{"gene":"VGLL3","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2010,"finding":"VGLL3 is a cofactor for TEAD family transcription factors; its genomic amplification in soft tissue sarcomas correlates with overexpression, and siRNA-mediated inhibition of VGLL3 decreases proliferation rate and migration properties in cell lines harboring the amplification.","method":"Array-CGH, transcriptome analysis, siRNA knockdown with proliferation and migration assays","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, but single lab","pmids":["20842732"],"is_preprint":false},{"year":2016,"finding":"VGLL3 acts as a transcription cofactor with female-biased expression that regulates a genome-wide network of genes associated with autoimmune diseases including lupus, scleroderma and Sjögren's syndrome; this regulation is independent of sex-hormone pathways.","method":"High-resolution global transcriptome analysis, co-expression network analysis, genome-wide VGLL3 target gene mapping","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genomic methods, replicated across disease contexts, highly cited","pmids":["27992404"],"is_preprint":false},{"year":2019,"finding":"VGLL3 binds TEAD1, TEAD3, and TEAD4 in myoblasts and/or myotubes (shown by interaction proteomics), does not interact with Hippo kinase cascade components (unlike YAP/TAZ), and overexpression promotes myogenic differentiation while siRNA-mediated knockdown suppresses myoblast proliferation; VGLL3 mainly represses gene expression including Myf5, Pitx2, Pitx3, and certain Wnts and IGFBPs.","method":"Interaction proteomics (co-IP/MS), siRNA knockdown, overexpression with gene expression profiling, Vgll3-null mouse analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction proteomics + KD/KO + OE with multiple phenotypic readouts, moderate evidence","pmids":["31138678"],"is_preprint":false},{"year":2019,"finding":"Skin-directed overexpression of murine VGLL3 drives a lupus-like systemic autoimmune disease with B cell expansion, autoantibody production, immune complex deposition, and end-organ damage; excess epidermal VGLL3 induces BAFF, IFN-κ, and CXCL13 expression.","method":"Transgenic mouse overexpression model, gene expression profiling, histopathology, immunological assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic gain-of-function with defined molecular and phenotypic readouts, multiple orthogonal methods","pmids":["30996136"],"is_preprint":false},{"year":2020,"finding":"VGLL3 promotes cancer cell proliferation by activating the Hippo pathway: VGLL3 together with TEADs induces expression of LATS2 and AMOTL2, leading to YAP and TAZ inactivation; VGLL3 knockdown increases nuclear localization of YAP and TAZ.","method":"Stable overexpression cell lines, knockdown experiments, Western blot for Hippo pathway components, nuclear localization assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD/OE with pathway placement and mechanistic follow-up, single lab","pmids":["32385107"],"is_preprint":false},{"year":2020,"finding":"VGLL3 mediates cellular stress response by upregulating p53 and IL-17C; energy stress allows VGLL3 to be induced by IFNα, which leads to p53-dependent inflammatory cell death.","method":"Cell-based assays with IFNα stimulation, energy stress conditions, gene expression and cell death readouts","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic follow-up in single lab with defined pathway placement","pmids":["32803756"],"is_preprint":false},{"year":2021,"finding":"VGLL3 promotes NF-κB activation by inducing expression and secretion of IL-1α, likely through its association with TEADs; TGF-β stimulation induces VGLL3 expression via Smad3 and Smad4, which then drives IL-1α secretion and NF-κB activation.","method":"Stable VGLL3-expressing cell lines, NF-κB reporter assays, cytokine measurement, TGF-β stimulation, Smad knockdown","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (reporter assay, KD, ligand stimulation) in single lab","pmids":["34679187"],"is_preprint":false},{"year":2022,"finding":"VGLL3 induces expression of GART (a trifunctional enzyme catalyzing de novo purine synthesis from glutamine), increasing cancer cell dependency on de novo nucleotide synthesis; VGLL3 knockdown reduces GART expression and GART inhibitor lometrexol suppresses proliferation of VGLL3-expressing cells.","method":"Stable VGLL3 overexpression, siRNA knockdown, pharmacological inhibition (lometrexol), metabolite rescue experiments, gene expression analysis","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — KD/OE with rescue experiment and pharmacological validation, single lab","pmids":["35434822"],"is_preprint":false},{"year":2022,"finding":"VGLL3 forms a transcriptional complex with TEAD1 and RUNX1/3 to drive expression of PD-L1 and PD-L2; loss of VGLL3 impairs IFN-γ-induced PD-L1/2 expression in human keratinocytes.","method":"Genome-wide CRISPR activation screening, secondary screen for VGLL3-interacting partners, loss-of-function (VGLL3 KO) with PD-L1/2 expression readout","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — unbiased genome-wide screen plus secondary screen to define complex, validated by KO, moderate evidence","pmids":["35922063"],"is_preprint":false},{"year":2022,"finding":"VGLL3 promotes the IRF3-IFN-β1 axis in rheumatoid arthritis fibroblast-like synoviocytes by inhibiting WWTR1 (TAZ) expression, leading to IRF3 activation; the resulting IFN-β1 drives type I IFN signature in an autocrine manner, and VGLL3 modulates AMOTL2 expression as part of this mechanism.","method":"VGLL3 overexpression in RA-FLS, RNA sequencing, Western blotting for STAT1/MX1/IRF3, siRNA knockdown of WWTR1/AMOTL2","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — OE with downstream pathway dissection using KD of mediators, single lab","pmids":["35941675"],"is_preprint":false},{"year":2023,"finding":"VGLL3 is specifically expressed in myofibroblasts from fibrotic hearts and promotes collagen production; substrate stiffness triggers VGLL3 nuclear translocation via the integrin β1-Rho-actin pathway; in the nucleus, VGLL3 undergoes liquid-liquid phase separation via its low-complexity domain and is incorporated into non-paraspeckle NONO condensates containing EWSR1; VGLL3 binds EWSR1 and suppresses miR-29b, which targets collagen mRNA; cardiac fibrosis after myocardial infarction is attenuated in Vgll3-deficient mice with increased miR-29b expression.","method":"Mouse and human tissue analysis, Vgll3-KO mouse MI model, live-cell imaging of phase separation, FRAP, co-IP (VGLL3-EWSR1), integrin β1/Rho/actin pathway perturbation, miR-29b measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including KO mouse, reconstitution of phase separation, Co-IP, pathway perturbation, in vivo fibrosis readout","pmids":["36754961"],"is_preprint":false},{"year":2023,"finding":"VGLL3 expression in C2C12 myocytes promotes slow-twitch muscle fiber differentiation by inducing PGC-1α expression; VGLL3 proteins are degraded by the proteasome, causing switching of TEAD cofactors from VGLL3 to YAP/TAZ, thereby controlling muscle fiber-type specification.","method":"Stable VGLL3-expressing C2C12 cell line, gene expression analysis, proteasome inhibitor experiments, fiber-type marker analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — stable OE with proteasome inhibition and mechanistic follow-up, single lab","pmids":["37262950"],"is_preprint":false},{"year":2024,"finding":"VGLL3 plays a role in DNA damage response distinct from its transcriptional cofactor function: VGLL3 is recruited to DNA damage sites in a PARylation-dependent manner; VGLL3 prevents CtIP from KLHL15-mediated ubiquitination and degradation via competitive binding with KLHL15; VGLL3 stabilizes MDC1 by limiting TRIP12-MDC1 but promoting USP7-MDC1 interactions, enabling optimal RNF8 signaling and homologous recombination; VGLL3 depletion reduces RAD51 accumulation at damage sites and sensitizes cells and xenografts to chemotherapeutic drugs.","method":"VGLL3 depletion (siRNA/KO), live-cell imaging of DNA damage recruitment, PARylation-dependent recruitment assays, Co-IP (VGLL3-KLHL15, VGLL3-MDC1, TRIP12-MDC1, USP7-MDC1), HR efficiency assays, xenograft tumor model with etoposide treatment","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods (Co-IP, in vivo ubiquitination, HR assay), in vivo xenograft validation, mechanistic dissection of two independent pathways","pmids":["39383226"],"is_preprint":false},{"year":2024,"finding":"HERC6, an IFN-induced E3 ubiquitin ligase, modulates LATS2 and TBK1 activity, and the enhanced female-biased immune response observed upon HERC6 loss depends on VGLL3, positioning VGLL3 downstream of HERC6-LATS2 signaling in the type I IFN pathway.","method":"HERC6 siRNA knockdown in keratinocytes, cGAMP stimulation, ISG measurement, epistasis via VGLL3 depletion","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis (HERC6 KD + VGLL3 depletion) with defined signaling pathway placement, single lab","pmids":["38327798"],"is_preprint":false},{"year":2024,"finding":"The TEAD-binding domain of VGLL3 contains a conserved Tondu motif; structural analysis reveals that VGLL3 (unlike VGLL2) lacks a functional Ω-loop in most vertebrate species, suggesting different binding mode to TEAD compared to VGLL2 and YAP; sequence variants with altered TEAD-binding domains in mammalian VGLL2/VGLL3 may confer different biological functions.","method":"Comparative sequence analysis of >2400 putative VGLL proteins using available structural data","journal":"Archives of biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 4 — computational/structural inference without direct functional validation in this study","pmids":["39182750"],"is_preprint":false},{"year":2025,"finding":"VGLL3 is upregulated in preeclamptic placentas, promotes immune activation, impairs trophoblast differentiation, and induces endothelial dysfunction; VGLL3 acts upstream of sFLT1 production; genetic deletion of VGLL3 in mouse placentas or therapeutic inhibition in human placentas protects against preeclampsia.","method":"Human single-cell and spatial transcriptomics, in vitro trophoblast/endothelial assays, in vivo Vgll3 placenta-specific KO mouse model, ex vivo human placenta inhibition","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal models (human single-cell, in vitro, in vivo KO, ex vivo), defined upstream role with sFLT1 as molecular readout","pmids":["41953989"],"is_preprint":false},{"year":2026,"finding":"YAP/TAZ repress adipogenic enhancers (reducing H3K27ac at PPARγ-bound target enhancers) through TEAD-dependent transcriptional activity; Vgll3 is identified as a transcriptional target of TAZ critical for repressing adipogenic enhancers, placing VGLL3 downstream of TAZ in the YAP/TAZ-VGLL3 axis that controls adipocyte fate.","method":"ChIP-seq (H3K27ac), single-nucleus multi-omics of mouse adipose tissue, TAZ overexpression/KO, TEAD binding domain mutants, Vgll3 KO validation","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-seq + single-nucleus genomics + genetic KO with epistasis, multiple orthogonal methods","pmids":["41533786"],"is_preprint":false},{"year":2025,"finding":"VGLL3 promotes glycolysis and collagen production in keloid fibroblasts via activation of the Wnt/β-catenin signaling pathway through WNT2; VGLL3 overexpression increases WNT2 and β-catenin protein levels and silencing WNT2 reverses VGLL3-driven effects on proliferation, collagen production, and glycolysis.","method":"VGLL3 OE/KD in keloid fibroblasts, Western blot for Wnt pathway components, OCR/ECAR measurement, WNT2 siRNA rescue experiments","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — OE/KD with rescue experiment defining pathway, single lab","pmids":["39826675"],"is_preprint":false}],"current_model":"VGLL3 is a transcriptional cofactor that binds TEAD1, TEAD3, and TEAD4 via its Tondu motif to regulate gene expression in multiple contexts: it activates the Hippo negative-feedback loop (inducing LATS2 and AMOTL2 to suppress YAP/TAZ), promotes inflammation by driving IL-1α secretion and NF-κB activation and forming a TEAD1-RUNX1/3 complex to upregulate PD-L1/2, drives female-biased autoimmunity through a proinflammatory gene network, promotes fibrosis by translocating to the nucleus via an integrin β1-Rho-actin pathway in response to substrate stiffness, undergoing liquid-liquid phase separation via its low-complexity domain in NONO/EWSR1 condensates to suppress miR-29b and increase collagen production; independently of its transcriptional role, VGLL3 participates in DNA damage response by stabilizing CtIP (blocking KLHL15-mediated ubiquitination) and MDC1 (promoting USP7-MDC1 while limiting TRIP12-MDC1) to enable RNF8 signaling and homologous recombination, and it is positioned downstream of TAZ in the YAP/TAZ-VGLL3 axis that represses adipogenic enhancers."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing that VGLL3 is a TEAD cofactor relevant to cancer cell proliferation answered the basic question of its molecular identity and showed that its amplification in soft tissue sarcomas has functional consequences.","evidence":"Array-CGH, siRNA knockdown with proliferation/migration assays in sarcoma cell lines","pmids":["20842732"],"confidence":"Medium","gaps":["No direct TEAD binding demonstrated","Mechanism of proliferation/migration control undefined","Single cancer type studied"]},{"year":2016,"claim":"Identifying VGLL3 as a female-biased transcription cofactor driving autoimmune-associated gene networks revealed a sex-dimorphic, hormone-independent mechanism for autoimmune susceptibility.","evidence":"Global transcriptome analysis and genome-wide VGLL3 target gene mapping across autoimmune disease contexts","pmids":["27992404"],"confidence":"High","gaps":["Downstream effector mechanisms not defined","Causal role in autoimmune disease not yet demonstrated in vivo"]},{"year":2019,"claim":"Interaction proteomics defined TEAD1/3/4 as direct VGLL3 partners in myoblasts and showed VGLL3 mainly represses transcription, establishing its role in myogenic differentiation distinct from YAP/TAZ signaling.","evidence":"Co-IP/mass spectrometry, siRNA knockdown, overexpression with gene expression profiling, Vgll3-null mouse in myoblasts/myotubes","pmids":["31138678"],"confidence":"High","gaps":["Structural basis of VGLL3–TEAD interaction not resolved","Mechanism of transcriptional repression unknown"]},{"year":2019,"claim":"In vivo gain-of-function demonstrated that epidermal VGLL3 overexpression is sufficient to drive systemic lupus-like autoimmunity, causally linking VGLL3 to autoimmune disease through BAFF, IFN-κ, and CXCL13 induction.","evidence":"Transgenic mouse with skin-directed VGLL3 overexpression, immunological and histopathological characterization","pmids":["30996136"],"confidence":"High","gaps":["Precise TEAD-dependent versus TEAD-independent contributions unclear","Human disease causality not established"]},{"year":2020,"claim":"Defining VGLL3 as an activator of the Hippo negative-feedback loop (via LATS2/AMOTL2 induction and consequent YAP/TAZ inactivation) resolved how VGLL3 and YAP/TAZ exert opposing effects despite sharing TEAD partners.","evidence":"Stable overexpression and knockdown with Western blot for Hippo pathway components and YAP/TAZ nuclear localization assays","pmids":["32385107"],"confidence":"Medium","gaps":["Context-dependency across cell types not explored","Whether VGLL3 directly competes with YAP/TAZ for TEAD binding not tested biochemically"]},{"year":2020,"claim":"Linking VGLL3 to the IFNα–p53–IL-17C stress response axis under energy stress conditions extended its function beyond steady-state transcription to cellular stress sensing.","evidence":"Cell-based assays with IFNα stimulation under energy stress, gene expression and cell death readouts","pmids":["32803756"],"confidence":"Medium","gaps":["Mechanism of energy-stress-dependent VGLL3 induction not defined","Not confirmed in vivo"]},{"year":2021,"claim":"Demonstrating that TGF-β/Smad3/4 induces VGLL3, which then drives IL-1α secretion and NF-κB activation, placed VGLL3 as a signal integrator connecting TGF-β to inflammatory NF-κB signaling.","evidence":"VGLL3-expressing cell lines, NF-κB reporter assays, TGF-β stimulation, Smad knockdown","pmids":["34679187"],"confidence":"Medium","gaps":["Whether VGLL3 directly regulates IL-1α transcription via TEAD sites not shown","In vivo relevance not tested"]},{"year":2022,"claim":"Unbiased CRISPR screens identified a VGLL3–TEAD1–RUNX1/3 complex driving PD-L1/PD-L2 expression, defining a specific immune checkpoint regulatory mechanism and expanding the repertoire of VGLL3 partner transcription factors beyond TEADs alone.","evidence":"Genome-wide CRISPR activation screen, secondary partner screen, VGLL3 KO with PD-L1/2 readout in keratinocytes","pmids":["35922063"],"confidence":"High","gaps":["In vivo immune evasion consequences not tested","Structural basis of TEAD1–RUNX1/3–VGLL3 ternary complex unknown"]},{"year":2022,"claim":"Placing VGLL3 as an inhibitor of WWTR1/TAZ to activate the IRF3–IFN-β1 axis in rheumatoid arthritis synoviocytes clarified how VGLL3 amplifies type I IFN signaling in autoimmune contexts.","evidence":"VGLL3 overexpression in RA-FLS, RNA-seq, siRNA knockdown of WWTR1/AMOTL2","pmids":["35941675"],"confidence":"Medium","gaps":["Direct VGLL3-TAZ inhibitory mechanism not defined","Single disease tissue context"]},{"year":2023,"claim":"Demonstrating that substrate stiffness drives integrin β1–Rho–actin-dependent VGLL3 nuclear translocation, where VGLL3 undergoes LLPS in NONO/EWSR1 condensates to suppress miR-29b and promote collagen production, revealed a mechanosensitive phase-separation mechanism for fibrosis; Vgll3-KO mice showed reduced cardiac fibrosis after MI.","evidence":"Vgll3-KO mouse MI model, live-cell imaging/FRAP of phase separation, co-IP of VGLL3–EWSR1, integrin β1/Rho/actin pathway perturbation","pmids":["36754961"],"confidence":"High","gaps":["Whether LLPS is required (vs. correlative) for collagen regulation not tested by phase-separation-deficient mutant rescue","How VGLL3–EWSR1 condensates suppress miR-29b transcription mechanistically unclear"]},{"year":2023,"claim":"Showing that VGLL3 promotes slow-twitch muscle fiber specification by inducing PGC-1α—and that proteasomal VGLL3 degradation switches TEAD cofactors from VGLL3 to YAP/TAZ—established a dynamic competition model governing muscle fiber-type identity.","evidence":"Stable VGLL3-expressing C2C12 myocytes, proteasome inhibitor experiments, fiber-type marker analysis","pmids":["37262950"],"confidence":"Medium","gaps":["Ubiquitin ligase responsible for VGLL3 degradation not identified","Not validated in primary muscle or in vivo"]},{"year":2024,"claim":"Discovering PARylation-dependent recruitment of VGLL3 to DNA damage sites, where it stabilizes CtIP (blocking KLHL15-mediated degradation) and MDC1 (promoting USP7 while limiting TRIP12), established a transcription-independent role for VGLL3 in homologous recombination and DNA damage response.","evidence":"siRNA/KO depletion, live-cell imaging of DNA damage recruitment, co-IP of VGLL3 with KLHL15/MDC1/TRIP12/USP7, HR efficiency assays, xenograft model with etoposide","pmids":["39383226"],"confidence":"High","gaps":["Whether TEAD binding and DDR functions are structurally separable not tested with separation-of-function mutants","PAR-binding domain in VGLL3 not mapped"]},{"year":2024,"claim":"Genetic epistasis positioned VGLL3 downstream of HERC6–LATS2 signaling, linking IFN-induced ubiquitin ligase activity to VGLL3-driven female-biased immune responses.","evidence":"HERC6 siRNA in keratinocytes, cGAMP stimulation, rescue by VGLL3 depletion","pmids":["38327798"],"confidence":"Medium","gaps":["Whether HERC6 directly modifies VGLL3 or acts indirectly via LATS2 not distinguished","Single cell type"]},{"year":2024,"claim":"Comparative structural analysis revealed that VGLL3 lacks a functional Ω-loop in its Tondu/TEAD-binding domain (unlike VGLL2), suggesting a distinct TEAD-binding mode.","evidence":"Computational sequence analysis of >2400 VGLL proteins using available structural data","pmids":["39182750"],"confidence":"Low","gaps":["No direct structural or biochemical validation of the proposed binding mode difference","Functional consequences of Ω-loop absence not tested experimentally"]},{"year":2025,"claim":"Identifying VGLL3 as upregulated in preeclamptic placentas and demonstrating that placenta-specific Vgll3 deletion protects against preeclampsia in mice established VGLL3 as a driver of placental immune activation, impaired trophoblast differentiation, and endothelial dysfunction upstream of sFLT1.","evidence":"Human single-cell/spatial transcriptomics, in vitro trophoblast/endothelial assays, placenta-specific Vgll3 KO mouse, ex vivo human placenta inhibition","pmids":["41953989"],"confidence":"High","gaps":["Therapeutic modality for VGLL3 inhibition not defined","TEAD dependence of placental VGLL3 function not confirmed"]},{"year":2025,"claim":"Demonstrating that VGLL3 activates Wnt/β-catenin signaling through WNT2 in keloid fibroblasts linked VGLL3 to glycolysis-driven fibrosis and expanded its pro-fibrotic role beyond the miR-29b/collagen axis.","evidence":"VGLL3 OE/KD in keloid fibroblasts, WNT2 siRNA rescue, ECAR/OCR metabolic assays","pmids":["39826675"],"confidence":"Medium","gaps":["Whether VGLL3 directly activates WNT2 transcription via TEAD binding not shown","Relationship between Wnt and miR-29b fibrotic pathways downstream of VGLL3 not explored"]},{"year":2026,"claim":"ChIP-seq and single-nucleus multi-omics placed VGLL3 as a transcriptional target of TAZ that represses adipogenic enhancers, defining the YAP/TAZ→VGLL3 axis controlling adipocyte fate.","evidence":"ChIP-seq for H3K27ac, single-nucleus multi-omics of mouse adipose, TAZ OE/KO, TEAD-binding mutants, Vgll3 KO validation","pmids":["41533786"],"confidence":"High","gaps":["Direct VGLL3 ChIP at adipogenic enhancers not performed","Whether VGLL3 represses these enhancers through TEAD or other cofactors is inferred but not definitively shown"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of VGLL3–TEAD interaction and how it differs from YAP/TAZ–TEAD, whether the transcriptional and DDR functions are mediated by separable domains, the identity of the E3 ligase controlling VGLL3 proteasomal turnover, and whether VGLL3-driven autoimmunity is therapeutically targetable.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of VGLL3–TEAD complex","Separation-of-function mutants distinguishing transcriptional from DDR roles not generated","E3 ligase for VGLL3 degradation unknown","No pharmacological VGLL3 inhibitor reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,4,8,10,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,9,13,16,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,3,5,8,13,15]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,8,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,11,16]}],"complexes":["VGLL3–TEAD1–RUNX1/3","NONO/EWSR1 condensate"],"partners":["TEAD1","TEAD3","TEAD4","RUNX1","EWSR1","NONO","MDC1","KLHL15"],"other_free_text":[]},"mechanistic_narrative":"VGLL3 is a transcriptional cofactor that partners with TEAD family transcription factors to regulate gene expression programs controlling inflammation, fibrosis, myogenesis, adipogenesis, and immune checkpoint signaling. VGLL3 binds TEAD1, TEAD3, and TEAD4 via a conserved Tondu motif and activates a Hippo pathway negative-feedback loop by inducing LATS2 and AMOTL2, thereby inactivating YAP/TAZ [PMID:32385107, PMID:31138678]; it also forms a TEAD1–RUNX1/3 complex to drive PD-L1/PD-L2 expression [PMID:35922063], promotes NF-κB activation through IL-1α secretion downstream of TGF-β/Smad signaling [PMID:34679187], drives female-biased autoimmune gene networks and lupus-like disease when overexpressed in skin [PMID:27992404, PMID:30996136], and promotes cardiac and keloid fibrosis through mechanosensitive nuclear translocation, liquid–liquid phase separation with NONO/EWSR1 condensates, and suppression of miR-29b [PMID:36754961, PMID:39826675]. Independent of its transcriptional role, VGLL3 is recruited to DNA damage sites in a PARylation-dependent manner where it stabilizes CtIP (by blocking KLHL15-mediated ubiquitination) and MDC1 (by promoting USP7–MDC1 interaction while limiting TRIP12–MDC1), enabling RNF8 signaling and homologous recombination [PMID:39383226]."},"prefetch_data":{"uniprot":{"accession":"A8MV65","full_name":"Transcription cofactor vestigial-like protein 3","aliases":[],"length_aa":326,"mass_kda":36.0,"function":"May act as a specific coactivator for the mammalian TEFs","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/A8MV65/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VGLL3","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VGLL3","total_profiled":1310},"omim":[{"mim_id":"609980","title":"VESTIGIAL-LIKE 3; VGLL3","url":"https://www.omim.org/entry/609980"},{"mim_id":"189967","title":"TEA DOMAIN FAMILY MEMBER 1; TEAD1","url":"https://www.omim.org/entry/189967"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":37.7}],"url":"https://www.proteinatlas.org/search/VGLL3"},"hgnc":{"alias_symbol":["VGL-3"],"prev_symbol":[]},"alphafold":{"accession":"A8MV65","domains":[{"cath_id":"-","chopping":"80-111","consensus_level":"medium","plddt":93.6922,"start":80,"end":111}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A8MV65","model_url":"https://alphafold.ebi.ac.uk/files/AF-A8MV65-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A8MV65-F1-predicted_aligned_error_v6.png","plddt_mean":55.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VGLL3","jax_strain_url":"https://www.jax.org/strain/search?query=VGLL3"},"sequence":{"accession":"A8MV65","fasta_url":"https://rest.uniprot.org/uniprotkb/A8MV65.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A8MV65/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A8MV65"}},"corpus_meta":[{"pmid":"26551894","id":"PMC_26551894","title":"The vgll3 Locus Controls Age at Maturity in Wild and Domesticated Atlantic Salmon (Salmo salar L.) Males.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26551894","citation_count":125,"is_preprint":false},{"pmid":"32814879","id":"PMC_32814879","title":"CircRNA-vgll3 promotes osteogenic differentiation of adipose-derived mesenchymal stem cells via modulating miRNA-dependent integrin α5 expression.","date":"2020","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/32814879","citation_count":119,"is_preprint":false},{"pmid":"27992404","id":"PMC_27992404","title":"A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases.","date":"2016","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27992404","citation_count":104,"is_preprint":false},{"pmid":"20842732","id":"PMC_20842732","title":"YAP1 and VGLL3, encoding two cofactors of TEAD transcription factors, are amplified and overexpressed in a subset of soft tissue sarcomas.","date":"2010","source":"Genes, 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sarcomas correlates with overexpression, and siRNA-mediated inhibition of VGLL3 decreases proliferation rate and migration properties in cell lines harboring the amplification.\",\n      \"method\": \"Array-CGH, transcriptome analysis, siRNA knockdown with proliferation and migration assays\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, but single lab\",\n      \"pmids\": [\"20842732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"VGLL3 acts as a transcription cofactor with female-biased expression that regulates a genome-wide network of genes associated with autoimmune diseases including lupus, scleroderma and Sjögren's syndrome; this regulation is independent of sex-hormone pathways.\",\n      \"method\": \"High-resolution global transcriptome analysis, co-expression network analysis, genome-wide VGLL3 target gene mapping\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genomic methods, replicated across disease contexts, highly cited\",\n      \"pmids\": [\"27992404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VGLL3 binds TEAD1, TEAD3, and TEAD4 in myoblasts and/or myotubes (shown by interaction proteomics), does not interact with Hippo kinase cascade components (unlike YAP/TAZ), and overexpression promotes myogenic differentiation while siRNA-mediated knockdown suppresses myoblast proliferation; VGLL3 mainly represses gene expression including Myf5, Pitx2, Pitx3, and certain Wnts and IGFBPs.\",\n      \"method\": \"Interaction proteomics (co-IP/MS), siRNA knockdown, overexpression with gene expression profiling, Vgll3-null mouse analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction proteomics + KD/KO + OE with multiple phenotypic readouts, moderate evidence\",\n      \"pmids\": [\"31138678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Skin-directed overexpression of murine VGLL3 drives a lupus-like systemic autoimmune disease with B cell expansion, autoantibody production, immune complex deposition, and end-organ damage; excess epidermal VGLL3 induces BAFF, IFN-κ, and CXCL13 expression.\",\n      \"method\": \"Transgenic mouse overexpression model, gene expression profiling, histopathology, immunological assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic gain-of-function with defined molecular and phenotypic readouts, multiple orthogonal methods\",\n      \"pmids\": [\"30996136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VGLL3 promotes cancer cell proliferation by activating the Hippo pathway: VGLL3 together with TEADs induces expression of LATS2 and AMOTL2, leading to YAP and TAZ inactivation; VGLL3 knockdown increases nuclear localization of YAP and TAZ.\",\n      \"method\": \"Stable overexpression cell lines, knockdown experiments, Western blot for Hippo pathway components, nuclear localization assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD/OE with pathway placement and mechanistic follow-up, single lab\",\n      \"pmids\": [\"32385107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VGLL3 mediates cellular stress response by upregulating p53 and IL-17C; energy stress allows VGLL3 to be induced by IFNα, which leads to p53-dependent inflammatory cell death.\",\n      \"method\": \"Cell-based assays with IFNα stimulation, energy stress conditions, gene expression and cell death readouts\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic follow-up in single lab with defined pathway placement\",\n      \"pmids\": [\"32803756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VGLL3 promotes NF-κB activation by inducing expression and secretion of IL-1α, likely through its association with TEADs; TGF-β stimulation induces VGLL3 expression via Smad3 and Smad4, which then drives IL-1α secretion and NF-κB activation.\",\n      \"method\": \"Stable VGLL3-expressing cell lines, NF-κB reporter assays, cytokine measurement, TGF-β stimulation, Smad knockdown\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter assay, KD, ligand stimulation) in single lab\",\n      \"pmids\": [\"34679187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VGLL3 induces expression of GART (a trifunctional enzyme catalyzing de novo purine synthesis from glutamine), increasing cancer cell dependency on de novo nucleotide synthesis; VGLL3 knockdown reduces GART expression and GART inhibitor lometrexol suppresses proliferation of VGLL3-expressing cells.\",\n      \"method\": \"Stable VGLL3 overexpression, siRNA knockdown, pharmacological inhibition (lometrexol), metabolite rescue experiments, gene expression analysis\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD/OE with rescue experiment and pharmacological validation, single lab\",\n      \"pmids\": [\"35434822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VGLL3 forms a transcriptional complex with TEAD1 and RUNX1/3 to drive expression of PD-L1 and PD-L2; loss of VGLL3 impairs IFN-γ-induced PD-L1/2 expression in human keratinocytes.\",\n      \"method\": \"Genome-wide CRISPR activation screening, secondary screen for VGLL3-interacting partners, loss-of-function (VGLL3 KO) with PD-L1/2 expression readout\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased genome-wide screen plus secondary screen to define complex, validated by KO, moderate evidence\",\n      \"pmids\": [\"35922063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VGLL3 promotes the IRF3-IFN-β1 axis in rheumatoid arthritis fibroblast-like synoviocytes by inhibiting WWTR1 (TAZ) expression, leading to IRF3 activation; the resulting IFN-β1 drives type I IFN signature in an autocrine manner, and VGLL3 modulates AMOTL2 expression as part of this mechanism.\",\n      \"method\": \"VGLL3 overexpression in RA-FLS, RNA sequencing, Western blotting for STAT1/MX1/IRF3, siRNA knockdown of WWTR1/AMOTL2\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — OE with downstream pathway dissection using KD of mediators, single lab\",\n      \"pmids\": [\"35941675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VGLL3 is specifically expressed in myofibroblasts from fibrotic hearts and promotes collagen production; substrate stiffness triggers VGLL3 nuclear translocation via the integrin β1-Rho-actin pathway; in the nucleus, VGLL3 undergoes liquid-liquid phase separation via its low-complexity domain and is incorporated into non-paraspeckle NONO condensates containing EWSR1; VGLL3 binds EWSR1 and suppresses miR-29b, which targets collagen mRNA; cardiac fibrosis after myocardial infarction is attenuated in Vgll3-deficient mice with increased miR-29b expression.\",\n      \"method\": \"Mouse and human tissue analysis, Vgll3-KO mouse MI model, live-cell imaging of phase separation, FRAP, co-IP (VGLL3-EWSR1), integrin β1/Rho/actin pathway perturbation, miR-29b measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including KO mouse, reconstitution of phase separation, Co-IP, pathway perturbation, in vivo fibrosis readout\",\n      \"pmids\": [\"36754961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VGLL3 expression in C2C12 myocytes promotes slow-twitch muscle fiber differentiation by inducing PGC-1α expression; VGLL3 proteins are degraded by the proteasome, causing switching of TEAD cofactors from VGLL3 to YAP/TAZ, thereby controlling muscle fiber-type specification.\",\n      \"method\": \"Stable VGLL3-expressing C2C12 cell line, gene expression analysis, proteasome inhibitor experiments, fiber-type marker analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — stable OE with proteasome inhibition and mechanistic follow-up, single lab\",\n      \"pmids\": [\"37262950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VGLL3 plays a role in DNA damage response distinct from its transcriptional cofactor function: VGLL3 is recruited to DNA damage sites in a PARylation-dependent manner; VGLL3 prevents CtIP from KLHL15-mediated ubiquitination and degradation via competitive binding with KLHL15; VGLL3 stabilizes MDC1 by limiting TRIP12-MDC1 but promoting USP7-MDC1 interactions, enabling optimal RNF8 signaling and homologous recombination; VGLL3 depletion reduces RAD51 accumulation at damage sites and sensitizes cells and xenografts to chemotherapeutic drugs.\",\n      \"method\": \"VGLL3 depletion (siRNA/KO), live-cell imaging of DNA damage recruitment, PARylation-dependent recruitment assays, Co-IP (VGLL3-KLHL15, VGLL3-MDC1, TRIP12-MDC1, USP7-MDC1), HR efficiency assays, xenograft tumor model with etoposide treatment\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods (Co-IP, in vivo ubiquitination, HR assay), in vivo xenograft validation, mechanistic dissection of two independent pathways\",\n      \"pmids\": [\"39383226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HERC6, an IFN-induced E3 ubiquitin ligase, modulates LATS2 and TBK1 activity, and the enhanced female-biased immune response observed upon HERC6 loss depends on VGLL3, positioning VGLL3 downstream of HERC6-LATS2 signaling in the type I IFN pathway.\",\n      \"method\": \"HERC6 siRNA knockdown in keratinocytes, cGAMP stimulation, ISG measurement, epistasis via VGLL3 depletion\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (HERC6 KD + VGLL3 depletion) with defined signaling pathway placement, single lab\",\n      \"pmids\": [\"38327798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The TEAD-binding domain of VGLL3 contains a conserved Tondu motif; structural analysis reveals that VGLL3 (unlike VGLL2) lacks a functional Ω-loop in most vertebrate species, suggesting different binding mode to TEAD compared to VGLL2 and YAP; sequence variants with altered TEAD-binding domains in mammalian VGLL2/VGLL3 may confer different biological functions.\",\n      \"method\": \"Comparative sequence analysis of >2400 putative VGLL proteins using available structural data\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/structural inference without direct functional validation in this study\",\n      \"pmids\": [\"39182750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VGLL3 is upregulated in preeclamptic placentas, promotes immune activation, impairs trophoblast differentiation, and induces endothelial dysfunction; VGLL3 acts upstream of sFLT1 production; genetic deletion of VGLL3 in mouse placentas or therapeutic inhibition in human placentas protects against preeclampsia.\",\n      \"method\": \"Human single-cell and spatial transcriptomics, in vitro trophoblast/endothelial assays, in vivo Vgll3 placenta-specific KO mouse model, ex vivo human placenta inhibition\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal models (human single-cell, in vitro, in vivo KO, ex vivo), defined upstream role with sFLT1 as molecular readout\",\n      \"pmids\": [\"41953989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YAP/TAZ repress adipogenic enhancers (reducing H3K27ac at PPARγ-bound target enhancers) through TEAD-dependent transcriptional activity; Vgll3 is identified as a transcriptional target of TAZ critical for repressing adipogenic enhancers, placing VGLL3 downstream of TAZ in the YAP/TAZ-VGLL3 axis that controls adipocyte fate.\",\n      \"method\": \"ChIP-seq (H3K27ac), single-nucleus multi-omics of mouse adipose tissue, TAZ overexpression/KO, TEAD binding domain mutants, Vgll3 KO validation\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq + single-nucleus genomics + genetic KO with epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"41533786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VGLL3 promotes glycolysis and collagen production in keloid fibroblasts via activation of the Wnt/β-catenin signaling pathway through WNT2; VGLL3 overexpression increases WNT2 and β-catenin protein levels and silencing WNT2 reverses VGLL3-driven effects on proliferation, collagen production, and glycolysis.\",\n      \"method\": \"VGLL3 OE/KD in keloid fibroblasts, Western blot for Wnt pathway components, OCR/ECAR measurement, WNT2 siRNA rescue experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — OE/KD with rescue experiment defining pathway, single lab\",\n      \"pmids\": [\"39826675\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VGLL3 is a transcriptional cofactor that binds TEAD1, TEAD3, and TEAD4 via its Tondu motif to regulate gene expression in multiple contexts: it activates the Hippo negative-feedback loop (inducing LATS2 and AMOTL2 to suppress YAP/TAZ), promotes inflammation by driving IL-1α secretion and NF-κB activation and forming a TEAD1-RUNX1/3 complex to upregulate PD-L1/2, drives female-biased autoimmunity through a proinflammatory gene network, promotes fibrosis by translocating to the nucleus via an integrin β1-Rho-actin pathway in response to substrate stiffness, undergoing liquid-liquid phase separation via its low-complexity domain in NONO/EWSR1 condensates to suppress miR-29b and increase collagen production; independently of its transcriptional role, VGLL3 participates in DNA damage response by stabilizing CtIP (blocking KLHL15-mediated ubiquitination) and MDC1 (promoting USP7-MDC1 while limiting TRIP12-MDC1) to enable RNF8 signaling and homologous recombination, and it is positioned downstream of TAZ in the YAP/TAZ-VGLL3 axis that represses adipogenic enhancers.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"VGLL3 is a transcriptional cofactor that partners with TEAD family transcription factors to regulate gene expression programs controlling inflammation, fibrosis, myogenesis, adipogenesis, and immune checkpoint signaling. VGLL3 binds TEAD1, TEAD3, and TEAD4 via a conserved Tondu motif and activates a Hippo pathway negative-feedback loop by inducing LATS2 and AMOTL2, thereby inactivating YAP/TAZ [PMID:32385107, PMID:31138678]; it also forms a TEAD1–RUNX1/3 complex to drive PD-L1/PD-L2 expression [PMID:35922063], promotes NF-κB activation through IL-1α secretion downstream of TGF-β/Smad signaling [PMID:34679187], drives female-biased autoimmune gene networks and lupus-like disease when overexpressed in skin [PMID:27992404, PMID:30996136], and promotes cardiac and keloid fibrosis through mechanosensitive nuclear translocation, liquid–liquid phase separation with NONO/EWSR1 condensates, and suppression of miR-29b [PMID:36754961, PMID:39826675]. Independent of its transcriptional role, VGLL3 is recruited to DNA damage sites in a PARylation-dependent manner where it stabilizes CtIP (by blocking KLHL15-mediated ubiquitination) and MDC1 (by promoting USP7–MDC1 interaction while limiting TRIP12–MDC1), enabling RNF8 signaling and homologous recombination [PMID:39383226].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that VGLL3 is a TEAD cofactor relevant to cancer cell proliferation answered the basic question of its molecular identity and showed that its amplification in soft tissue sarcomas has functional consequences.\",\n      \"evidence\": \"Array-CGH, siRNA knockdown with proliferation/migration assays in sarcoma cell lines\",\n      \"pmids\": [\"20842732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct TEAD binding demonstrated\", \"Mechanism of proliferation/migration control undefined\", \"Single cancer type studied\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying VGLL3 as a female-biased transcription cofactor driving autoimmune-associated gene networks revealed a sex-dimorphic, hormone-independent mechanism for autoimmune susceptibility.\",\n      \"evidence\": \"Global transcriptome analysis and genome-wide VGLL3 target gene mapping across autoimmune disease contexts\",\n      \"pmids\": [\"27992404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector mechanisms not defined\", \"Causal role in autoimmune disease not yet demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Interaction proteomics defined TEAD1/3/4 as direct VGLL3 partners in myoblasts and showed VGLL3 mainly represses transcription, establishing its role in myogenic differentiation distinct from YAP/TAZ signaling.\",\n      \"evidence\": \"Co-IP/mass spectrometry, siRNA knockdown, overexpression with gene expression profiling, Vgll3-null mouse in myoblasts/myotubes\",\n      \"pmids\": [\"31138678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of VGLL3–TEAD interaction not resolved\", \"Mechanism of transcriptional repression unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"In vivo gain-of-function demonstrated that epidermal VGLL3 overexpression is sufficient to drive systemic lupus-like autoimmunity, causally linking VGLL3 to autoimmune disease through BAFF, IFN-κ, and CXCL13 induction.\",\n      \"evidence\": \"Transgenic mouse with skin-directed VGLL3 overexpression, immunological and histopathological characterization\",\n      \"pmids\": [\"30996136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise TEAD-dependent versus TEAD-independent contributions unclear\", \"Human disease causality not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining VGLL3 as an activator of the Hippo negative-feedback loop (via LATS2/AMOTL2 induction and consequent YAP/TAZ inactivation) resolved how VGLL3 and YAP/TAZ exert opposing effects despite sharing TEAD partners.\",\n      \"evidence\": \"Stable overexpression and knockdown with Western blot for Hippo pathway components and YAP/TAZ nuclear localization assays\",\n      \"pmids\": [\"32385107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependency across cell types not explored\", \"Whether VGLL3 directly competes with YAP/TAZ for TEAD binding not tested biochemically\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linking VGLL3 to the IFNα–p53–IL-17C stress response axis under energy stress conditions extended its function beyond steady-state transcription to cellular stress sensing.\",\n      \"evidence\": \"Cell-based assays with IFNα stimulation under energy stress, gene expression and cell death readouts\",\n      \"pmids\": [\"32803756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of energy-stress-dependent VGLL3 induction not defined\", \"Not confirmed in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that TGF-β/Smad3/4 induces VGLL3, which then drives IL-1α secretion and NF-κB activation, placed VGLL3 as a signal integrator connecting TGF-β to inflammatory NF-κB signaling.\",\n      \"evidence\": \"VGLL3-expressing cell lines, NF-κB reporter assays, TGF-β stimulation, Smad knockdown\",\n      \"pmids\": [\"34679187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VGLL3 directly regulates IL-1α transcription via TEAD sites not shown\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Unbiased CRISPR screens identified a VGLL3–TEAD1–RUNX1/3 complex driving PD-L1/PD-L2 expression, defining a specific immune checkpoint regulatory mechanism and expanding the repertoire of VGLL3 partner transcription factors beyond TEADs alone.\",\n      \"evidence\": \"Genome-wide CRISPR activation screen, secondary partner screen, VGLL3 KO with PD-L1/2 readout in keratinocytes\",\n      \"pmids\": [\"35922063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo immune evasion consequences not tested\", \"Structural basis of TEAD1–RUNX1/3–VGLL3 ternary complex unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placing VGLL3 as an inhibitor of WWTR1/TAZ to activate the IRF3–IFN-β1 axis in rheumatoid arthritis synoviocytes clarified how VGLL3 amplifies type I IFN signaling in autoimmune contexts.\",\n      \"evidence\": \"VGLL3 overexpression in RA-FLS, RNA-seq, siRNA knockdown of WWTR1/AMOTL2\",\n      \"pmids\": [\"35941675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct VGLL3-TAZ inhibitory mechanism not defined\", \"Single disease tissue context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that substrate stiffness drives integrin β1–Rho–actin-dependent VGLL3 nuclear translocation, where VGLL3 undergoes LLPS in NONO/EWSR1 condensates to suppress miR-29b and promote collagen production, revealed a mechanosensitive phase-separation mechanism for fibrosis; Vgll3-KO mice showed reduced cardiac fibrosis after MI.\",\n      \"evidence\": \"Vgll3-KO mouse MI model, live-cell imaging/FRAP of phase separation, co-IP of VGLL3–EWSR1, integrin β1/Rho/actin pathway perturbation\",\n      \"pmids\": [\"36754961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LLPS is required (vs. correlative) for collagen regulation not tested by phase-separation-deficient mutant rescue\", \"How VGLL3–EWSR1 condensates suppress miR-29b transcription mechanistically unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that VGLL3 promotes slow-twitch muscle fiber specification by inducing PGC-1α—and that proteasomal VGLL3 degradation switches TEAD cofactors from VGLL3 to YAP/TAZ—established a dynamic competition model governing muscle fiber-type identity.\",\n      \"evidence\": \"Stable VGLL3-expressing C2C12 myocytes, proteasome inhibitor experiments, fiber-type marker analysis\",\n      \"pmids\": [\"37262950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase responsible for VGLL3 degradation not identified\", \"Not validated in primary muscle or in vivo\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovering PARylation-dependent recruitment of VGLL3 to DNA damage sites, where it stabilizes CtIP (blocking KLHL15-mediated degradation) and MDC1 (promoting USP7 while limiting TRIP12), established a transcription-independent role for VGLL3 in homologous recombination and DNA damage response.\",\n      \"evidence\": \"siRNA/KO depletion, live-cell imaging of DNA damage recruitment, co-IP of VGLL3 with KLHL15/MDC1/TRIP12/USP7, HR efficiency assays, xenograft model with etoposide\",\n      \"pmids\": [\"39383226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TEAD binding and DDR functions are structurally separable not tested with separation-of-function mutants\", \"PAR-binding domain in VGLL3 not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genetic epistasis positioned VGLL3 downstream of HERC6–LATS2 signaling, linking IFN-induced ubiquitin ligase activity to VGLL3-driven female-biased immune responses.\",\n      \"evidence\": \"HERC6 siRNA in keratinocytes, cGAMP stimulation, rescue by VGLL3 depletion\",\n      \"pmids\": [\"38327798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HERC6 directly modifies VGLL3 or acts indirectly via LATS2 not distinguished\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Comparative structural analysis revealed that VGLL3 lacks a functional Ω-loop in its Tondu/TEAD-binding domain (unlike VGLL2), suggesting a distinct TEAD-binding mode.\",\n      \"evidence\": \"Computational sequence analysis of >2400 VGLL proteins using available structural data\",\n      \"pmids\": [\"39182750\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct structural or biochemical validation of the proposed binding mode difference\", \"Functional consequences of Ω-loop absence not tested experimentally\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying VGLL3 as upregulated in preeclamptic placentas and demonstrating that placenta-specific Vgll3 deletion protects against preeclampsia in mice established VGLL3 as a driver of placental immune activation, impaired trophoblast differentiation, and endothelial dysfunction upstream of sFLT1.\",\n      \"evidence\": \"Human single-cell/spatial transcriptomics, in vitro trophoblast/endothelial assays, placenta-specific Vgll3 KO mouse, ex vivo human placenta inhibition\",\n      \"pmids\": [\"41953989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic modality for VGLL3 inhibition not defined\", \"TEAD dependence of placental VGLL3 function not confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that VGLL3 activates Wnt/β-catenin signaling through WNT2 in keloid fibroblasts linked VGLL3 to glycolysis-driven fibrosis and expanded its pro-fibrotic role beyond the miR-29b/collagen axis.\",\n      \"evidence\": \"VGLL3 OE/KD in keloid fibroblasts, WNT2 siRNA rescue, ECAR/OCR metabolic assays\",\n      \"pmids\": [\"39826675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VGLL3 directly activates WNT2 transcription via TEAD binding not shown\", \"Relationship between Wnt and miR-29b fibrotic pathways downstream of VGLL3 not explored\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"ChIP-seq and single-nucleus multi-omics placed VGLL3 as a transcriptional target of TAZ that represses adipogenic enhancers, defining the YAP/TAZ→VGLL3 axis controlling adipocyte fate.\",\n      \"evidence\": \"ChIP-seq for H3K27ac, single-nucleus multi-omics of mouse adipose, TAZ OE/KO, TEAD-binding mutants, Vgll3 KO validation\",\n      \"pmids\": [\"41533786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct VGLL3 ChIP at adipogenic enhancers not performed\", \"Whether VGLL3 represses these enhancers through TEAD or other cofactors is inferred but not definitively shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of VGLL3–TEAD interaction and how it differs from YAP/TAZ–TEAD, whether the transcriptional and DDR functions are mediated by separable domains, the identity of the E3 ligase controlling VGLL3 proteasomal turnover, and whether VGLL3-driven autoimmunity is therapeutically targetable.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of VGLL3–TEAD complex\", \"Separation-of-function mutants distinguishing transcriptional from DDR roles not generated\", \"E3 ligase for VGLL3 degradation unknown\", \"No pharmacological VGLL3 inhibitor reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 4, 8, 10, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 9, 13, 16, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3, 5, 8, 13, 15]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 8, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 11, 16]}\n    ],\n    \"complexes\": [\n      \"VGLL3–TEAD1–RUNX1/3\",\n      \"NONO/EWSR1 condensate\"\n    ],\n    \"partners\": [\n      \"TEAD1\",\n      \"TEAD3\",\n      \"TEAD4\",\n      \"RUNX1\",\n      \"EWSR1\",\n      \"NONO\",\n      \"MDC1\",\n      \"KLHL15\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}