{"gene":"VGLL3","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2019,"finding":"VGLL3 binds TEAD1, TEAD3, and TEAD4 in myoblasts and/or myotubes, as determined by interaction proteomics. Unlike YAP/TAZ, VGLL3 showed no interaction with proteins of the Hippo kinase cascade. Vgll3 overexpression reduced Hippo negative-feedback loop activity, promoted myogenic differentiation, and mainly repressed gene expression including Myf5, Pitx2, Pitx3, and certain Wnt and IGFBP genes. siRNA-mediated Vgll3 knockdown suppressed myoblast proliferation.","method":"Interaction proteomics (pulldown/MS), siRNA knockdown, overexpression with transcriptomic readout","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — interaction proteomics identifying specific TEAD partners, combined with loss-of-function and gain-of-function cellular phenotypes in the same study","pmids":["31138678"],"is_preprint":false},{"year":2020,"finding":"VGLL3 (together with TEADs) promotes cancer cell proliferation by activating the Hippo pathway: VGLL3 expression induces transcription of LATS2 and AMOTL2, leading to YAP/TAZ inactivation. VGLL3 knockdown increased nuclear localization of YAP and TAZ, and knockdown of LATS2 or AMOTL2 repressed breast tumor cell proliferation.","method":"Stable VGLL3-expressing cell lines, knockdown of LATS2/AMOTL2, YAP/TAZ nuclear localization assay, proliferation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal cellular assays (stable expression, knockdown, localization) in a single lab","pmids":["32385107"],"is_preprint":false},{"year":2023,"finding":"VGLL3 is specifically expressed in myofibroblasts in 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, is incorporated into non-paraspeckle NONO condensates containing EWSR1, binds EWSR1, and suppresses miR-29b (which targets collagen mRNA). Vgll3-deficient mice showed significantly attenuated cardiac fibrosis after myocardial infarction, with increased miR-29b expression.","method":"Vgll3-deficient mouse model (cardiac fibrosis), live-cell imaging/fractionation for nuclear translocation, LLPS assays, Co-IP for EWSR1 interaction, miR-29b functional assays, pharmacological inhibition of integrin β1-Rho-actin pathway","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including in vivo knockout, LLPS demonstration, protein interaction (Co-IP), pathway inhibition, and mechanistic miRNA link in a single rigorous study","pmids":["36754961"],"is_preprint":false},{"year":2016,"finding":"VGLL3 acts as a transcription cofactor with female-biased expression that regulates a genome-wide network of genes strongly associated with multiple autoimmune diseases (lupus, scleroderma, Sjögren's syndrome). The VGLL3-regulated gene network overlaps with inflammatory processes in cutaneous lupus and is independent of biological age and sex-hormone regulation.","method":"High-resolution global transcriptome analyses, sex-dependent co-expression network analysis","journal":"Nature immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genome-wide transcriptome approach identifies the network, but direct mechanistic experiments on VGLL3 binding/activity are not described in the abstract; replicated by subsequent studies","pmids":["27992404"],"is_preprint":false},{"year":2019,"finding":"Skin-directed overexpression of murine VGLL3 is sufficient to drive cutaneous and systemic autoimmune disease resembling SLE, including B cell expansion, autoantibody production, immune complex deposition, and end-organ damage. Excess epidermal VGLL3 drives a proinflammatory gene expression program including upregulation of BAFF, IFN-κ, and CXCL13.","method":"Transgenic mouse model with skin-directed VGLL3 overexpression; gene expression profiling; immunological phenotyping","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gain-of-function mouse model with multiple orthogonal immunological readouts, confirmed downstream targets, replicated across multiple disease hallmarks","pmids":["30996136"],"is_preprint":false},{"year":2021,"finding":"VGLL3 promotes expression and secretion of IL-1α, likely through its association with TEADs, which activates NF-κB. TGF-β signaling induces VGLL3 (via Smad3 and Smad4), and VGLL3 is required for TGF-β-induced IL-1α secretion and NF-κB activation. VGLL3-dependent IL-1α secretion contributes to constitutive NF-κB activation in highly malignant breast cancer cells.","method":"Stable VGLL3-expressing cell lines, NF-κB reporter assay, TGF-β stimulation, Smad3/4 knockdown, IL-1α ELISA/secretion assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays with epistasis (Smad3/4 knockdown), single lab","pmids":["34679187"],"is_preprint":false},{"year":2010,"finding":"VGLL3 is a cofactor for TEAD family transcription factors and is amplified in ~10% of soft tissue sarcomas (chromosome 3p12 amplicon). Inhibition of VGLL3 in cell lines with amplification/overexpression leads to decreased proliferation rate and, to a lesser extent, decreased migration properties.","method":"Array-CGH, transcriptome analysis, VGLL3 inhibition (siRNA/knockdown) with proliferation and migration assays","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in cell lines with defined phenotypic readouts, supported by genomic amplification data; single lab","pmids":["20842732"],"is_preprint":false},{"year":2022,"finding":"VGLL3 forms a transcriptional complex with TEAD1 and RUNX1/3 to drive PD-L1/2 expression. VGLL3 loss impaired IFN-γ-induced PD-L1/2 expression in human keratinocytes. A genome-wide CRISPR activation screen identified VGLL3 as an upregulator of PD-L1.","method":"Genome-wide CRISPR activation screen, secondary CRISPR screen for co-factors, VGLL3 loss-of-function in keratinocytes, PD-L1/2 expression assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent genome-wide screens identifying VGLL3 and its complex members, combined with loss-of-function validation in human cells","pmids":["35922063"],"is_preprint":false},{"year":2022,"finding":"VGLL3 promotes IRF3 activation and IFN-β1 expression in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), which then drives expression of IFN-stimulated genes in an autocrine manner. Mechanistically, VGLL3 inhibits WWTR1 (TAZ) expression and modulates AMOTL2, and these Hippo pathway molecules mediate VGLL3's regulation of IRF3 activation and IFN-β1 production.","method":"VGLL3 overexpression in RA-FLS, RNA sequencing, Western blotting for STAT1/MX1/IRF3/IFN-β1, WWTR1/AMOTL2 knockdown epistasis experiments","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression + epistasis (WWTR1/AMOTL2 knockdown) showing pathway placement, single lab","pmids":["35941675"],"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, leading to p53-dependent, lupus-associated inflammatory cell death.","method":"Cell-based assays with IFNα stimulation, energy stress conditions; measurement of p53 and IL-17C induction; loss-of-function approaches","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cellular mechanistic findings (p53 and IL-17C induction by VGLL3 under stress/IFNα), single lab, limited methodological detail in abstract","pmids":["32803756"],"is_preprint":false},{"year":2022,"finding":"VGLL3 induces expression of GART (a trifunctional enzyme for de novo purine synthesis from glutamine), thereby increasing cancer cell dependency on de novo nucleotide synthesis. VGLL3 knockdown in breast cancer cells reduced GART expression, and GART inhibition or knockdown repressed proliferation of VGLL3-expressing cells, which was rescued by inosine monophosphate supplementation.","method":"Stable VGLL3 expression in A549 cells, GART knockdown/inhibitor (lometrexol), IMP rescue experiment, VGLL3 knockdown in breast cancer cell lines","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function combined with metabolic rescue experiment; single lab","pmids":["35434822"],"is_preprint":false},{"year":2024,"finding":"VGLL3 plays a role in DNA damage response (DDR): it is recruited to DNA damage sites in a PARylation-dependent manner. VGLL3 depletion impairs accumulation of RNF8 and RAD51 at damage sites, reducing homologous recombination efficiency. Mechanistically, VGLL3 prevents CtIP from KLHL15-mediated ubiquitination and degradation via competitive binding with KLHL15, and stabilizes MDC1 by limiting TRIP12-MDC1 interaction while promoting USP7-MDC1 association, enabling optimal RNF8 signaling. VGLL3 depletion sensitizes tumor xenografts to etoposide.","method":"VGLL3 depletion/Co-IP, PARylation-dependent recruitment assays, HR efficiency measurement, ubiquitination assays (CtIP/KLHL15), MDC1 stability assays (TRIP12, USP7), xenograft tumor model with etoposide","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal mechanistic experiments (PARylation-dependent recruitment, competitive binding, ubiquitination assay, in vivo xenograft) establishing a novel DDR function distinct from transcriptional cofactor role","pmids":["39383226"],"is_preprint":false},{"year":2024,"finding":"HERC6, an IFN-induced E3 ubiquitin ligase, negatively regulates STING-TBK1 signaling in a female-biased manner. HERC6 knockdown leads to enhanced ISG responses dependent on VGLL3, establishing that HERC6 acts through modulation of LATS2 and TBK1 activity upstream of VGLL3 to control female-biased type I IFN responses to dsDNA.","method":"HERC6 knockdown in human keratinocytes, cGAMP stimulation, TBK1/LATS2 signaling measurement, VGLL3-dependent rescue experiments","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis placing VGLL3 downstream of HERC6/LATS2 in STING signaling; single lab, VGLL3-dependence validated by rescue","pmids":["38327798"],"is_preprint":false},{"year":2023,"finding":"VGLL3 expression promotes slow-twitch muscle differentiation by inducing PGC-1α expression in C2C12 myoblasts. VGLL3 proteins are degraded by the proteasome, causing a switch of TEAD cofactors from VGLL3 to YAP/TAZ, thereby controlling muscle fiber-type specification.","method":"Stable VGLL3-overexpressing C2C12 cell line, qPCR/Western blot for slow-twitch markers and PGC-1α, proteasome inhibitor treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined downstream target (PGC-1α), proteasome-dependent degradation shown; single lab, limited methodological detail in abstract","pmids":["37262950"],"is_preprint":false},{"year":2025,"finding":"VGLL3 is upregulated in preeclamptic placentas and acts upstream of preeclampsia-associated processes including sFLT1 production. VGLL3 promotes immune activation, impairs trophoblast differentiation, and induces endothelial dysfunction. Genetic deletion of VGLL3 in mouse placentas or therapeutic inhibition in human placentas protected against preeclampsia and alleviated disease pathology.","method":"Human single-cell and spatial transcriptomic analysis, in vitro trophoblast/endothelial assays, in vivo placenta-specific Vgll3 knockout mouse, ex vivo human placenta inhibition experiments","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro, in vivo (KO mouse), and ex vivo (human placenta) methods across human and mouse models; replicated across two publications (preprint and peer-reviewed)","pmids":["41953989","40502186"],"is_preprint":false},{"year":2024,"finding":"VGLL3 promotes hepatic fibrosis through the VGLL3/HMGB1/TLR4 axis. Vgll3 knockdown in HSC-T6 cells reduced α-SMA, NLRP3, and cleaved-caspase-1 expression, while VGLL3 overexpression increased these markers and promoted inflammasome activation.","method":"Vgll3 knockdown and overexpression in HSC-T6 hepatic stellate cells, TGF-β stimulation, Western blot for fibrosis and inflammasome markers, mouse TAA-induced fibrosis model","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional loss/gain of function in cells plus in vivo model, single lab, limited mechanistic detail on HMGB1/TLR4 direct interaction with VGLL3","pmids":["38489889"],"is_preprint":false},{"year":2025,"finding":"VGLL3 in keloid fibroblasts promotes glycolysis and collagen production via activation of Wnt/β-catenin signaling. VGLL3 overexpression increased WNT2 and β-catenin protein levels; silencing of WNT2 reversed VGLL3's effects on apoptosis, proliferation, collagen production, and glycolysis in keloid fibroblasts.","method":"VGLL3 overexpression and knockdown in keloid fibroblasts, WNT2 silencing epistasis, Western blot, OCR/ECAR metabolic measurements, GSEA","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis (WNT2 knockdown rescues VGLL3 overexpression phenotype) plus metabolic assays; single lab","pmids":["39826675"],"is_preprint":false},{"year":2026,"finding":"VGLL3 is a transcriptional target of TAZ (WWTR1) and is required for TAZ-mediated repression of adipogenic enhancers. TAZ represses PPARγ-bound target enhancers (reducing H3K27ac occupancy) in a TEAD-dependent manner, and Vgll3 is a key downstream effector mediating this repression of adipocyte differentiation.","method":"Single-nucleus genomic analyses of mouse adipose tissue, ChIP-seq for H3K27ac, Vgll3 genetic targeting, TAZ overexpression with TEAD-binding mutants, epistasis experiments","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-seq, single-nucleus genomics, genetic epistasis, and domain mutants in a single rigorous study demonstrating epigenetic mechanism","pmids":["41533786"],"is_preprint":false},{"year":2024,"finding":"A structure-function analysis of VGLL1, VGLL2, and VGLL3 TEAD-binding domains across >2400 vertebrate sequences reveals that VGLL3 binds TEAD via a conserved Tondu motif. The analysis identifies that one vertebrate VGLL paralog with both a Tondu motif and an Ω-loop (present in arthropod Vg and YAP) is conserved, suggesting selective pressure to maintain this structural feature. VGLL2 and VGLL3 variants with altered TEAD-binding domains in mammals may have distinct biological functions.","method":"Structural data analysis combined with comparative sequence analysis of >2400 VGLL proteins; functional mapping of Tondu motif residues","journal":"Archives of biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — primarily computational/structural bioinformatics analysis of available structural data; no new direct binding experiments described in the abstract","pmids":["39182750"],"is_preprint":false},{"year":2026,"finding":"VGLL3 regulates DAPK2-mediated autophagy to promote osteoblast differentiation. Vgll3 knockdown in MC3T3-E1 cells suppressed autophagic flux (fewer autophagic vacuoles, decreased LC3-II, increased p62). DAPK2 was identified as a downstream effector of VGLL3; Dapk2 knockdown phenocopied Vgll3 knockdown. DAPK2 overexpression partially rescued autophagic activity and osteogenic differentiation in Vgll3-deficient cells. Rapamycin partially restored autophagy and differentiation in Vgll3-deficient cells. FOXM1 was implicated as a potential transcriptional regulator of DAPK2.","method":"Vgll3 knockdown in MC3T3-E1 osteoblasts, RNA-seq, transmission electron microscopy (autophagic vacuoles), LC3-II/p62 Western blot, DAPK2 knockdown and overexpression, rapamycin treatment, ALP/Alizarin Red staining","journal":"BioFactors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (TEM, Western blot, epistasis with DAPK2 rescue) in a single study; single lab","pmids":["42052791"],"is_preprint":false}],"current_model":"VGLL3 is a transcriptional cofactor that binds TEAD1, TEAD3, and TEAD4 (via a conserved Tondu motif) to regulate gene expression programs controlling myogenesis, autoimmunity, fibrosis, and cancer cell proliferation; it activates Hippo pathway components LATS2 and AMOTL2 to suppress YAP/TAZ, drives inflammatory responses by inducing IL-1α secretion and IFN-β1/IRF3 signaling, undergoes liquid-liquid phase separation via its low-complexity domain to suppress miR-29b and promote collagen production in myofibroblasts, forms a complex with TEAD1 and RUNX1/3 to drive PD-L1/2 expression, participates in DNA damage response through PARylation-dependent recruitment that stabilizes MDC1 and prevents CtIP degradation, and is regulated by proteasomal degradation that controls a VGLL3/YAP/TAZ cofactor switch at TEADs."},"narrative":{"mechanistic_narrative":"VGLL3 is a TEAD-binding transcriptional cofactor that programs cell-context-specific gene expression governing myogenesis, fibrosis, autoimmunity, and proliferation [PMID:31138678, PMID:20842732]. It interacts with TEAD1, TEAD3, and TEAD4 through a conserved Tondu motif and, unlike YAP/TAZ, does not engage the Hippo kinase cascade directly; instead it activates Hippo components LATS2 and AMOTL2 to drive YAP/TAZ inactivation, with VGLL3 and YAP/TAZ competing as alternative TEAD cofactors in a switch controlled by VGLL3 proteasomal turnover [PMID:31138678, PMID:32385107, PMID:37262950]. In fibrotic and inflammatory settings VGLL3 acts as a mechanosensitive effector: substrate stiffness drives its integrin-β1–Rho–actin–dependent nuclear translocation, where it undergoes liquid-liquid phase separation via a low-complexity domain, joins EWSR1-containing NONO condensates, and suppresses miR-29b to promote collagen production in myofibroblasts [PMID:36754961]. It is induced by TGF-β via Smad3/4 and promotes inflammatory output including IL-1α secretion with NF-κB activation, IRF3/IFN-β1 signaling, and a female-biased autoimmune gene network whose epidermal overexpression is sufficient to drive lupus-like disease [PMID:27992404, PMID:30996136, PMID:34679187, PMID:35941675]. VGLL3 forms a complex with TEAD1 and RUNX1/3 to drive PD-L1/2 expression [PMID:35922063], supports proliferation through induction of the purine-synthesis enzyme GART [PMID:35434822], and is upregulated in preeclamptic placentas where its deletion is protective [PMID:41953989, PMID:40502186]. Independently of transcription, VGLL3 functions in the DNA damage response, being recruited to damage sites in a PARylation-dependent manner where it stabilizes MDC1 and protects CtIP from KLHL15-mediated degradation to support homologous recombination [PMID:39383226].","teleology":[{"year":2010,"claim":"Established VGLL3 as a TEAD cofactor with oncogenic relevance by linking its amplification to sarcoma proliferation, framing it as a transcription-regulatory rather than structural protein.","evidence":"Array-CGH, transcriptome analysis, and siRNA knockdown with proliferation/migration readouts in amplified cell lines","pmids":["20842732"],"confidence":"Medium","gaps":["No direct demonstration of TEAD binding in this study","Did not define which target genes drive the proliferation phenotype"]},{"year":2016,"claim":"Identified VGLL3 as a female-biased transcriptional cofactor controlling a genome-wide autoimmune gene network, answering why it might confer sex-biased disease risk.","evidence":"Global transcriptome and sex-dependent co-expression network analysis","pmids":["27992404"],"confidence":"Medium","gaps":["Correlative network; no direct VGLL3 binding or causal mechanistic experiments","Did not identify the molecular effectors of the regulated network"]},{"year":2019,"claim":"Defined the specific TEAD partners (TEAD1/3/4) and distinguished VGLL3 from YAP/TAZ by its lack of Hippo-kinase interaction, while showing it represses myogenic genes and is needed for myoblast proliferation.","evidence":"Interaction proteomics, siRNA knockdown, and overexpression with transcriptomic readout in myoblasts/myotubes","pmids":["31138678"],"confidence":"High","gaps":["Mechanism of transcriptional repression at target genes not resolved","Did not address how cofactor selection between VGLL3 and YAP/TAZ is controlled"]},{"year":2019,"claim":"Demonstrated causality for autoimmunity by showing epidermal VGLL3 overexpression alone is sufficient to drive SLE-like disease, identifying downstream proinflammatory targets.","evidence":"Skin-directed VGLL3 transgenic mouse with immunological phenotyping and gene expression profiling","pmids":["30996136"],"confidence":"High","gaps":["Direct transcriptional targets (BAFF, IFN-κ, CXCL13) not shown to be bound by VGLL3","TEAD-dependence of the autoimmune program not tested"]},{"year":2020,"claim":"Resolved an apparent paradox by showing VGLL3 activates Hippo components LATS2/AMOTL2 to suppress YAP/TAZ, yet still promotes proliferation, placing it upstream of the Hippo core.","evidence":"Stable expression, LATS2/AMOTL2 knockdown, YAP/TAZ localization, and proliferation assays in breast tumor cells","pmids":["32385107"],"confidence":"Medium","gaps":["Mechanism reconciling YAP/TAZ suppression with pro-proliferative effect unclear","Single lineage; generality across cancers untested"]},{"year":2020,"claim":"Connected VGLL3 to stress-coupled inflammatory cell death by showing IFNα and energy stress induce VGLL3 to drive p53- and IL-17C-dependent responses.","evidence":"IFNα stimulation and energy-stress cell assays with p53/IL-17C induction and loss-of-function","pmids":["32803756"],"confidence":"Medium","gaps":["Direct molecular link between VGLL3 and p53 induction not defined","Limited methodological detail"]},{"year":2021,"claim":"Placed VGLL3 in the TGF-β–Smad axis and identified IL-1α/NF-κB as an output, explaining how it sustains inflammatory signaling in malignant cells.","evidence":"Stable expression, NF-κB reporter, TGF-β stimulation, Smad3/4 knockdown, IL-1α secretion assays","pmids":["34679187"],"confidence":"Medium","gaps":["TEAD-dependence of IL-1α induction inferred but not directly proven","Single lab"]},{"year":2022,"claim":"Identified VGLL3 as a TEAD1/RUNX1/3 complex member driving immune-checkpoint ligand PD-L1/2 expression, linking it to immune evasion programs.","evidence":"Genome-wide CRISPR activation screen, secondary cofactor screen, and loss-of-function in keratinocytes","pmids":["35922063"],"confidence":"High","gaps":["Stoichiometry and assembly order of the VGLL3-TEAD1-RUNX complex not defined","In vivo relevance for tumor immune evasion untested here"]},{"year":2022,"claim":"Established that VGLL3 drives type I IFN responses through IRF3/IFN-β1 in synoviocytes, acting via Hippo molecules WWTR1/TAZ and AMOTL2.","evidence":"Overexpression in RA-FLS, RNA-seq, Western blotting, and WWTR1/AMOTL2 knockdown epistasis","pmids":["35941675"],"confidence":"Medium","gaps":["Direct mechanism linking VGLL3 to IRF3 activation not resolved","Single lab"]},{"year":2022,"claim":"Linked VGLL3-driven proliferation to a metabolic dependency by showing it induces the purine-synthesis enzyme GART.","evidence":"Stable expression, GART knockdown/inhibition, IMP rescue, and VGLL3 knockdown in breast cancer cells","pmids":["35434822"],"confidence":"Medium","gaps":["Whether GART is a direct transcriptional target unknown","TEAD-dependence not tested"]},{"year":2023,"claim":"Revealed a mechanosensitive, phase-separation-based mechanism by which VGLL3 promotes fibrosis: stiffness-driven nuclear entry, LLPS into EWSR1/NONO condensates, and miR-29b suppression.","evidence":"Vgll3-deficient cardiac fibrosis mouse, LLPS assays, Co-IP, pathway inhibition, and miR-29b functional assays","pmids":["36754961"],"confidence":"High","gaps":["How LLPS mechanistically links to miR-29b repression not fully resolved","Relationship between condensate behavior and TEAD-dependent transcription unclear"]},{"year":2023,"claim":"Defined a VGLL3-to-YAP/TAZ cofactor switch governed by proteasomal degradation, controlling muscle fiber-type specification via PGC-1α.","evidence":"Stable VGLL3-overexpressing C2C12 cells, slow-twitch/PGC-1α marker assays, proteasome inhibitor treatment","pmids":["37262950"],"confidence":"Medium","gaps":["E3 ligase mediating VGLL3 degradation not identified","Direct PGC-1α promoter regulation by VGLL3 not shown"]},{"year":2024,"claim":"Uncovered a transcription-independent role for VGLL3 in the DNA damage response, recruited via PARylation to stabilize MDC1 and protect CtIP, supporting homologous recombination.","evidence":"Co-IP, PARylation-dependent recruitment, HR assays, ubiquitination and stability assays, and etoposide xenograft model","pmids":["39383226"],"confidence":"High","gaps":["How the same protein partitions between transcriptional and DDR functions unknown","Structural basis for KLHL15-competitive binding not defined"]},{"year":2024,"claim":"Placed VGLL3 downstream of an IFN-induced negative regulator (HERC6) in STING-TBK1 signaling, explaining female-biased type I IFN responses to dsDNA.","evidence":"HERC6 knockdown, cGAMP stimulation, TBK1/LATS2 measurement, and VGLL3-dependent rescue in keratinocytes","pmids":["38327798"],"confidence":"Medium","gaps":["Direct biochemical connection between LATS2/TBK1 and VGLL3 not shown","Single lab"]},{"year":2024,"claim":"Extended VGLL3's profibrotic role to liver via an HMGB1/TLR4/inflammasome axis in hepatic stellate cells.","evidence":"Vgll3 knockdown/overexpression in HSC-T6, TGF-β stimulation, fibrosis/inflammasome marker blots, and TAA fibrosis mouse model","pmids":["38489889"],"confidence":"Medium","gaps":["Whether VGLL3 directly regulates HMGB1/TLR4 not established","Mechanism of inflammasome activation downstream unclear"]},{"year":2024,"claim":"Comparative structural analysis confirmed VGLL3 binds TEAD through a conserved Tondu motif and mapped paralog-specific TEAD-binding determinants.","evidence":"Structural data analysis and comparative sequence analysis of >2400 VGLL proteins","pmids":["39182750"],"confidence":"Low","gaps":["Computational/bioinformatic; no new direct binding experiments","Functional consequences of paralog-specific differences not tested"]},{"year":2025,"claim":"Demonstrated VGLL3 is a causal driver of preeclampsia, promoting immune activation, impairing trophoblast differentiation, and inducing endothelial dysfunction with sFLT1 production.","evidence":"Human single-cell/spatial transcriptomics, in vitro trophoblast/endothelial assays, placenta-specific Vgll3 knockout mouse, and ex vivo human placenta inhibition","pmids":["41953989","40502186"],"confidence":"High","gaps":["Direct transcriptional targets driving sFLT1 not defined","TEAD-dependence in placenta untested"]},{"year":2025,"claim":"Linked VGLL3-driven keloid fibrosis and glycolysis to Wnt/β-catenin via WNT2 induction.","evidence":"Overexpression/knockdown in keloid fibroblasts, WNT2 silencing epistasis, metabolic OCR/ECAR assays, GSEA","pmids":["39826675"],"confidence":"Medium","gaps":["Whether WNT2 is a direct VGLL3 target unknown","Single lab"]},{"year":2026,"claim":"Placed VGLL3 within an epigenetic repression circuit as a TAZ-induced effector that represses PPARγ-bound adipogenic enhancers, blocking adipocyte differentiation.","evidence":"Single-nucleus genomics, H3K27ac ChIP-seq, Vgll3 genetic targeting, TAZ TEAD-binding mutants, and epistasis in mouse adipose tissue","pmids":["41533786"],"confidence":"High","gaps":["Mechanism by which VGLL3 reduces enhancer H3K27ac not defined","Recruitment to PPARγ enhancers not directly mapped"]},{"year":2026,"claim":"Connected VGLL3 to autophagy-dependent osteoblast differentiation through a DAPK2 effector, broadening its developmental roles.","evidence":"Vgll3 knockdown in MC3T3-E1 osteoblasts, RNA-seq, TEM, LC3-II/p62 blots, DAPK2 epistasis/rescue, rapamycin treatment","pmids":["42052791"],"confidence":"Medium","gaps":["Whether VGLL3 directly regulates DAPK2 transcription not shown","Role of implicated FOXM1 not validated"]},{"year":null,"claim":"It remains unknown how VGLL3 partitions between its TEAD-dependent transcriptional cofactor role, its phase-separation behavior, and its transcription-independent DNA damage response function, and what determines its context-specific target selection across these programs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model integrating transcriptional, condensate, and DDR functions","Determinants of cofactor switching and target-gene selectivity undefined","No high-resolution structure of VGLL3-TEAD-partner complexes in functional context"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,6,7,17]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[3,6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,11]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,8,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,7,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4,5,7,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,13,17,19]}],"complexes":["VGLL3-TEAD1-RUNX1/3 transcriptional complex","EWSR1/NONO nuclear condensate"],"partners":["TEAD1","TEAD3","TEAD4","RUNX1","RUNX3","EWSR1","KLHL15","MDC1"],"other_free_text":[]}},"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; 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Unlike YAP/TAZ, VGLL3 showed no interaction with proteins of the Hippo kinase cascade. Vgll3 overexpression reduced Hippo negative-feedback loop activity, promoted myogenic differentiation, and mainly repressed gene expression including Myf5, Pitx2, Pitx3, and certain Wnt and IGFBP genes. siRNA-mediated Vgll3 knockdown suppressed myoblast proliferation.\",\n      \"method\": \"Interaction proteomics (pulldown/MS), siRNA knockdown, overexpression with transcriptomic readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction proteomics identifying specific TEAD partners, combined with loss-of-function and gain-of-function cellular phenotypes in the same study\",\n      \"pmids\": [\"31138678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VGLL3 (together with TEADs) promotes cancer cell proliferation by activating the Hippo pathway: VGLL3 expression induces transcription of LATS2 and AMOTL2, leading to YAP/TAZ inactivation. VGLL3 knockdown increased nuclear localization of YAP and TAZ, and knockdown of LATS2 or AMOTL2 repressed breast tumor cell proliferation.\",\n      \"method\": \"Stable VGLL3-expressing cell lines, knockdown of LATS2/AMOTL2, YAP/TAZ nuclear localization assay, proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal cellular assays (stable expression, knockdown, localization) in a single lab\",\n      \"pmids\": [\"32385107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VGLL3 is specifically expressed in myofibroblasts in 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, is incorporated into non-paraspeckle NONO condensates containing EWSR1, binds EWSR1, and suppresses miR-29b (which targets collagen mRNA). Vgll3-deficient mice showed significantly attenuated cardiac fibrosis after myocardial infarction, with increased miR-29b expression.\",\n      \"method\": \"Vgll3-deficient mouse model (cardiac fibrosis), live-cell imaging/fractionation for nuclear translocation, LLPS assays, Co-IP for EWSR1 interaction, miR-29b functional assays, pharmacological inhibition of integrin β1-Rho-actin pathway\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including in vivo knockout, LLPS demonstration, protein interaction (Co-IP), pathway inhibition, and mechanistic miRNA link in a single rigorous study\",\n      \"pmids\": [\"36754961\"],\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 strongly associated with multiple autoimmune diseases (lupus, scleroderma, Sjögren's syndrome). The VGLL3-regulated gene network overlaps with inflammatory processes in cutaneous lupus and is independent of biological age and sex-hormone regulation.\",\n      \"method\": \"High-resolution global transcriptome analyses, sex-dependent co-expression network analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genome-wide transcriptome approach identifies the network, but direct mechanistic experiments on VGLL3 binding/activity are not described in the abstract; replicated by subsequent studies\",\n      \"pmids\": [\"27992404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Skin-directed overexpression of murine VGLL3 is sufficient to drive cutaneous and systemic autoimmune disease resembling SLE, including B cell expansion, autoantibody production, immune complex deposition, and end-organ damage. Excess epidermal VGLL3 drives a proinflammatory gene expression program including upregulation of BAFF, IFN-κ, and CXCL13.\",\n      \"method\": \"Transgenic mouse model with skin-directed VGLL3 overexpression; gene expression profiling; immunological phenotyping\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gain-of-function mouse model with multiple orthogonal immunological readouts, confirmed downstream targets, replicated across multiple disease hallmarks\",\n      \"pmids\": [\"30996136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VGLL3 promotes expression and secretion of IL-1α, likely through its association with TEADs, which activates NF-κB. TGF-β signaling induces VGLL3 (via Smad3 and Smad4), and VGLL3 is required for TGF-β-induced IL-1α secretion and NF-κB activation. VGLL3-dependent IL-1α secretion contributes to constitutive NF-κB activation in highly malignant breast cancer cells.\",\n      \"method\": \"Stable VGLL3-expressing cell lines, NF-κB reporter assay, TGF-β stimulation, Smad3/4 knockdown, IL-1α ELISA/secretion assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays with epistasis (Smad3/4 knockdown), single lab\",\n      \"pmids\": [\"34679187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"VGLL3 is a cofactor for TEAD family transcription factors and is amplified in ~10% of soft tissue sarcomas (chromosome 3p12 amplicon). Inhibition of VGLL3 in cell lines with amplification/overexpression leads to decreased proliferation rate and, to a lesser extent, decreased migration properties.\",\n      \"method\": \"Array-CGH, transcriptome analysis, VGLL3 inhibition (siRNA/knockdown) with proliferation and migration assays\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in cell lines with defined phenotypic readouts, supported by genomic amplification data; single lab\",\n      \"pmids\": [\"20842732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VGLL3 forms a transcriptional complex with TEAD1 and RUNX1/3 to drive PD-L1/2 expression. VGLL3 loss impaired IFN-γ-induced PD-L1/2 expression in human keratinocytes. A genome-wide CRISPR activation screen identified VGLL3 as an upregulator of PD-L1.\",\n      \"method\": \"Genome-wide CRISPR activation screen, secondary CRISPR screen for co-factors, VGLL3 loss-of-function in keratinocytes, PD-L1/2 expression assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent genome-wide screens identifying VGLL3 and its complex members, combined with loss-of-function validation in human cells\",\n      \"pmids\": [\"35922063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VGLL3 promotes IRF3 activation and IFN-β1 expression in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), which then drives expression of IFN-stimulated genes in an autocrine manner. Mechanistically, VGLL3 inhibits WWTR1 (TAZ) expression and modulates AMOTL2, and these Hippo pathway molecules mediate VGLL3's regulation of IRF3 activation and IFN-β1 production.\",\n      \"method\": \"VGLL3 overexpression in RA-FLS, RNA sequencing, Western blotting for STAT1/MX1/IRF3/IFN-β1, WWTR1/AMOTL2 knockdown epistasis experiments\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression + epistasis (WWTR1/AMOTL2 knockdown) showing pathway placement, single lab\",\n      \"pmids\": [\"35941675\"],\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, leading to p53-dependent, lupus-associated inflammatory cell death.\",\n      \"method\": \"Cell-based assays with IFNα stimulation, energy stress conditions; measurement of p53 and IL-17C induction; loss-of-function approaches\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cellular mechanistic findings (p53 and IL-17C induction by VGLL3 under stress/IFNα), single lab, limited methodological detail in abstract\",\n      \"pmids\": [\"32803756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VGLL3 induces expression of GART (a trifunctional enzyme for de novo purine synthesis from glutamine), thereby increasing cancer cell dependency on de novo nucleotide synthesis. VGLL3 knockdown in breast cancer cells reduced GART expression, and GART inhibition or knockdown repressed proliferation of VGLL3-expressing cells, which was rescued by inosine monophosphate supplementation.\",\n      \"method\": \"Stable VGLL3 expression in A549 cells, GART knockdown/inhibitor (lometrexol), IMP rescue experiment, VGLL3 knockdown in breast cancer cell lines\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function combined with metabolic rescue experiment; single lab\",\n      \"pmids\": [\"35434822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VGLL3 plays a role in DNA damage response (DDR): it is recruited to DNA damage sites in a PARylation-dependent manner. VGLL3 depletion impairs accumulation of RNF8 and RAD51 at damage sites, reducing homologous recombination efficiency. Mechanistically, VGLL3 prevents CtIP from KLHL15-mediated ubiquitination and degradation via competitive binding with KLHL15, and stabilizes MDC1 by limiting TRIP12-MDC1 interaction while promoting USP7-MDC1 association, enabling optimal RNF8 signaling. VGLL3 depletion sensitizes tumor xenografts to etoposide.\",\n      \"method\": \"VGLL3 depletion/Co-IP, PARylation-dependent recruitment assays, HR efficiency measurement, ubiquitination assays (CtIP/KLHL15), MDC1 stability assays (TRIP12, USP7), xenograft tumor model with etoposide\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal mechanistic experiments (PARylation-dependent recruitment, competitive binding, ubiquitination assay, in vivo xenograft) establishing a novel DDR function distinct from transcriptional cofactor role\",\n      \"pmids\": [\"39383226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HERC6, an IFN-induced E3 ubiquitin ligase, negatively regulates STING-TBK1 signaling in a female-biased manner. HERC6 knockdown leads to enhanced ISG responses dependent on VGLL3, establishing that HERC6 acts through modulation of LATS2 and TBK1 activity upstream of VGLL3 to control female-biased type I IFN responses to dsDNA.\",\n      \"method\": \"HERC6 knockdown in human keratinocytes, cGAMP stimulation, TBK1/LATS2 signaling measurement, VGLL3-dependent rescue experiments\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis placing VGLL3 downstream of HERC6/LATS2 in STING signaling; single lab, VGLL3-dependence validated by rescue\",\n      \"pmids\": [\"38327798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VGLL3 expression promotes slow-twitch muscle differentiation by inducing PGC-1α expression in C2C12 myoblasts. VGLL3 proteins are degraded by the proteasome, causing a switch of TEAD cofactors from VGLL3 to YAP/TAZ, thereby controlling muscle fiber-type specification.\",\n      \"method\": \"Stable VGLL3-overexpressing C2C12 cell line, qPCR/Western blot for slow-twitch markers and PGC-1α, proteasome inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined downstream target (PGC-1α), proteasome-dependent degradation shown; single lab, limited methodological detail in abstract\",\n      \"pmids\": [\"37262950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VGLL3 is upregulated in preeclamptic placentas and acts upstream of preeclampsia-associated processes including sFLT1 production. VGLL3 promotes immune activation, impairs trophoblast differentiation, and induces endothelial dysfunction. Genetic deletion of VGLL3 in mouse placentas or therapeutic inhibition in human placentas protected against preeclampsia and alleviated disease pathology.\",\n      \"method\": \"Human single-cell and spatial transcriptomic analysis, in vitro trophoblast/endothelial assays, in vivo placenta-specific Vgll3 knockout mouse, ex vivo human placenta inhibition experiments\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro, in vivo (KO mouse), and ex vivo (human placenta) methods across human and mouse models; replicated across two publications (preprint and peer-reviewed)\",\n      \"pmids\": [\"41953989\", \"40502186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VGLL3 promotes hepatic fibrosis through the VGLL3/HMGB1/TLR4 axis. Vgll3 knockdown in HSC-T6 cells reduced α-SMA, NLRP3, and cleaved-caspase-1 expression, while VGLL3 overexpression increased these markers and promoted inflammasome activation.\",\n      \"method\": \"Vgll3 knockdown and overexpression in HSC-T6 hepatic stellate cells, TGF-β stimulation, Western blot for fibrosis and inflammasome markers, mouse TAA-induced fibrosis model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional loss/gain of function in cells plus in vivo model, single lab, limited mechanistic detail on HMGB1/TLR4 direct interaction with VGLL3\",\n      \"pmids\": [\"38489889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VGLL3 in keloid fibroblasts promotes glycolysis and collagen production via activation of Wnt/β-catenin signaling. VGLL3 overexpression increased WNT2 and β-catenin protein levels; silencing of WNT2 reversed VGLL3's effects on apoptosis, proliferation, collagen production, and glycolysis in keloid fibroblasts.\",\n      \"method\": \"VGLL3 overexpression and knockdown in keloid fibroblasts, WNT2 silencing epistasis, Western blot, OCR/ECAR metabolic measurements, GSEA\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis (WNT2 knockdown rescues VGLL3 overexpression phenotype) plus metabolic assays; single lab\",\n      \"pmids\": [\"39826675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"VGLL3 is a transcriptional target of TAZ (WWTR1) and is required for TAZ-mediated repression of adipogenic enhancers. TAZ represses PPARγ-bound target enhancers (reducing H3K27ac occupancy) in a TEAD-dependent manner, and Vgll3 is a key downstream effector mediating this repression of adipocyte differentiation.\",\n      \"method\": \"Single-nucleus genomic analyses of mouse adipose tissue, ChIP-seq for H3K27ac, Vgll3 genetic targeting, TAZ overexpression with TEAD-binding mutants, epistasis experiments\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-seq, single-nucleus genomics, genetic epistasis, and domain mutants in a single rigorous study demonstrating epigenetic mechanism\",\n      \"pmids\": [\"41533786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A structure-function analysis of VGLL1, VGLL2, and VGLL3 TEAD-binding domains across >2400 vertebrate sequences reveals that VGLL3 binds TEAD via a conserved Tondu motif. The analysis identifies that one vertebrate VGLL paralog with both a Tondu motif and an Ω-loop (present in arthropod Vg and YAP) is conserved, suggesting selective pressure to maintain this structural feature. VGLL2 and VGLL3 variants with altered TEAD-binding domains in mammals may have distinct biological functions.\",\n      \"method\": \"Structural data analysis combined with comparative sequence analysis of >2400 VGLL proteins; functional mapping of Tondu motif residues\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — primarily computational/structural bioinformatics analysis of available structural data; no new direct binding experiments described in the abstract\",\n      \"pmids\": [\"39182750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"VGLL3 regulates DAPK2-mediated autophagy to promote osteoblast differentiation. Vgll3 knockdown in MC3T3-E1 cells suppressed autophagic flux (fewer autophagic vacuoles, decreased LC3-II, increased p62). DAPK2 was identified as a downstream effector of VGLL3; Dapk2 knockdown phenocopied Vgll3 knockdown. DAPK2 overexpression partially rescued autophagic activity and osteogenic differentiation in Vgll3-deficient cells. Rapamycin partially restored autophagy and differentiation in Vgll3-deficient cells. FOXM1 was implicated as a potential transcriptional regulator of DAPK2.\",\n      \"method\": \"Vgll3 knockdown in MC3T3-E1 osteoblasts, RNA-seq, transmission electron microscopy (autophagic vacuoles), LC3-II/p62 Western blot, DAPK2 knockdown and overexpression, rapamycin treatment, ALP/Alizarin Red staining\",\n      \"journal\": \"BioFactors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (TEM, Western blot, epistasis with DAPK2 rescue) in a single study; single lab\",\n      \"pmids\": [\"42052791\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VGLL3 is a transcriptional cofactor that binds TEAD1, TEAD3, and TEAD4 (via a conserved Tondu motif) to regulate gene expression programs controlling myogenesis, autoimmunity, fibrosis, and cancer cell proliferation; it activates Hippo pathway components LATS2 and AMOTL2 to suppress YAP/TAZ, drives inflammatory responses by inducing IL-1α secretion and IFN-β1/IRF3 signaling, undergoes liquid-liquid phase separation via its low-complexity domain to suppress miR-29b and promote collagen production in myofibroblasts, forms a complex with TEAD1 and RUNX1/3 to drive PD-L1/2 expression, participates in DNA damage response through PARylation-dependent recruitment that stabilizes MDC1 and prevents CtIP degradation, and is regulated by proteasomal degradation that controls a VGLL3/YAP/TAZ cofactor switch at TEADs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VGLL3 is a TEAD-binding transcriptional cofactor that programs cell-context-specific gene expression governing myogenesis, fibrosis, autoimmunity, and proliferation [#0, #6]. It interacts with TEAD1, TEAD3, and TEAD4 through a conserved Tondu motif and, unlike YAP/TAZ, does not engage the Hippo kinase cascade directly; instead it activates Hippo components LATS2 and AMOTL2 to drive YAP/TAZ inactivation, with VGLL3 and YAP/TAZ competing as alternative TEAD cofactors in a switch controlled by VGLL3 proteasomal turnover [#0, #1, #13]. In fibrotic and inflammatory settings VGLL3 acts as a mechanosensitive effector: substrate stiffness drives its integrin-\\u03b21\\u2013Rho\\u2013actin\\u2013dependent nuclear translocation, where it undergoes liquid-liquid phase separation via a low-complexity domain, joins EWSR1-containing NONO condensates, and suppresses miR-29b to promote collagen production in myofibroblasts [#2]. It is induced by TGF-\\u03b2 via Smad3/4 and promotes inflammatory output including IL-1\\u03b1 secretion with NF-\\u03baB activation, IRF3/IFN-\\u03b21 signaling, and a female-biased autoimmune gene network whose epidermal overexpression is sufficient to drive lupus-like disease [#3, #4, #5, #8]. VGLL3 forms a complex with TEAD1 and RUNX1/3 to drive PD-L1/2 expression [#7], supports proliferation through induction of the purine-synthesis enzyme GART [#10], and is upregulated in preeclamptic placentas where its deletion is protective [#14]. Independently of transcription, VGLL3 functions in the DNA damage response, being recruited to damage sites in a PARylation-dependent manner where it stabilizes MDC1 and protects CtIP from KLHL15-mediated degradation to support homologous recombination [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established VGLL3 as a TEAD cofactor with oncogenic relevance by linking its amplification to sarcoma proliferation, framing it as a transcription-regulatory rather than structural protein.\",\n      \"evidence\": \"Array-CGH, transcriptome analysis, and siRNA knockdown with proliferation/migration readouts in amplified cell lines\",\n      \"pmids\": [\"20842732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct demonstration of TEAD binding in this study\", \"Did not define which target genes drive the proliferation phenotype\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified VGLL3 as a female-biased transcriptional cofactor controlling a genome-wide autoimmune gene network, answering why it might confer sex-biased disease risk.\",\n      \"evidence\": \"Global transcriptome and sex-dependent co-expression network analysis\",\n      \"pmids\": [\"27992404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative network; no direct VGLL3 binding or causal mechanistic experiments\", \"Did not identify the molecular effectors of the regulated network\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the specific TEAD partners (TEAD1/3/4) and distinguished VGLL3 from YAP/TAZ by its lack of Hippo-kinase interaction, while showing it represses myogenic genes and is needed for myoblast proliferation.\",\n      \"evidence\": \"Interaction proteomics, siRNA knockdown, and overexpression with transcriptomic readout in myoblasts/myotubes\",\n      \"pmids\": [\"31138678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of transcriptional repression at target genes not resolved\", \"Did not address how cofactor selection between VGLL3 and YAP/TAZ is controlled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated causality for autoimmunity by showing epidermal VGLL3 overexpression alone is sufficient to drive SLE-like disease, identifying downstream proinflammatory targets.\",\n      \"evidence\": \"Skin-directed VGLL3 transgenic mouse with immunological phenotyping and gene expression profiling\",\n      \"pmids\": [\"30996136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets (BAFF, IFN-\\u03ba, CXCL13) not shown to be bound by VGLL3\", \"TEAD-dependence of the autoimmune program not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved an apparent paradox by showing VGLL3 activates Hippo components LATS2/AMOTL2 to suppress YAP/TAZ, yet still promotes proliferation, placing it upstream of the Hippo core.\",\n      \"evidence\": \"Stable expression, LATS2/AMOTL2 knockdown, YAP/TAZ localization, and proliferation assays in breast tumor cells\",\n      \"pmids\": [\"32385107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism reconciling YAP/TAZ suppression with pro-proliferative effect unclear\", \"Single lineage; generality across cancers untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected VGLL3 to stress-coupled inflammatory cell death by showing IFN\\u03b1 and energy stress induce VGLL3 to drive p53- and IL-17C-dependent responses.\",\n      \"evidence\": \"IFN\\u03b1 stimulation and energy-stress cell assays with p53/IL-17C induction and loss-of-function\",\n      \"pmids\": [\"32803756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between VGLL3 and p53 induction not defined\", \"Limited methodological detail\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed VGLL3 in the TGF-\\u03b2\\u2013Smad axis and identified IL-1\\u03b1/NF-\\u03baB as an output, explaining how it sustains inflammatory signaling in malignant cells.\",\n      \"evidence\": \"Stable expression, NF-\\u03baB reporter, TGF-\\u03b2 stimulation, Smad3/4 knockdown, IL-1\\u03b1 secretion assays\",\n      \"pmids\": [\"34679187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TEAD-dependence of IL-1\\u03b1 induction inferred but not directly proven\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified VGLL3 as a TEAD1/RUNX1/3 complex member driving immune-checkpoint ligand PD-L1/2 expression, linking it to immune evasion programs.\",\n      \"evidence\": \"Genome-wide CRISPR activation screen, secondary cofactor screen, and loss-of-function in keratinocytes\",\n      \"pmids\": [\"35922063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the VGLL3-TEAD1-RUNX complex not defined\", \"In vivo relevance for tumor immune evasion untested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established that VGLL3 drives type I IFN responses through IRF3/IFN-\\u03b21 in synoviocytes, acting via Hippo molecules WWTR1/TAZ and AMOTL2.\",\n      \"evidence\": \"Overexpression in RA-FLS, RNA-seq, Western blotting, and WWTR1/AMOTL2 knockdown epistasis\",\n      \"pmids\": [\"35941675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking VGLL3 to IRF3 activation not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked VGLL3-driven proliferation to a metabolic dependency by showing it induces the purine-synthesis enzyme GART.\",\n      \"evidence\": \"Stable expression, GART knockdown/inhibition, IMP rescue, and VGLL3 knockdown in breast cancer cells\",\n      \"pmids\": [\"35434822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GART is a direct transcriptional target unknown\", \"TEAD-dependence not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a mechanosensitive, phase-separation-based mechanism by which VGLL3 promotes fibrosis: stiffness-driven nuclear entry, LLPS into EWSR1/NONO condensates, and miR-29b suppression.\",\n      \"evidence\": \"Vgll3-deficient cardiac fibrosis mouse, LLPS assays, Co-IP, pathway inhibition, and miR-29b functional assays\",\n      \"pmids\": [\"36754961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LLPS mechanistically links to miR-29b repression not fully resolved\", \"Relationship between condensate behavior and TEAD-dependent transcription unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a VGLL3-to-YAP/TAZ cofactor switch governed by proteasomal degradation, controlling muscle fiber-type specification via PGC-1\\u03b1.\",\n      \"evidence\": \"Stable VGLL3-overexpressing C2C12 cells, slow-twitch/PGC-1\\u03b1 marker assays, proteasome inhibitor treatment\",\n      \"pmids\": [\"37262950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating VGLL3 degradation not identified\", \"Direct PGC-1\\u03b1 promoter regulation by VGLL3 not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a transcription-independent role for VGLL3 in the DNA damage response, recruited via PARylation to stabilize MDC1 and protect CtIP, supporting homologous recombination.\",\n      \"evidence\": \"Co-IP, PARylation-dependent recruitment, HR assays, ubiquitination and stability assays, and etoposide xenograft model\",\n      \"pmids\": [\"39383226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same protein partitions between transcriptional and DDR functions unknown\", \"Structural basis for KLHL15-competitive binding not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed VGLL3 downstream of an IFN-induced negative regulator (HERC6) in STING-TBK1 signaling, explaining female-biased type I IFN responses to dsDNA.\",\n      \"evidence\": \"HERC6 knockdown, cGAMP stimulation, TBK1/LATS2 measurement, and VGLL3-dependent rescue in keratinocytes\",\n      \"pmids\": [\"38327798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical connection between LATS2/TBK1 and VGLL3 not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended VGLL3's profibrotic role to liver via an HMGB1/TLR4/inflammasome axis in hepatic stellate cells.\",\n      \"evidence\": \"Vgll3 knockdown/overexpression in HSC-T6, TGF-\\u03b2 stimulation, fibrosis/inflammasome marker blots, and TAA fibrosis mouse model\",\n      \"pmids\": [\"38489889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VGLL3 directly regulates HMGB1/TLR4 not established\", \"Mechanism of inflammasome activation downstream unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Comparative structural analysis confirmed VGLL3 binds TEAD through a conserved Tondu motif and mapped paralog-specific TEAD-binding determinants.\",\n      \"evidence\": \"Structural data analysis and comparative sequence analysis of >2400 VGLL proteins\",\n      \"pmids\": [\"39182750\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational/bioinformatic; no new direct binding experiments\", \"Functional consequences of paralog-specific differences not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated VGLL3 is a causal driver of preeclampsia, promoting immune activation, impairing trophoblast differentiation, and inducing endothelial dysfunction with sFLT1 production.\",\n      \"evidence\": \"Human single-cell/spatial transcriptomics, in vitro trophoblast/endothelial assays, placenta-specific Vgll3 knockout mouse, and ex vivo human placenta inhibition\",\n      \"pmids\": [\"41953989\", \"40502186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets driving sFLT1 not defined\", \"TEAD-dependence in placenta untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked VGLL3-driven keloid fibrosis and glycolysis to Wnt/\\u03b2-catenin via WNT2 induction.\",\n      \"evidence\": \"Overexpression/knockdown in keloid fibroblasts, WNT2 silencing epistasis, metabolic OCR/ECAR assays, GSEA\",\n      \"pmids\": [\"39826675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether WNT2 is a direct VGLL3 target unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed VGLL3 within an epigenetic repression circuit as a TAZ-induced effector that represses PPAR\\u03b3-bound adipogenic enhancers, blocking adipocyte differentiation.\",\n      \"evidence\": \"Single-nucleus genomics, H3K27ac ChIP-seq, Vgll3 genetic targeting, TAZ TEAD-binding mutants, and epistasis in mouse adipose tissue\",\n      \"pmids\": [\"41533786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which VGLL3 reduces enhancer H3K27ac not defined\", \"Recruitment to PPAR\\u03b3 enhancers not directly mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected VGLL3 to autophagy-dependent osteoblast differentiation through a DAPK2 effector, broadening its developmental roles.\",\n      \"evidence\": \"Vgll3 knockdown in MC3T3-E1 osteoblasts, RNA-seq, TEM, LC3-II/p62 blots, DAPK2 epistasis/rescue, rapamycin treatment\",\n      \"pmids\": [\"42052791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VGLL3 directly regulates DAPK2 transcription not shown\", \"Role of implicated FOXM1 not validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how VGLL3 partitions between its TEAD-dependent transcriptional cofactor role, its phase-separation behavior, and its transcription-independent DNA damage response function, and what determines its context-specific target selection across these programs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model integrating transcriptional, condensate, and DDR functions\", \"Determinants of cofactor switching and target-gene selectivity undefined\", \"No high-resolution structure of VGLL3-TEAD-partner complexes in functional context\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 6, 7, 17]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 8, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 7, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 13, 17, 19]}\n    ],\n    \"complexes\": [\n      \"VGLL3-TEAD1-RUNX1/3 transcriptional complex\",\n      \"EWSR1/NONO nuclear condensate\"\n    ],\n    \"partners\": [\n      \"TEAD1\",\n      \"TEAD3\",\n      \"TEAD4\",\n      \"RUNX1\",\n      \"RUNX3\",\n      \"EWSR1\",\n      \"KLHL15\",\n      \"MDC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}