-IP, proteasome inhibitor experiments, syngeneic mouse tumor models with Vgll4 knockout, promoter binding assays\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for VGLL4-IRF2BP2 interaction, proteasome assay, in vivo syngeneic models, multiple orthogonal methods\",\n      \"pmids\": [\"30396996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VGLL4 interacts with STAT3 and suppresses STAT3 phosphorylation/activation, leading to inactivation of STAT3 downstream transcription in triple-negative breast cancer cells.\",\n      \"method\": \"Co-IP, VGLL4 overexpression/knockdown, STAT3 reporter assays, in vivo nude mouse tumor model\",\n      \"journal\": \"Experimental & Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP demonstrating interaction, reporter assay for functional consequence, in vivo validation, single lab\",\n      \"pmids\": [\"31748508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VGLL4 expressed in endothelial cell lineage is required for heart valve development; tissue-specific knockout of VGLL4 in endothelial cells leads to valve malformation with expanded expression of YAP targets. Genetic semi-knockout of YAP in VGLL4-ablated hearts significantly constrains hyper-proliferation of arterial valve interstitial cells, placing VGLL4 upstream of YAP targets in valve development.\",\n      \"method\": \"Tissue-specific conditional knockout in mice, genetic epistasis (semi-knockout of YAP in VGLL4-null background), histology, immunostaining\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined phenotype plus genetic epistasis experiment, in vivo mouse model\",\n      \"pmids\": [\"30789911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VGLL4 plays dual roles in muscle regeneration: (1) as a conventional repressor of YAP during the proliferation stage; (2) as a co-activator of TEAD4 to promote MyoG transactivation in a YAP-independent manner during differentiation. VGLL4 stabilizes protein-protein interactions between MyoD and TEAD4 to achieve efficient MyoG transactivation.\",\n      \"method\": \"VGLL4 knockout in mice, Co-IP for MyoD-TEAD4 interaction, reporter assays, in vivo muscle regeneration phenotype analysis\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — VGLL4 KO mouse, Co-IP for ternary complex, reporter assay, in vivo regeneration phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"31328806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Genetic inactivation of Vgll4 bypasses the requirement for YAP in liver and lung development (striking antagonistic epistasis), establishing that the major physiological function of YAP is to antagonize VGLL4. Vgll4 inactivation dramatically enhanced intrahepatic cholangiocarcinoma in Nf2-deficient livers and ameliorated CCl4-induced liver damage.\",\n      \"method\": \"Genetic epistasis in mice: Vgll4 knockout rescuing YAP-null developmental lethality; Nf2/Vgll4 double knockout tumor model; CCl4 liver injury model\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in multiple in vivo contexts, double-mutant rescue of essential developmental function, replicated across tissue types\",\n      \"pmids\": [\"36522128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biochemical characterization shows that full-length VGLL4 and Drosophila Tgi are intrinsically disordered proteins. VGLL4 has two TEAD4-binding sites with one high-affinity site (100-fold tighter than the low-affinity site). In solution, VGLL4 predominantly forms dimeric complexes with TEAD4 via the high-affinity site; at high concentrations or when TEAD4 is immobilized/bound to DNA, one VGLL4 molecule can bridge two TEAD molecules, potentially enhancing repression at DNA-bound TEADs.\",\n      \"method\": \"Surface plasmon resonance (SPR) binding assays, size exclusion chromatography, biophysical characterization of intrinsic disorder\",\n      \"journal\": \"Protein Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted SPR binding assays with quantitative affinity measurement, SEC complex analysis, multiple biophysical methods in single study\",\n      \"pmids\": [\"34075638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VGLL4 and MENIN function as TEAD1 co-repressors in pancreatic β cells; both proteins bind TEAD1 and repress expression of target genes FZD7 and CCN2, leading to inhibition of β cell proliferation. β cell-specific deletion of YAP/TAZ does not affect proliferation, whereas TEAD1 deletion increases proliferation, implicating VGLL4/MENIN as the relevant TEAD1 co-repressors.\",\n      \"method\": \"β cell-specific TEAD1/YAP/TAZ knockout mice, split-GFP system and yeast two-hybrid for VGLL4/MENIN-TEAD1 interaction, reporter assays for FZD7/CCN2\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO epistasis, two independent protein-interaction platforms (split-GFP and Y2H), target gene reporter assays\",\n      \"pmids\": [\"36662616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In zebrafish, VGLL4 (vgll4b) sequesters IRF2BP2 via its TDU1 domain interacting with IRF2BP2's ring finger domain, thereby preventing IRF2BP2 from repressing alas2 expression and heme biosynthesis. This places VGLL4 downstream of NOTCH1/HIF1α in an oxygen-sensing pathway controlling erythroid terminal differentiation.\",\n      \"method\": \"CRISPR/Cas9 vgll4b knockout zebrafish, domain mapping (TDU1 and IRF2BP2 ring finger), rescue experiments with irf2bp2 depletion, heme/erythroid phenotype analysis\",\n      \"journal\": \"Redox Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO zebrafish with defined phenotype, domain-level interaction mapping, genetic rescue epistasis, single lab\",\n      \"pmids\": [\"31539803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VGLL4 promotes vascular smooth muscle cell (VSMC) differentiation from hESCs by interacting with TEAD1; the VGLL4-TEAD1 complex directly activates TET2 (a DNA dioxygenase) expression, which in turn demethylates VSMC marker genes to facilitate their expression.\",\n      \"method\": \"CRISPR/Cas9 VGLL4 knockdown hESCs, PiggyBac VGLL4 overexpression, Co-IP for VGLL4-TEAD1 interaction, luciferase reporter assay for TET2 promoter, VSMC differentiation assay\",\n      \"journal\": \"Journal of Molecular and Cellular Cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus luciferase reporter identifying TET2 as target, CRISPR KD and OE in stem cells, single lab\",\n      \"pmids\": [\"36657637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VGLL4 promotes vascular endothelial cell specification from hESCs by binding TEAD1 and facilitating expression of endothelial master transcription factor FLI1; TEAD1 overexpression rescues the inhibitory effects of VGLL4 knockdown on endothelial differentiation.\",\n      \"method\": \"Co-IP for VGLL4-TEAD1 interaction, inducible VGLL4 overexpression (PiggyBac), VGLL4 heterozygous knockout (CRISPR), 3D vascular organoids and 2D endothelial differentiation assays\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, gain- and loss-of-function, genetic rescue with TEAD1, single lab\",\n      \"pmids\": [\"37468661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VGLL4 forms a complex with TEAD4 and SMAD3 in chondrocytes to maintain extracellular matrix homeostasis; structural analysis defined that TEAD4 residues E263/D266/Q269/H427 bind SMAD3 residues K81/F260 via hydrogen bonds and hydrophobic contacts, while VGLL4 residues H240/F241 engage TEAD4 residues F337/F373 via π-stacking. VGLL4 deficiency causes ECM disorganization and osteoarthritis; interaction-deficient mutants lose therapeutic efficacy.\",\n      \"method\": \"Conditional KO mice (Col2-CreERT2;Vgll4fl/fl), structural interaction analysis, Co-IP, AAV-mediated gene delivery rescue, interaction-deficient mutants\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structural interaction mapping with specific residues, conditional KO with defined phenotype, mutant rescue, AAV functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"41125571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VGLL4 drives TEAD4 multimerization, which increases TEAD4 DNA residence time and promotes YAP recruitment to DNA-bound TEAD4. At low VGLL4:TEAD4 ratios, VGLL4 enhances YAP recruitment to DNA-bound TEAD4 multimers; at high VGLL4:TEAD4 ratios, VGLL4 inhibits YAP recruitment. Both YAP and VGLL4 can promote TEAD4 multimerization.\",\n      \"method\": \"Fluorescence-combined optical tweezers, single-molecule DNA binding assays, stoichiometry-dependent co-factor recruitment experiments\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted single-molecule optical tweezers assay with precise stoichiometric control, novel mechanistic finding with rigorous biophysical method\",\n      \"pmids\": [\"41965334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In zebrafish, Vgll4 restricts Tead-dependent transcription through two co-existing mechanisms: (1) competition with Yap1 for Tead binding (Yap1-dependent repression) and (2) Tead-dependent repression independent of Yap1. Loss- and gain-of-function epistasis experiments and transcriptional reporters confirmed both mechanisms operate in vivo.\",\n      \"method\": \"Loss- and gain-of-function in zebrafish posterior lateral line, genetic epistasis experiments, transcriptional reporter quantification, pharmacological treatments\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo epistasis in zebrafish with reporters, gain- and loss-of-function, pharmacological validation, multiple orthogonal approaches\",\n      \"pmids\": [\"42032219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SAMD4A/B RNA-binding proteins destabilize VGLL4 mRNA and repress its translation, thereby activating TEAD-dependent transcription. Inhibiting SAMD4A/B elevates VGLL4 mRNA levels, suppresses TEAD activity, and inhibits cancer progression. Liver-specific SAMD4B transgenic mice show accelerated intrahepatic cholangiocarcinoma development in Nf2-deficient background.\",\n      \"method\": \"Whole-genome siRNA screen, SAMD4A/B knockdown, RNA stability and translation assays, SAMD4B liver-specific transgenic mice with Nf2 knockout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen identification, RNA stability assay, in vivo transgenic mouse model, single lab\",\n      \"pmids\": [\"42014888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"VGLL4 forms a complex with TEAD4 and ATOH1 to stimulate GFI1 expression and promote Paneth cell differentiation; separately, VGLL4 forms a complex with TEAD4 and TCF4 to induce defensin expression, thereby maintaining intestinal microbiota composition and intestinal homeostasis.\",\n      \"method\": \"Intestinal epithelium-specific VGLL4 knockout mice, Co-IP for VGLL4-TEAD4-ATOH1 and VGLL4-TEAD4-TCF4 complexes, gene expression analysis, Paneth cell number quantification\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with defined phenotype, Co-IP for two distinct complexes, single lab\",\n      \"pmids\": [\"41629625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VGLL4 inhibits ubiquitination and proteasomal degradation of LDHA, increasing LDHA protein levels and lactate production in response to hypoxia. This neuroprotective mechanism reduces APP amyloidogenic processing. Sodium oxamate (LDHA inhibitor) blocks this neuroprotective function of VGLL4.\",\n      \"method\": \"VGLL4 overexpression in AD model cells, ubiquitination assay for LDHA, pharmacological inhibition with sodium oxamate, APP processing assay\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method for LDHA ubiquitination, limited mechanistic follow-up on interaction mechanism\",\n      \"pmids\": [\"37921465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP15 deubiquitinates VGLL4 via K48-linked ubiquitin chains, stabilizing VGLL4 protein. This USP15-mediated VGLL4 stabilization suppresses STAT3 activation and PD-L1 transcription. SART3 regulates VGLL4 stability by influencing the nuclear translocation of USP15.\",\n      \"method\": \"Co-IP, deubiquitination assay (K48-linkage specificity), STAT3 reporter, PD-L1 expression analysis, CD8+ T cell infiltration assays\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, K48-specific deubiquitination assay, functional downstream read-outs, single lab\",\n      \"pmids\": [\"38431034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Select sulfonamide TEAD lipid-pocket-binding small molecules promote TEAD interaction with VGLL4 (a cofactor switch from YAP to VGLL4), inducing chemically-driven VGLL4-TEAD complexes that repress pro-growth gene networks. Genetic deletion of VGLL4 causes resistance to these compounds in vitro and in vivo, demonstrating that VGLL4 is required for their anti-proliferative activity.\",\n      \"method\": \"Co-IP after compound treatment, chromatin assays, VGLL4 genetic deletion with compound resistance phenotype, in vitro and in vivo proliferation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic deletion resistance assay, in vivo validation, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VGLL4 containing intact TDU domains regulates classical brown adipose tissue (BAT) adipogenesis; deletion of TDU domains causes perinatal lethality and paucity of interscapular BAT. AAV-mediated brown adipocyte-specific VGLL4 overexpression increases BAT volume. Genomic studies indicate the VGLL4/TEAD1 complex directly regulates myogenic and adipogenic gene expression programs in BAT.\",\n      \"method\": \"TDU-domain deletion mouse mutant, histology, MRI, AAV-mediated overexpression, genomic/ChIP studies of VGLL4/TEAD1 complex\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific KO with defined phenotype, AAV rescue, ChIP genomic evidence, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"VGLL4 overexpression in human embryonic stem cells significantly decreases cell death in response to dissociation stress, enhances colony formation from single cells, and decreases activity of initiator and effector caspases. An interaction between VGLL4 and the Rho/ROCK pathway was identified in hESC survival context.\",\n      \"method\": \"Gain-of-function ORF screen, caspase activity assays, colony formation assays, Rho/ROCK pathway interaction experiments\",\n      \"journal\": \"Stem Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab gain-of-function screen, caspase assay and colony formation, Rho/ROCK interaction not fully characterized mechanistically\",\n      \"pmids\": [\"23765749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM6B (JMJD3) demethylase activity promotes VGLL4 expression in the hippocampus during LPS-induced neuroinflammation; KDM6B inhibition with GSK-J4 attenuates LPS-induced VGLL4, STAT3, IL-1β, and microglial activation. VGLL4 knockdown prevents LPS-induced anxiety-like behavior and STAT3/IL-1β upregulation, placing VGLL4 downstream of KDM6B in a neuroinflammatory pathway.\",\n      \"method\": \"KDM6B inhibitor (GSK-J4), adeno-associated virus-mediated Vgll4 shRNA knockdown, behavioral assays, western blotting\",\n      \"journal\": \"Behavioural Brain Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological inhibitor and AAV knockdown without direct biochemical KDM6B-VGLL4 promoter interaction validated\",\n      \"pmids\": [\"33865886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VGLL4 knockdown attenuates hypoxia-induced pulmonary hypertension and STAT3 signaling in mice; VGLL4 acetylation is enhanced by chronic normobaric hypoxia and increases interaction with ac-H3K9 and p-STAT3. Abrogation of VGLL4 acetylation reverses hypoxia-induced pulmonary arterial remodeling and suppresses STAT3 signaling.\",\n      \"method\": \"AAV-mediated VGLL4 knockdown/overexpression in mice, VGLL4 acetylation mutant, Co-IP for ac-H3K9/VGLL4/STAT3 interaction, immunoprecipitation, pulmonary hypertension model\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — acetylation mutant phenotype in vivo, Co-IP, in vivo mouse model, single lab\",\n      \"pmids\": [\"34314061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACSL4 reduces VGLL4 expression to promote NF-κB signal transduction in microglia; ACSL4 knockdown increases VGLL4 levels and decreases proinflammatory cytokine production, placing VGLL4 downstream of ACSL4 as a negative regulator of NF-κB signaling in microglial neuroinflammation.\",\n      \"method\": \"ACSL4 knockdown in microglia, VGLL4 expression measurement, NF-κB signaling assays, in vivo LPS and MPTP mouse models\",\n      \"journal\": \"Brain, Behavior, and Immunity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ACSL4 knockdown with indirect VGLL4 regulation inferred, no direct ACSL4-VGLL4 biochemical interaction shown\",\n      \"pmids\": [\"36791893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VGLL4 suppresses cardiomyocyte maturational hypertrophy by inhibiting the YAP/TAZ-TEAD complex and its downstream activation of the PI3K-AKT pathway; disrupting VGLL4-TEAD interaction abolishes this inhibition of PI3K-AKT.\",\n      \"method\": \"VGLL4 activation in neonatal rat ventricular myocytes and postnatal mouse heart, PI3K-AKT pathway measurements, VGLL4 interaction-disrupting mutant\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — interaction-disrupting mutant identifying PI3K-AKT as downstream pathway, in vitro and in vivo cardiac phenotype, single lab\",\n      \"pmids\": [\"39195232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FTO (m6A demethylase) reduces m6A modification levels on VGLL4 mRNA, leading to decreased VGLL4 expression and consequent activation of STAT3 signaling in triple-negative breast cancer. MeRIP assay confirmed VGLL4 as the target of FTO-mediated m6A modification.\",\n      \"method\": \"MeRIP (m6A-RNA immunoprecipitation), RNA immunoprecipitation, RNA stability assay, FTO overexpression/knockdown, STAT3 signaling readout\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP directly confirming m6A on VGLL4 mRNA, RNA stability assay, functional STAT3 readout, single lab\",\n      \"pmids\": [\"42264087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD4 directly binds RUNX2 to repress RUNX2-driven osteogenesis, and VGLL4 antagonizes this repression by disrupting TEAD4-RUNX2 interactions; Co-IP confirmed VGLL4 reduces TEAD4-RUNX2 binding, and VGLL4 knockdown diminishes osteoblast differentiation.\",\n      \"method\": \"Co-IP and proximity ligation assay (PLA) for TEAD4-RUNX2 interaction, VGLL4 knockdown in BMSCs, osteogenic differentiation assays, OVX rat model\",\n      \"journal\": \"Journal of Ethnopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and PLA for interaction disruption, single lab, indirect pharmacological context\",\n      \"pmids\": [\"39142621\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VGLL4 is an intrinsically disordered transcriptional co-repressor that primarily acts by directly competing with YAP for binding to TEAD1-4 transcription factors via its tandem Tondu (TDU) domains, thereby suppressing YAP-TEAD target gene transcription; it also functions as a co-activator or adaptor in multi-protein complexes (e.g., TEAD4-VGLL4-CtBP2, VGLL4-TEAD1-MENIN, VGLL4-TEAD4-SMAD3, VGLL4-TEAD4-TCF4) that regulate adipogenesis, β-cell proliferation, cartilage homeostasis, and Wnt signaling, while its activity is post-translationally regulated by CDK1-mediated phosphorylation (inhibitory), acetylation at K225 (inhibitory for TEAD binding), and deubiquitination by USP11/USP15 (stabilizing), with SAMD4A/B and FTO acting as upstream regulators of VGLL4 mRNA stability and m6A modification respectively.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VGLL4 is an intrinsically disordered transcriptional co-factor that governs TEAD-dependent transcription, acting principally as a repressor by competing with YAP for binding to TEAD1-4 through its tandem Tondu (TDU) domains, which are necessary and sufficient for its inhibitory activity and which form the basis of a peptide that suppresses tumor growth [#0, #1, #12]. Biophysical reconstitution shows VGLL4 carries two TEAD-binding sites of differing affinity and forms dimeric complexes with TEAD4, and that its action is stoichiometry-dependent: by driving TEAD4 multimerization VGLL4 enhances YAP recruitment to DNA-bound TEAD at low VGLL4:TEAD ratios but inhibits it at high ratios [#12, #18]. Genetic epistasis establishes that the major physiological role of YAP is to antagonize VGLL4, since Vgll4 inactivation bypasses the requirement for YAP in liver and lung development [#11]. Beyond simple competition, VGLL4 nucleates distinct TEAD4-containing multiprotein complexes that repress or activate specific programs — a TEAD4-VGLL4-CtBP2 complex represses adipogenic PPARγ/Adipoq promoters [#6], a TEAD4-VGLL4-SMAD3 complex maintains chondrocyte extracellular matrix homeostasis with osteoarthritis arising upon loss [#17], a VGLL4-TEAD1-MENIN complex restrains β-cell proliferation [#13], and VGLL4-TEAD4-ATOH1 and VGLL4-TEAD4-TCF4 complexes drive Paneth cell differentiation and defensin expression in the intestine [#21]; it can also act as a TEAD4 co-activator, stabilizing MyoD-TEAD4 to promote MyoG transactivation during muscle differentiation [#10]. VGLL4 additionally suppresses Wnt/β-catenin signaling by disrupting a TEAD4-TCF4 complex [#2] and is required for heart valve and cardiomyocyte development through restraint of YAP targets [#9, #3]. VGLL4 abundance and activity are tightly controlled: CDK1 phosphorylation and K225 acetylation inhibit TEAD binding [#5, #3], deubiquitination by USP11 and USP15 stabilizes the protein [#4, #23], and SAMD4A/B and FTO regulate VGLL4 mRNA stability and m6A modification [#20, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing how VGLL4 opposes YAP defined the core mechanism: it answered whether VGLL4 is a passive bystander or an active competitor for the oncogenic transcriptional output of the Hippo pathway.\",\n      \"evidence\": \"Co-IP, competitive binding assays, domain deletion/mutagenesis, and a TDU-mimicking peptide tested in tumor models\",\n      \"pmids\": [\"24525233\", \"24458094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve binding stoichiometry or affinity differences between the two TDU sites\", \"Did not address VGLL4's roles outside competition\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of inhibitory acetylation at K225 and TEAD1 destabilization showed VGLL4 activity is post-translationally tuned and that it can deplete TEAD1 protein, not only block its complex.\",\n      \"evidence\": \"Mass spectrometry PTM mapping, K225R acetylation-refractory mutant, Co-IP, and neonatal mouse heart proliferation assays\",\n      \"pmids\": [\"27720608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase/deacetylase responsible for K225 not identified\", \"Mechanism linking VGLL4 to TEAD1 proteasomal degradation unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"USP11-mediated deubiquitination revealed that VGLL4 protein levels are set by regulated turnover, linking its tumor-suppressive dosage to the ubiquitin system.\",\n      \"evidence\": \"Co-IP, domain mapping, deubiquitination assay, and USP11 knockdown with YAP-dependent growth rescue\",\n      \"pmids\": [\"28042509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase that ubiquitinates VGLL4 not identified\", \"Single lab, ubiquitin linkage type not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that VGLL4 disrupts a TEAD4-TCF4 complex and that CDK1 phosphorylates VGLL4 broadened its reach beyond YAP, coupling it to Wnt signaling and to mitotic kinase control.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays, mouse CRC model (TCF4); in vitro kinase assay and phosphomutant VGLL4-4A binding/tumor assays (CDK1)\",\n      \"pmids\": [\"28051067\", \"28739871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same VGLL4 pool simultaneously engages TEAD-YAP and TEAD-TCF4 is unclear\", \"Physiological trigger for CDK1 phosphorylation of VGLL4 outside mitosis not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"VGLL4 was shown to act as a positive adaptor in defined ternary complexes (TEAD4-CtBP2) and to stabilize partner proteins (IRF2BP2), redefining it as more than a competitive repressor.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP on PPARγ/Adipoq promoters in preadipocytes; Co-IP, proteasome inhibition, and Vgll4-knockout syngeneic tumor/PD-L1 models\",\n      \"pmids\": [\"30209132\", \"30396996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How VGLL4 switches between repressive competition and adaptor/stabilizer roles unresolved\", \"Direct structural basis of the ternary complexes not defined here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"In vivo conditional knockouts and dual-role analyses placed VGLL4 upstream of YAP targets in tissue development and revealed YAP-independent co-activator functions.\",\n      \"evidence\": \"Endothelial-specific Vgll4 KO with YAP genetic epistasis in valve development; Vgll4 KO with MyoD-TEAD4 Co-IP in muscle regeneration; CRISPR zebrafish vgll4b KO mapping IRF2BP2 sequestration\",\n      \"pmids\": [\"30789911\", \"31328806\", \"31539803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants that select repressive versus co-activator outcome in different tissues not defined\", \"Mechanism of context-specific partner choice unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Biophysical reconstitution established VGLL4 as an intrinsically disordered protein with two TEAD-binding sites of distinct affinity, providing a physical model for dimeric and bridging modes of engagement.\",\n      \"evidence\": \"Surface plasmon resonance, size-exclusion chromatography, and intrinsic disorder characterization of full-length VGLL4 and Drosophila Tgi\",\n      \"pmids\": [\"34075638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell relevance of the bridging mode not established\", \"How disorder relates to PTM-based regulation not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Antagonistic genetic epistasis demonstrated that VGLL4 is the principal physiological effector opposed by YAP, since Vgll4 loss rescues YAP-null lethality in liver and lung.\",\n      \"evidence\": \"Vgll4 KO rescue of YAP-null developmental lethality, Nf2/Vgll4 double-knockout tumor model, CCl4 liver injury in mice\",\n      \"pmids\": [\"36522128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissues where VGLL4 is not the dominant TEAD repressor not delineated\", \"Quantitative contribution of competition versus other complexes in vivo unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple studies expanded VGLL4's TEAD-partnered complexes (MENIN, TET2, FLI1) and identified additional regulatory inputs (USP15 deubiquitination), connecting it to β-cell proliferation, vascular cell specification, and immune evasion.\",\n      \"evidence\": \"β-cell-specific KO with split-GFP/Y2H interaction assays; Co-IP and reporter assays in hESC-derived VSMC and endothelial differentiation; K48-specific deubiquitination assay for USP15-VGLL4\",\n      \"pmids\": [\"36662616\", \"36657637\", \"37468661\", \"38431034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VGLL4 directly or indirectly activates TET2/FLI1 not fully resolved\", \"USP15 findings from single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Single-molecule biophysics resolved the stoichiometry-dependent dual behavior of VGLL4, showing it drives TEAD4 multimerization that can either enhance or inhibit YAP recruitment depending on ratio.\",\n      \"evidence\": \"Fluorescence-combined optical tweezers and single-molecule DNA-binding assays with controlled VGLL4:TEAD4 stoichiometry\",\n      \"pmids\": [\"41965334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular concentrations that set the switch point not measured in vivo\", \"Whether PTMs shift the stoichiometric threshold not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Structural mapping of a TEAD4-VGLL4-SMAD3 chondrocyte complex with defined interface residues, plus mutant-rescue, established a specific therapeutic mechanism in cartilage homeostasis and osteoarthritis.\",\n      \"evidence\": \"Col2-CreERT2;Vgll4fl/fl conditional KO, structural interface analysis, Co-IP, interaction-deficient mutants, and AAV rescue\",\n      \"pmids\": [\"41125571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the SMAD3-bridging mechanism to other tissues unknown\", \"How VGLL4 selects SMAD3 over other partners not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Upstream RNA-level regulation (SAMD4A/B, FTO) and in vivo dual-mechanism dissection in zebrafish defined how VGLL4 abundance is set and confirmed both YAP-dependent and YAP-independent TEAD repression operate together.\",\n      \"evidence\": \"Genome-wide siRNA screen with RNA stability assays and SAMD4B transgenic mice; MeRIP m6A mapping with FTO manipulation; zebrafish loss/gain-of-function epistasis with transcriptional reporters; intestinal-specific KO with Co-IP of ATOH1/TCF4 complexes\",\n      \"pmids\": [\"42014888\", \"42264087\", \"42032219\", \"41629625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration of multiple upstream RNA regulators into a single dosage model lacking\", \"Relative in vivo weight of YAP-dependent versus independent repression not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how VGLL4's many context-specific complex assemblies and post-translational/RNA-level regulatory inputs are integrated into a unified rule that determines, in a given cell, whether VGLL4 represses or activates TEAD-dependent transcription.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking stoichiometry, PTM state, and partner availability to functional output\", \"Endogenous VGLL4 concentration and complex occupancy across tissues unmeasured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 6, 10, 13, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 12, 18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 10, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 6, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 11, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 6, 13, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 10, 16, 25]}\n    ],\n    \"complexes\": [\n      \"TEAD4-VGLL4-CtBP2\",\n      \"VGLL4-TEAD1-MENIN\",\n      \"TEAD4-VGLL4-SMAD3\",\n      \"VGLL4-TEAD4-TCF4\"\n    ],\n    \"partners\": [\n      \"TEAD1\",\n      \"TEAD4\",\n      \"YAP1\",\n      \"CtBP2\",\n      \"IRF2BP2\",\n      \"SMAD3\",\n      \"USP11\",\n      \"USP15\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}