{"gene":"TEAD1","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2005,"finding":"TAZ (transcriptional co-activator with PDZ-binding motif) interacts with TEAD1 (TEF-1) both in vitro and in vivo; GST pull-down assays showed TAZ interacts with TEAD1 bound to MCAT DNA, and TAZ can activate MCAT-dependent reporter promoters through endogenous TEAD1; TAZ interacts more efficiently with TEAD1 than with RTEF-1 (TEAD4), indicating differential cofactor association among family members.","method":"GST pull-down, co-immunoprecipitation, mammalian two-hybrid, EMSA, reporter assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (GST pulldown, Co-IP, two-hybrid, EMSA, reporter) in a single study","pmids":["15628970"],"is_preprint":false},{"year":2002,"finding":"Mammalian Vestigial-like 2 (Vgl-2) interacts with TEAD1 (TEF-1) in vitro and in vivo via a conserved TEF-1 interaction domain; during skeletal muscle differentiation, Vgl-2 protein translocates from cytoplasm to nucleus and co-activates TEAD1-dependent promoters alongside MEF2.","method":"Mammalian two-hybrid, in vitro binding, co-expression reporter assay, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods with functional validation","pmids":["12376544"],"is_preprint":false},{"year":1994,"finding":"Chicken TEF-1 (TEAD1) isoforms TEF-1A and TEF-1B both bind M-CAT elements with high affinity and sequence specificity; the C-terminal portion of TEF-1B (containing a unique 13-amino acid exon) can activate transcription when fused to a heterologous DNA-binding domain, whereas the equivalent domain of TEF-1A cannot, demonstrating isoform-specific transcriptional activation activity.","method":"Binding assays, transcriptional activation assay with heterologous DBD fusion, isoform cloning","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct functional dissection of isoforms with multiple assays, foundational paper","pmids":["8106348"],"is_preprint":false},{"year":2004,"finding":"A missense mutation Y421H in TEAD1 is the causative allele for Sveinsson's chorioretinal atrophy (SCRA); the mutation resides in a conserved C-terminal region proposed to be the YAP65 binding site; TEAD1 and YAP65 are both expressed in human retina by RT-PCR.","method":"Genome-wide linkage analysis, sequencing, RT-PCR expression analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic disease causation with LOD score 18.9, conservation analysis, replication across 81 patients and 502 controls","pmids":["15016762"],"is_preprint":false},{"year":2007,"finding":"The SCRA-associated mutation Y410H (equivalent to human Y421H) in mouse Tead1 specifically abolishes interaction with co-factors YAP and TAZ but not with Vgl-1, -2, or -3; direct interaction between Tead1 and YAP or TAZ is lost due to this mutation as shown by GST pull-down; the Y410H mutation also abolishes TEAD1 transcriptional activity under YAP or TAZ co-expression, establishing that Tyr410 is essential for YAP/TAZ binding.","method":"Mammalian two-hybrid, GST pull-down, site-directed mutagenesis, reporter assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with mutagenesis plus functional reporter assay","pmids":["17689488"],"is_preprint":false},{"year":1996,"finding":"TEAD1 (TEF-1) represses transcription in BeWo choriocarcinoma cells through direct physical interaction with the TATA-binding protein (TBP); GST-TEF-1 fusion peptides retained in vitro-generated TBP, with the proline-rich domain essential for TBP binding; TEF-1 inhibited TBP binding to the TATA motif in vitro; co-expression of TBP with TEF-1 relieved TEF-1-mediated transrepression in vivo.","method":"GST pull-down, in vitro TBP binding/competition assay, co-transfection reporter assay, antisense oligonucleotide","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of interaction plus mutagenesis of domain, corroborated by in vivo relief experiment","pmids":["8621623"],"is_preprint":false},{"year":1997,"finding":"Human TEAD1 (TEF-1) can functionally substitute for Drosophila Scalloped (TEF-1 homolog) in vivo, rescuing wingblade defects and lethality of loss-of-function alleles and promoting sd gene regulation in imaginal wing discs, establishing functional conservation of the DNA-binding and activation domains.","method":"Transgenic Drosophila rescue of loss-of-function alleles, enhancer-trap reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic complementation with functional readout, ortholog confirmed by domain conservation","pmids":["9099715"],"is_preprint":false},{"year":2017,"finding":"Adult cardiomyocyte-specific Tead1 deletion causes lethal acute-onset dilated cardiomyopathy with impaired excitation-contraction coupling; Tead1 directly activates SERCA2a and Inhibitor-1 (I-1) transcription, and its loss leads to decreased SERCA2a and I-1 protein, increased PP1 activity, accumulation of dephosphorylated phospholamban, and decreased SERCA2a activity.","method":"Tamoxifen-inducible cardiac-specific knockout mice, transcriptome analysis, ChIP (implied by direct target characterization), functional cardiac assays, human iPS-derived cardiomyocyte validation","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with clear molecular mechanism (direct transcriptional targets identified), replicated in human iPS-CMs","pmids":["28878117"],"is_preprint":false},{"year":2019,"finding":"TEAD1 is essential for vascular smooth muscle cell (VSMC) differentiation and proliferation; VSMC-specific Tead1 knockout mice exhibit embryonic lethality (E14.5) with hypoplastic vascular walls; Tead1 deletion downregulates muscle contractile genes and key transcription factors including Pitx2c and myocardin; Pitx2c is identified as a novel direct transcriptional target of TEAD1, and PITX2c synergizes with myocardin (via direct interaction) to rescue TEAD1-dependent VSMC differentiation defects.","method":"Conditional knockout mice, whole-transcriptome analysis, in vitro rescue experiments, ChIP (implied by direct target analysis)","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — in vivo conditional KO with defined molecular mechanism and rescue","pmids":["31024075"],"is_preprint":false},{"year":2021,"finding":"Tead1 deletion in adult cardiomyocytes activates necroptosis (not apoptosis) and causes dilated cardiomyopathy; genome-wide ChIP-seq and transcriptomics revealed Tead1 directly activates nuclear DNA-encoded mitochondrial genes required for electron transfer complex assembly and ATP production; Tead1 loss increases mitochondrial ROS, disrupts mitochondrial structure, and reduces complex I-IV oxygen consumption; blocking necroptosis with necrostatin-1 rescues Tead1 deletion-induced heart failure.","method":"Conditional and ubiquitous Tead1 KO mice, ChIP-seq, RNA-seq, mitochondrial functional assays, necrostatin-1 rescue","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-seq cistromics plus transcriptomics, pharmacological rescue, multiple orthogonal methods","pmids":["33469230"],"is_preprint":false},{"year":2018,"finding":"In glioblastoma, TEAD1 directly occupies chromatin at the AQP4, EGFR, and CDH4 loci (validated by ChIP-PCR); CRISPR-Cas9 knockout of TEAD1 robustly diminishes glioblastoma migration in vitro and in vivo, with consistent downregulation of AQP4; TEAD1 overexpression restores AQP4 expression, and overexpression of either TEAD1 or AQP4 rescues migratory deficits in TEAD1-KO cells, establishing a TEAD1–AQP4 regulatory axis for GBM migration.","method":"ATAC-seq, ChIP-PCR, CRISPR-Cas9 KO, migration assays in vitro and in vivo, overexpression rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP-PCR, CRISPR KO, rescue), in vivo validation","pmids":["30275445"],"is_preprint":false},{"year":2018,"finding":"YAP1-TEAD1 signaling controls mitochondrial biogenesis and angiogenesis in endothelial cells through PGC1α; TEAD1 knockdown decreases PGC1α expression and suppresses mitochondrial biogenesis, glycolysis, and oxygen consumption; a YAP1 mutant (S94A) that cannot bind TEAD1 fails to upregulate PGC1α or induce mitochondrial biogenesis, while the TEAD1-binding mutant (S127A) does; PGC1α knockdown inhibits YAP1-induced angiogenesis.","method":"siRNA knockdown, YAP1 domain mutants (S127A vs S94A), mitochondrial biogenesis assays, in vitro sprouting, in vivo fibrin gel vascular morphogenesis","journal":"Microvascular research","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with binding-deficient mutant controls plus in vivo validation","pmids":["29680477"],"is_preprint":false},{"year":2019,"finding":"VGLL3 binds TEAD1, TEAD3, and TEAD4 in myoblasts and/or myotubes (identified by interaction proteomics); unlike YAP and TAZ, VGLL3 does not interact with components of the Hippo kinase cascade; VGLL3 overexpression reduces Hippo negative-feedback loop activity and promotes myogenic differentiation, while siRNA-mediated Vgll3 knockdown suppresses myoblast proliferation.","method":"Interaction proteomics (pull-down/MS), siRNA knockdown, overexpression, gene expression profiling","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — interaction proteomics identifying TEAD1 as binding partner, combined with functional KD/OE phenotypes","pmids":["31138678"],"is_preprint":false},{"year":2011,"finding":"TEAD1 directly regulates FoxO3a transcription in skeletal muscle by binding to an M-CAT element in the foxo3a promoter, demonstrated by ChIP-on-chip, independent ChIP-PCR, EMSA, and luciferase reporter assay; overexpression and inhibition experiments confirm that foxo3a is positively regulated by TEAD1.","method":"ChIP-on-chip, ChIP-PCR, EMSA, luciferase reporter assay, overexpression/knockdown","journal":"BMC molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods for direct target validation","pmids":["21211055"],"is_preprint":false},{"year":2015,"finding":"TEAD1 knockdown in prostate cell lines (PC3 and RWPE1) leads to decreased cell growth and disrupted acinar formation in 3D culture, establishing a cell-autonomous role for TEAD1 in prostate epithelial cell proliferation and glandular architecture.","method":"siRNA knockdown, cell growth assay, 3D culture acinar formation assay","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — clean siRNA KD with specific cellular phenotype, single lab","pmids":["19002168"],"is_preprint":false},{"year":2016,"finding":"Myofiber-specific TEAD1 overexpression in transgenic mice causes dramatic hyperplasia of muscle satellite cells (SCs) without affecting muscle size; hyperplastic SCs are normally quiescent, accelerate regeneration, and are accumulated non-cell-autonomously via signals from TEAD1-expressing myofibers; TEAD1 transgene also ameliorates dystrophic muscle pathology.","method":"Transgenic mouse overexpression, satellite cell quantification, injury-induced regeneration assays, transplantation/non-cell-autonomous signal analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic model with defined non-cell-autonomous signaling mechanism and functional rescue in disease model","pmids":["27725085"],"is_preprint":false},{"year":2015,"finding":"TEAD1 acts as a direct transcriptional activator of the HPV early promoter and cooperates with VGLL1 cofactor to drive HPV early gene expression; 11 TEAD1 target sites were identified in the HPV16 long control region (LCR) by in vitro DNA pulldown, 8 of which activate the early promoter in luciferase assays; VGLL1 binds to the LCR via its interaction with TEAD1 in vitro and in vivo; knockdown of VGLL1 and/or TEAD1 decreases viral early gene expression.","method":"In vitro DNA pulldown, luciferase reporter assay, ChIP, siRNA knockdown","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding identification, ChIP validation, luciferase reporters, and functional siRNA knockdown","pmids":["32132238"],"is_preprint":false},{"year":2016,"finding":"TEAD1 regulates C-MYC and GLUT1 expression in human leukemia cells through the MST1-YAP1-TEAD1 axis; YAP1 positively regulates C-MYC mRNA in complex with TEAD1; specific depletion of TEAD1 decreases lactate production; TEAD-binding motifs in C-MYC and GLUT1 promoters were identified bioinformatically, supporting direct transcriptional regulation.","method":"RNAi knockdown, lactate production assay, bioinformatics promoter analysis, shikonin-mediated MST1 activation","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional RNAi with metabolic readout, bioinformatic support for direct binding, single lab","pmids":["27793648"],"is_preprint":false},{"year":2021,"finding":"The YAP/TEAD1 complex acts as a default repressor of cardiac Toll-like receptor genes; TEAD1 directly binds genomic regions adjacent to Tlr1-7 and Tlr9 (by ChIP); in vitro luciferase assays show YAP/TEAD1 repression of Tlr4 requires a conserved TEAD1 binding motif near the Tlr4 TSS; cardiomyocyte-specific YAP depletion in vivo increases expression of most examined TLR genes and activates pro-inflammatory cytokine synthesis.","method":"ChIP, luciferase reporter assay with TEAD1 binding motif mutation, cardiomyocyte-specific YAP KO mouse, cytokine profiling","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus reporter assay with motif mutagenesis and in vivo KO validation","pmids":["34206257"],"is_preprint":false},{"year":2022,"finding":"RBFOX2 promotes inclusion of TEAD1 exon 6 via binding to a conserved GCAUG element in the downstream intron; the full-length TEAD1 isoform (with exon 6) has greater transcriptional activity and oncogenic properties than TEAD1ΔE6, with the difference in transcription related to YAP interaction; expression of YAP-TEAD target genes negatively correlates with TEAD1ΔE6 expression.","method":"Alternative splicing analysis, RNA binding assay (RBFOX2-GCAUG), transcriptional activity assays, YAP interaction assays, bioinformatics","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — mechanistic splicing regulation identified with functional consequences on YAP interaction and transcriptional activity","pmids":["35699208"],"is_preprint":false},{"year":2024,"finding":"TM7SF3 deletion promotes alternative splicing of TEAD1 by inhibiting the splicing factor hnRNPU, resulting in exclusion of inhibitory exon 5 and generation of a more transcriptionally active TEAD1 isoform that triggers hepatic stellate cell (HSC) activation and liver fibrosis; inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis in vivo.","method":"Conditional TM7SF3 KO, alternative splicing analysis, hnRNPU manipulation, ASO treatment, in vitro HSC activation assay, in vivo MASH model","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — causal chain established from upstream regulator (TM7SF3→hnRNPU→TEAD1 splicing→HSC activation), with in vivo ASO rescue","pmids":["38670107"],"is_preprint":false},{"year":2022,"finding":"TEAD1 exerts a pocket region-independent direct transcriptional repression mechanism by interfering with RNA Polymerase II binding to target promoters; conditional pancreatic β-cell TEAD1 knockout leads to cell-autonomous increase in β-cell proliferation independently of YAP/TAZ; genome-wide ChIP-seq and transcriptomics identified direct TEAD1-repressed target genes in a motif-dependent, orientation-independent manner.","method":"Conditional β-cell KO mice, ChIP-seq, RNA-seq, cancer cell line overexpression, POLII binding assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-seq cistromics, transcriptomics, in vivo KO, and mechanistic POLII assay","pmids":["36484096"],"is_preprint":false},{"year":2023,"finding":"VGLL4 and MENIN function as TEAD1 corepressors in pancreatic β cells; using split-GFP and yeast two-hybrid platforms, VGLL4 and MENIN were shown to bind TEAD1 and repress expression of target genes FZD7 and CCN2, thereby inhibiting β cell proliferation; β cell-specific deletion of TEAD1 (but not YAP/TAZ) increases β cell proliferation, confirming a YAP/TAZ-independent repressive mechanism.","method":"Split-GFP system, yeast two-hybrid, conditional β-cell KO mice (TEAD1, YAP, TAZ), gene expression analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — novel corepressor identification with multiple interaction platforms, corroborated by selective in vivo KO phenotypes","pmids":["36662616"],"is_preprint":false},{"year":2021,"finding":"Tead1 induces cardiac fibroblast-to-cardiomyocyte reprogramming; Tead1 overexpression (substituting for TBX5 in GMT cocktail) nearly triples cardiomyocyte marker cTnT expression in mouse embryonic and adult rat fibroblasts, enables sarcomere organization and contractility (beating) in reprogrammed cells; mechanistically, GMTd increases H3K4me3 marks at promoters of cardio-differentiation and mitochondrial biogenesis genes.","method":"Fibroblast reprogramming assay, flow cytometry for cTnT, sarcomere organization imaging, contractility measurement, ChIP for H3K4me3","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 — functional reprogramming with epigenetic mechanism (H3K4me3 ChIP), single lab","pmids":["34889103"],"is_preprint":false},{"year":2013,"finding":"TEAD1 positively activates transcription of the NAIP (neuronal apoptosis inhibitory protein) gene through an intronic regulatory region; this activation requires interaction with the endogenous YAP cofactor, as demonstrated by reporter assays and co-expression experiments.","method":"Reporter assay, co-expression with YAP, intronic regulatory region mapping","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — reporter assay plus co-expression, single lab, no direct binding assay for this target","pmids":["23994529"],"is_preprint":false},{"year":2024,"finding":"TEAD1 promotes cardiac fibroblast-to-myofibroblast transition through a BRD4/Wnt4 signaling pathway; co-IP combined with mass spectrometry identified BRD4 as a TEAD1 interactor; ChIP-seq and luciferase assays showed TEAD1 and BRD4 bind and activate the Wnt4 promoter; genetic Wnt4 knockdown inhibited the pro-transformation phenotype in cardiac fibroblasts with TEAD1 overexpression; CF/myofibroblast-specific TEAD1 KO and TEAD1 inhibitor VT103 both ameliorated TAC-induced cardiac remodeling in vivo.","method":"Co-IP with mass spectrometry, ChIP-seq, luciferase assay, RNA-seq, conditional KO mice, pharmacological inhibition (VT103), echocardiography","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1-2 — mass spectrometry-identified interaction, ChIP-seq, in vivo KO and pharmacological rescue with multiple orthogonal methods","pmids":["38374140"],"is_preprint":false},{"year":2024,"finding":"SUMOylation of TEAD1 at lysine 173 by SUMO1 (deSUMOylation regulated by SENP1) affects TEAD1 protein stability, nuclear localization, and DNA-binding ability, and enhances interaction between TEAD1 and YAP1; deSUMOylation of TEAD1 (KR mutant) exacerbates cardiomyocyte hypertrophy in vitro and in a mouse cardiac hypertrophy model (AAV9 delivery).","method":"Site-directed mutagenesis of K173, SUMOylation assay, nuclear localization analysis, co-IP (TEAD1-YAP1), DNA-binding assay, AAV9 in vivo delivery, echocardiography","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of SUMOylation site with multiple functional readouts (stability, localization, binding, transcription) and in vivo validation","pmids":["38225750"],"is_preprint":false},{"year":2024,"finding":"TEAD1 is essential for Schwann cell myelination; conditional TEAD1 KO abolishes SC myelination development and regeneration; TEAD1 promotes myelination by regulating SC proliferation, enabling Krox20/Egr2 to upregulate myelin proteins, and upregulating cholesterol biosynthetic enzymes FDPS and IDI1; non-myelinating SCs uniquely require TEAD1 to enwrap nociceptive axons in Remak bundles.","method":"Conditional and inducible Schwann cell-specific KO mice, electron microscopy, gene expression analysis, functional nerve assessments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined mechanistic targets (Krox20/Egr2, FDPS, IDI1) and cell-type-specific functional readouts","pmids":["38456457"],"is_preprint":false},{"year":2023,"finding":"TEAD1 and YAP1 co-localize in trophectoderm and primitive endoderm precursor cells during human preimplantation development, suggesting roles in both first (ICM vs TE) and second (EPI vs PrE) lineage segregation events; TEAD1 displays a distinct spatial pattern coinciding with YAP1/GATA3 co-localization in outer/TE cells, with lower levels in ICM cells.","method":"Immunofluorescence/confocal imaging of human preimplantation embryos, co-localization analysis","journal":"Human reproduction","confidence":"Medium","confidence_rationale":"Tier 3 — descriptive localization study without functional manipulation, but with systematic staging across 188 embryos","pmids":["37295962"],"is_preprint":false},{"year":2024,"finding":"TEAD1 interacts with PGC-1α (peroxisomal proliferator-γ coactivator-1α) to promote mitochondrial function in proximal tubule cells; proximal tubule-specific TEAD1 KO enhances necroptosis, inflammatory response, and mitochondrial dysfunction (increased ROS, reduced ATP) in cisplatin-induced acute kidney injury.","method":"Proximal tubule conditional KO mice, co-immunoprecipitation (TEAD1-PGC1α), mitochondrial bioenergetics assays, necroptosis pathway analysis","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — conditional KO with functional mitochondrial readouts and Co-IP for interaction, single lab","pmids":["39781453"],"is_preprint":false},{"year":2020,"finding":"YAP-TEAD1 complex targets key genes encoding proteins involved in cytoskeleton dynamics and focal adhesion stability in human pluripotent stem cells (PSCs); inactivation of YAP-TEAD1 is required for adjustment of PSC mechanical properties during germ layer specification; aberrant YAP-TEAD1 activation alters PSC potency by inhibiting cytoskeleton dynamics.","method":"Tankyrase inhibitor to modulate AMOT/YAP, gene expression analysis, mechanobiology assays on substrates of defined stiffness","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological modulation with transcriptome and mechanobiology readouts, no direct TEAD1 KO","pmids":["33116297"],"is_preprint":false},{"year":2021,"finding":"TEAD1 knockdown in mouse skin fibroblasts attenuates SA-β-Gal activity and partially alters the replicative senescence-associated transcriptome, identifying TEAD1 as a transcriptional regulator of the senescence program.","method":"siRNA knockdown, ATAC-seq/RRBS/RNA-seq multi-omics, SA-β-Gal activity assay","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2-3 — multi-omics with functional KD phenotype, single lab","pmids":["35023014"],"is_preprint":false},{"year":2021,"finding":"RGS12 negatively regulates the transcriptional activity of the YAP/TEAD1 complex through its PDZ domain to inhibit expression of the osteosarcoma marker Ezrin; RGS12 knockdown upregulates Ezrin via GNA12/13-RhoA-YAP pathway and TEAD1 complex activity.","method":"siRNA knockdown, PDZ domain peptide competition, luciferase reporter assay, orthotopic xenograft mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — PDZ domain-based mechanistic dissection with in vivo xenograft, single lab","pmids":["33686240"],"is_preprint":false},{"year":2024,"finding":"TEAD1 directly regulates ITGA1 and ITGA2 integrin gene expression in prostate cancer cells; TEAD1 loss phenocopies dual ITGA1/ITGA2 loss by inducing EMT via enhanced TGFβ1 secretion and nuclear YAP1 targeting in vitro and in vivo.","method":"Genome-wide co-expression analysis, TEAD1 loss-of-function, in vitro EMT assays, in vivo tumor model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo and in vitro functional studies with pathway placement, single lab","pmids":["38169150"],"is_preprint":false},{"year":2015,"finding":"TEAD1 positively feedback regulates miR-222 transcription in gastric cancer cells by physically binding to the miR-222 promoter (demonstrated by ChIP assay); miR-222 in turn suppresses VGLL4 (a TEAD1 co-repressor), maintaining over-activated YAP-TEAD1 signaling in a regulatory loop.","method":"ChIP assay for TEAD1 at miR-222 promoter, siRNA knockdown, luciferase reporter assay","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP plus reporter assay, single lab","pmids":["26045994"],"is_preprint":false},{"year":2024,"finding":"Endothelial YAP/TEAD1-CXCL17 signaling recruits myeloid-derived suppressor cells (MDSCs) during liver ischemia-reperfusion injury; hypoxia-reoxygenation stimulation activates the YAP/TEAD1 complex in hepatic endothelial cells to promote CXCL17 transcription, and CXCL17 recruits MDSCs via GPR35.","method":"Single-cell RNA-seq, bulk RNA-seq, in vivo YAP/TEAD1 modulation, adoptive MDSC transfer, mechanistic in vitro experiments","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic pathway established by RNA-seq and in vivo experiments, single lab","pmids":["38407233"],"is_preprint":false}],"current_model":"TEAD1 is a TEA domain transcription factor that binds M-CAT DNA elements and functions as the primary transcriptional effector of Hippo signaling by associating with co-activators (YAP, TAZ, VGLL1/2/3) or co-repressors (VGLL4, MENIN) through its conserved C-terminal YAP-binding pocket (disrupted by the SCRA-causing Y421H mutation) and a TBP-interacting proline-rich domain for repression; it drives organ-specific programs in the heart (directly activating SERCA2a, Inhibitor-1, and nuclear DNA-encoded mitochondrial genes to prevent necroptosis and maintain contractility), vasculature (upstream of Pitx2c/myocardin for smooth muscle differentiation), skeletal muscle (regulating satellite cell pool size non-cell-autonomously and activating FoxO3a), peripheral nerve (enabling Schwann cell myelination via Krox20/Egr2 and cholesterol biosynthetic enzymes), and various cancer contexts (promoting migration via AQP4 in GBM and driving fibroblast activation via BRD4/Wnt4 in cardiac fibrosis); its activity is further modulated by alternative splicing of exon 6 (regulated by RBFOX2 and hnRNPU/TM7SF3) and SUMOylation at K173, which controls protein stability, nuclear localization, and YAP interaction."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing that TEAD1 isoforms bind M-CAT elements with high affinity but differ in transcriptional activation capacity resolved how a single gene could produce both activating and non-activating forms.","evidence":"Binding assays and heterologous DBD-fusion activation assays of chicken TEF-1A vs TEF-1B isoforms","pmids":["8106348"],"confidence":"High","gaps":["Physiological relevance of isoform-specific activation not tested in vivo","Upstream splicing regulators not identified"]},{"year":1996,"claim":"Demonstrating that TEAD1 represses transcription by physically sequestering TBP away from TATA boxes revealed a cofactor-independent repression mechanism distinct from its activation function.","evidence":"GST pull-down of TBP, in vitro TBP-TATA competition assay, and co-transfection relief experiment in BeWo cells","pmids":["8621623"],"confidence":"High","gaps":["Genome-wide extent of TBP-dependent repression unknown","Whether this mechanism operates in non-placental contexts untested"]},{"year":1997,"claim":"Cross-species rescue of Drosophila Scalloped mutants by human TEAD1 established deep evolutionary conservation of its DNA-binding and transcriptional activation functions.","evidence":"Transgenic Drosophila complementation of sd loss-of-function alleles","pmids":["9099715"],"confidence":"High","gaps":["Whether mammalian cofactors (YAP/TAZ/VGLL) also complement Yki/Vg not tested"]},{"year":2002,"claim":"Identification of VGLL2 as a nuclear-translocating TEAD1 co-activator during myogenesis provided the first vertebrate Vestigial-like cofactor and linked TEAD1 to skeletal muscle differentiation.","evidence":"Mammalian two-hybrid, in vitro binding, reporter assays, and subcellular fractionation during C2C12 differentiation","pmids":["12376544"],"confidence":"High","gaps":["In vivo requirement of VGLL2 for TEAD1-driven myogenesis not demonstrated"]},{"year":2004,"claim":"Mapping the SCRA-causing Y421H mutation to TEAD1's C-terminal domain linked a human retinal dystrophy to loss of the YAP-binding interface, providing the first disease gene assignment for TEAD1.","evidence":"Genome-wide linkage (LOD 18.9) in Icelandic SCRA families, sequencing, segregation in 81 patients/502 controls","pmids":["15016762"],"confidence":"High","gaps":["Mechanism by which YAP-binding loss causes selective chorioretinal degeneration unknown"]},{"year":2005,"claim":"Discovery that TAZ physically engages TEAD1 on M-CAT DNA and activates TEAD1-dependent transcription established the second major Hippo effector–TEAD1 partnership and showed preferential TAZ binding to TEAD1 over TEAD4.","evidence":"GST pull-down, co-IP, mammalian two-hybrid, EMSA, and reporter assays","pmids":["15628970"],"confidence":"High","gaps":["Structural basis for TEAD1-vs-TEAD4 selectivity of TAZ unresolved"]},{"year":2007,"claim":"Mutagenesis of the SCRA residue (Y410H in mouse) selectively ablated YAP/TAZ but not VGLL binding, defining two mechanistically separable cofactor interfaces on TEAD1.","evidence":"GST pull-down and reporter assays comparing wild-type and Y410H TEAD1 with YAP, TAZ, and VGLL1-3","pmids":["17689488"],"confidence":"High","gaps":["Structural resolution of separate VGLL vs YAP/TAZ binding surfaces not provided"]},{"year":2011,"claim":"Identification of FoxO3a as a direct TEAD1 target in skeletal muscle connected TEAD1 to proteostasis and atrophy signaling beyond its known role in muscle-specific gene activation.","evidence":"ChIP-on-chip, ChIP-PCR, EMSA, luciferase reporter, and overexpression/knockdown in muscle cells","pmids":["21211055"],"confidence":"High","gaps":["In vivo significance of TEAD1-FoxO3a axis for muscle atrophy not tested"]},{"year":2016,"claim":"Myofiber-specific TEAD1 overexpression revealed a non-cell-autonomous mechanism by which TEAD1-expressing fibers expand the satellite cell pool, linking TEAD1 to muscle regenerative capacity.","evidence":"Transgenic mouse overexpression, satellite cell quantification, injury regeneration, transplantation analysis","pmids":["27725085"],"confidence":"High","gaps":["Identity of the secreted signal(s) mediating non-cell-autonomous satellite cell expansion unknown"]},{"year":2017,"claim":"Cardiomyocyte-specific Tead1 deletion causing lethal dilated cardiomyopathy via SERCA2a and Inhibitor-1 loss established TEAD1 as an essential regulator of cardiac calcium handling.","evidence":"Tamoxifen-inducible cardiac-specific KO mice, transcriptome analysis, validation in human iPS-cardiomyocytes","pmids":["28878117"],"confidence":"High","gaps":["Whether TEAD1 cofactors YAP or VGLL mediate cardiac-specific target selection not determined"]},{"year":2018,"claim":"ChIP-validated TEAD1 occupancy at AQP4, EGFR, and CDH4 loci in glioblastoma, combined with CRISPR KO and rescue experiments, established TEAD1 as a driver of GBM cell migration through AQP4.","evidence":"ATAC-seq, ChIP-PCR, CRISPR-Cas9 KO, migration assays in vitro and in vivo, overexpression rescue","pmids":["30275445"],"confidence":"High","gaps":["Whether AQP4-mediated migration requires YAP as cofactor not tested"]},{"year":2019,"claim":"VSMC-specific Tead1 KO embryonic lethality and identification of Pitx2c as a direct target—synergizing with myocardin—placed TEAD1 upstream of the core vascular smooth muscle differentiation cascade.","evidence":"Conditional KO mice (lethal E14.5), transcriptome analysis, rescue experiments","pmids":["31024075"],"confidence":"High","gaps":["Whether TEAD1-Pitx2c axis operates in postnatal vascular remodeling not addressed"]},{"year":2021,"claim":"Genome-wide ChIP-seq in cardiomyocytes revealed that TEAD1 directly activates nuclear-encoded mitochondrial genes, and that its loss triggers necroptosis (rescuable by necrostatin-1), unifying the cardiac phenotype under a mitochondrial dysfunction mechanism.","evidence":"ChIP-seq, RNA-seq, mitochondrial functional assays, necrostatin-1 rescue in conditional KO mice","pmids":["33469230"],"confidence":"High","gaps":["How TEAD1 coordinates mitochondrial gene regulation with SERCA2a/calcium targets unclear"]},{"year":2022,"claim":"Discovery of RBFOX2-mediated inclusion of TEAD1 exon 6 and its effect on YAP interaction strength provided the first upstream splicing code controlling TEAD1 transcriptional potency.","evidence":"Alternative splicing analysis, RBFOX2-GCAUG RNA binding, transcriptional and YAP interaction assays","pmids":["35699208"],"confidence":"High","gaps":["Tissue-specific RBFOX2 regulation of TEAD1 splicing not mapped in vivo"]},{"year":2022,"claim":"Demonstration that TEAD1 represses target genes in pancreatic β cells by blocking RNA Pol II loading—independently of its YAP-binding pocket—established a second, cofactor-independent repression mode beyond TBP sequestration.","evidence":"Conditional β-cell KO, ChIP-seq, RNA-seq, Pol II occupancy assays in cancer cell lines","pmids":["36484096"],"confidence":"High","gaps":["Structural basis for pocket-independent Pol II interference unknown","Whether this mechanism operates in cardiomyocytes untested"]},{"year":2023,"claim":"Identification of VGLL4 and MENIN as TEAD1 corepressors in β cells, repressing FZD7 and CCN2 independently of YAP/TAZ, revealed that TEAD1's role as a proliferation brake in endocrine cells uses a distinct cofactor repertoire.","evidence":"Split-GFP, yeast two-hybrid, conditional TEAD1/YAP/TAZ β-cell KO mice","pmids":["36662616"],"confidence":"High","gaps":["Whether MENIN binding competes with or is simultaneous to VGLL4 not resolved"]},{"year":2024,"claim":"Characterization of TM7SF3/hnRNPU-controlled exclusion of TEAD1 exon 5 in hepatic stellate cells, with ASO-mediated splice correction reducing liver fibrosis in vivo, identified a second regulated splicing event and a therapeutic strategy.","evidence":"Conditional TM7SF3 KO, hnRNPU manipulation, ASO treatment, in vivo MASH model","pmids":["38670107"],"confidence":"High","gaps":["Whether exon 5 and exon 6 splicing events interact or are independently regulated unknown"]},{"year":2024,"claim":"SUMOylation at K173 was shown to stabilize TEAD1 protein, promote nuclear retention, and enhance YAP interaction, with deSUMOylation exacerbating cardiac hypertrophy in vivo, adding a post-translational layer of TEAD1 regulation.","evidence":"K173 mutagenesis, SUMOylation assay, co-IP, DNA-binding assay, AAV9 delivery in mouse hypertrophy model","pmids":["38225750"],"confidence":"High","gaps":["Signal-dependent regulation of SENP1/SUMO1 balance at TEAD1 unknown","Whether SUMOylation affects VGLL4/MENIN co-repressor binding untested"]},{"year":2024,"claim":"Schwann cell-specific TEAD1 KO abolishing myelination and Remak bundle formation, via Krox20/Egr2 and cholesterol biosynthesis gene regulation, extended TEAD1's essential roles to the peripheral nervous system.","evidence":"Conditional and inducible SC-specific KO mice, electron microscopy, gene expression analysis, nerve function assays","pmids":["38456457"],"confidence":"High","gaps":["Whether TEAD1 acts with YAP or VGLL cofactors in Schwann cells not determined"]},{"year":2024,"claim":"Identification of BRD4 as a TEAD1 interactor driving Wnt4-dependent cardiac fibroblast activation, with both genetic KO and pharmacological TEAD1 inhibition (VT103) rescuing cardiac fibrosis, provided a druggable mechanism.","evidence":"Co-IP/MS, ChIP-seq, luciferase, conditional KO, VT103 treatment in TAC model","pmids":["38374140"],"confidence":"High","gaps":["Whether BRD4-TEAD1 interaction is direct or bridged by chromatin context not resolved","Selectivity of VT103 for TEAD1 vs other TEAD family members unclear"]},{"year":null,"claim":"Major unresolved questions include the structural basis for TEAD1's dual activation/repression switching, how tissue-specific cofactor selection (YAP/TAZ vs VGLL vs VGLL4/MENIN) is determined, and the interplay between alternative splicing (exon 5 vs exon 6) and post-translational modifications (SUMOylation, palmitoylation) in controlling TEAD1 output in different cell types.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length TEAD1 with cofactor switching intermediates","Integrated model of splicing and PTM regulation across tissues absent","Mechanistic basis for non-cell-autonomous signaling from TEAD1-expressing myofibers remains unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,5,10,13,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,5,7,9,10,13,16,21,22,25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,26,28]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,5,7,9,10,13,16,21,22,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,11,17,22,25,32]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,8,15,27]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[7]}],"complexes":["YAP-TEAD1","TAZ-TEAD1","TEAD1-BRD4"],"partners":["YAP1","WWTR1","VGLL2","VGLL3","VGLL4","MEN1","BRD4","VGLL1"],"other_free_text":[]},"mechanistic_narrative":"TEAD1 is a TEA domain transcription factor that binds M-CAT DNA elements to regulate tissue-specific gene programs governing cardiac contractility, vascular smooth muscle differentiation, skeletal muscle homeostasis, Schwann cell myelination, and cell proliferation across multiple lineages. It functions as the principal nuclear effector of Hippo pathway signaling by partnering with co-activators YAP, TAZ, and VGLL family members through a conserved C-terminal binding pocket, while also exerting YAP/TAZ-independent transcriptional repression—recruiting co-repressors VGLL4 and MENIN or directly interfering with RNA Polymerase II loading at target promoters [PMID:36484096, PMID:36662616, PMID:15628970, PMID:12376544]. In cardiomyocytes, TEAD1 directly activates SERCA2a, Inhibitor-1, and nuclear-encoded mitochondrial genes; its loss triggers mitochondrial dysfunction and necroptosis-driven dilated cardiomyopathy [PMID:28878117, PMID:33469230]. A Y421H missense mutation that selectively abolishes YAP/TAZ binding causes Sveinsson's chorioretinal atrophy, and TEAD1 activity is further tuned by RBFOX2/hnRNPU-regulated alternative splicing of exon 5/6 and by SUMO1 conjugation at K173, which modulates protein stability, nuclear retention, and YAP interaction strength [PMID:15016762, PMID:17689488, PMID:35699208, PMID:38670107, PMID:38225750]."},"prefetch_data":{"uniprot":{"accession":"P28347","full_name":"Transcriptional enhancer factor TEF-1","aliases":["NTEF-1","Protein GT-IIC","TEA domain family member 1","TEAD-1","Transcription factor 13","TCF-13"],"length_aa":426,"mass_kda":47.9,"function":"Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and cooperatively to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription in vivo in a cell-specific manner. The activation function appears to be mediated by a limiting cell-specific transcriptional intermediary factor (TIF). Involved in cardiac development. Binds to the M-CAT motif","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P28347/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEAD1","classification":"Not Classified","n_dependent_lines":269,"n_total_lines":1208,"dependency_fraction":0.222682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTTN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TEAD1","total_profiled":1310},"omim":[{"mim_id":"620862","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 52; ANKRD52","url":"https://www.omim.org/entry/620862"},{"mim_id":"618692","title":"VESTIGIAL-LIKE FAMILY MEMBER 4; VGLL4","url":"https://www.omim.org/entry/618692"},{"mim_id":"609980","title":"VESTIGIAL-LIKE 3; VGLL3","url":"https://www.omim.org/entry/609980"},{"mim_id":"609979","title":"VESTIGIAL-LIKE 2; VGLL2","url":"https://www.omim.org/entry/609979"},{"mim_id":"603988","title":"ZINC FINGER PROTEIN 106; ZNF106","url":"https://www.omim.org/entry/603988"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TEAD1"},"hgnc":{"alias_symbol":["TEF-1"],"prev_symbol":["TCF13","AA"]},"alphafold":{"accession":"P28347","domains":[{"cath_id":"-","chopping":"34-125","consensus_level":"medium","plddt":77.6824,"start":34,"end":125},{"cath_id":"2.70.50.80","chopping":"213-425","consensus_level":"high","plddt":92.2982,"start":213,"end":425}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P28347","model_url":"https://alphafold.ebi.ac.uk/files/AF-P28347-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P28347-F1-predicted_aligned_error_v6.png","plddt_mean":76.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEAD1","jax_strain_url":"https://www.jax.org/strain/search?query=TEAD1"},"sequence":{"accession":"P28347","fasta_url":"https://rest.uniprot.org/uniprotkb/P28347.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P28347/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P28347"}},"corpus_meta":[{"pmid":"32929754","id":"PMC_32929754","title":"Systemic amyloidosis from A (AA) to T (ATTR): a review.","date":"2020","source":"Journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32929754","citation_count":221,"is_preprint":false},{"pmid":"25387054","id":"PMC_25387054","title":"AA amyloidosis: pathogenesis and targeted therapy.","date":"2014","source":"Annual review of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25387054","citation_count":202,"is_preprint":false},{"pmid":"15628970","id":"PMC_15628970","title":"The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15628970","citation_count":180,"is_preprint":false},{"pmid":"11964039","id":"PMC_11964039","title":"Pathology, diagnosis and pathogenesis of AA amyloidosis.","date":"2002","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11964039","citation_count":169,"is_preprint":false},{"pmid":"30274625","id":"PMC_30274625","title":"Secondary, AA, Amyloidosis.","date":"2018","source":"Rheumatic diseases clinics of North America","url":"https://pubmed.ncbi.nlm.nih.gov/30274625","citation_count":144,"is_preprint":false},{"pmid":"18442989","id":"PMC_18442989","title":"GLUE-IT and PEDEL-AA: new programmes for analyzing protein diversity in randomized libraries.","date":"2008","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/18442989","citation_count":141,"is_preprint":false},{"pmid":"12376544","id":"PMC_12376544","title":"Mammalian vestigial-like 2, a cofactor of TEF-1 and MEF2 transcription factors that promotes skeletal muscle differentiation.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12376544","citation_count":139,"is_preprint":false},{"pmid":"3293363","id":"PMC_3293363","title":"Cerebral arteriovenous malformations (C. 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GST pull-down assays showed TAZ interacts with TEAD1 bound to MCAT DNA, and TAZ can activate MCAT-dependent reporter promoters through endogenous TEAD1; TAZ interacts more efficiently with TEAD1 than with RTEF-1 (TEAD4), indicating differential cofactor association among family members.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, mammalian two-hybrid, EMSA, reporter assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (GST pulldown, Co-IP, two-hybrid, EMSA, reporter) in a single study\",\n      \"pmids\": [\"15628970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mammalian Vestigial-like 2 (Vgl-2) interacts with TEAD1 (TEF-1) in vitro and in vivo via a conserved TEF-1 interaction domain; during skeletal muscle differentiation, Vgl-2 protein translocates from cytoplasm to nucleus and co-activates TEAD1-dependent promoters alongside MEF2.\",\n      \"method\": \"Mammalian two-hybrid, in vitro binding, co-expression reporter assay, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods with functional validation\",\n      \"pmids\": [\"12376544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Chicken TEF-1 (TEAD1) isoforms TEF-1A and TEF-1B both bind M-CAT elements with high affinity and sequence specificity; the C-terminal portion of TEF-1B (containing a unique 13-amino acid exon) can activate transcription when fused to a heterologous DNA-binding domain, whereas the equivalent domain of TEF-1A cannot, demonstrating isoform-specific transcriptional activation activity.\",\n      \"method\": \"Binding assays, transcriptional activation assay with heterologous DBD fusion, isoform cloning\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct functional dissection of isoforms with multiple assays, foundational paper\",\n      \"pmids\": [\"8106348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A missense mutation Y421H in TEAD1 is the causative allele for Sveinsson's chorioretinal atrophy (SCRA); the mutation resides in a conserved C-terminal region proposed to be the YAP65 binding site; TEAD1 and YAP65 are both expressed in human retina by RT-PCR.\",\n      \"method\": \"Genome-wide linkage analysis, sequencing, RT-PCR expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic disease causation with LOD score 18.9, conservation analysis, replication across 81 patients and 502 controls\",\n      \"pmids\": [\"15016762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The SCRA-associated mutation Y410H (equivalent to human Y421H) in mouse Tead1 specifically abolishes interaction with co-factors YAP and TAZ but not with Vgl-1, -2, or -3; direct interaction between Tead1 and YAP or TAZ is lost due to this mutation as shown by GST pull-down; the Y410H mutation also abolishes TEAD1 transcriptional activity under YAP or TAZ co-expression, establishing that Tyr410 is essential for YAP/TAZ binding.\",\n      \"method\": \"Mammalian two-hybrid, GST pull-down, site-directed mutagenesis, reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with mutagenesis plus functional reporter assay\",\n      \"pmids\": [\"17689488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TEAD1 (TEF-1) represses transcription in BeWo choriocarcinoma cells through direct physical interaction with the TATA-binding protein (TBP); GST-TEF-1 fusion peptides retained in vitro-generated TBP, with the proline-rich domain essential for TBP binding; TEF-1 inhibited TBP binding to the TATA motif in vitro; co-expression of TBP with TEF-1 relieved TEF-1-mediated transrepression in vivo.\",\n      \"method\": \"GST pull-down, in vitro TBP binding/competition assay, co-transfection reporter assay, antisense oligonucleotide\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of interaction plus mutagenesis of domain, corroborated by in vivo relief experiment\",\n      \"pmids\": [\"8621623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human TEAD1 (TEF-1) can functionally substitute for Drosophila Scalloped (TEF-1 homolog) in vivo, rescuing wingblade defects and lethality of loss-of-function alleles and promoting sd gene regulation in imaginal wing discs, establishing functional conservation of the DNA-binding and activation domains.\",\n      \"method\": \"Transgenic Drosophila rescue of loss-of-function alleles, enhancer-trap reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic complementation with functional readout, ortholog confirmed by domain conservation\",\n      \"pmids\": [\"9099715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Adult cardiomyocyte-specific Tead1 deletion causes lethal acute-onset dilated cardiomyopathy with impaired excitation-contraction coupling; Tead1 directly activates SERCA2a and Inhibitor-1 (I-1) transcription, and its loss leads to decreased SERCA2a and I-1 protein, increased PP1 activity, accumulation of dephosphorylated phospholamban, and decreased SERCA2a activity.\",\n      \"method\": \"Tamoxifen-inducible cardiac-specific knockout mice, transcriptome analysis, ChIP (implied by direct target characterization), functional cardiac assays, human iPS-derived cardiomyocyte validation\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with clear molecular mechanism (direct transcriptional targets identified), replicated in human iPS-CMs\",\n      \"pmids\": [\"28878117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEAD1 is essential for vascular smooth muscle cell (VSMC) differentiation and proliferation; VSMC-specific Tead1 knockout mice exhibit embryonic lethality (E14.5) with hypoplastic vascular walls; Tead1 deletion downregulates muscle contractile genes and key transcription factors including Pitx2c and myocardin; Pitx2c is identified as a novel direct transcriptional target of TEAD1, and PITX2c synergizes with myocardin (via direct interaction) to rescue TEAD1-dependent VSMC differentiation defects.\",\n      \"method\": \"Conditional knockout mice, whole-transcriptome analysis, in vitro rescue experiments, ChIP (implied by direct target analysis)\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo conditional KO with defined molecular mechanism and rescue\",\n      \"pmids\": [\"31024075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tead1 deletion in adult cardiomyocytes activates necroptosis (not apoptosis) and causes dilated cardiomyopathy; genome-wide ChIP-seq and transcriptomics revealed Tead1 directly activates nuclear DNA-encoded mitochondrial genes required for electron transfer complex assembly and ATP production; Tead1 loss increases mitochondrial ROS, disrupts mitochondrial structure, and reduces complex I-IV oxygen consumption; blocking necroptosis with necrostatin-1 rescues Tead1 deletion-induced heart failure.\",\n      \"method\": \"Conditional and ubiquitous Tead1 KO mice, ChIP-seq, RNA-seq, mitochondrial functional assays, necrostatin-1 rescue\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq cistromics plus transcriptomics, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"33469230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In glioblastoma, TEAD1 directly occupies chromatin at the AQP4, EGFR, and CDH4 loci (validated by ChIP-PCR); CRISPR-Cas9 knockout of TEAD1 robustly diminishes glioblastoma migration in vitro and in vivo, with consistent downregulation of AQP4; TEAD1 overexpression restores AQP4 expression, and overexpression of either TEAD1 or AQP4 rescues migratory deficits in TEAD1-KO cells, establishing a TEAD1–AQP4 regulatory axis for GBM migration.\",\n      \"method\": \"ATAC-seq, ChIP-PCR, CRISPR-Cas9 KO, migration assays in vitro and in vivo, overexpression rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP-PCR, CRISPR KO, rescue), in vivo validation\",\n      \"pmids\": [\"30275445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YAP1-TEAD1 signaling controls mitochondrial biogenesis and angiogenesis in endothelial cells through PGC1α; TEAD1 knockdown decreases PGC1α expression and suppresses mitochondrial biogenesis, glycolysis, and oxygen consumption; a YAP1 mutant (S94A) that cannot bind TEAD1 fails to upregulate PGC1α or induce mitochondrial biogenesis, while the TEAD1-binding mutant (S127A) does; PGC1α knockdown inhibits YAP1-induced angiogenesis.\",\n      \"method\": \"siRNA knockdown, YAP1 domain mutants (S127A vs S94A), mitochondrial biogenesis assays, in vitro sprouting, in vivo fibrin gel vascular morphogenesis\",\n      \"journal\": \"Microvascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with binding-deficient mutant controls plus in vivo validation\",\n      \"pmids\": [\"29680477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VGLL3 binds TEAD1, TEAD3, and TEAD4 in myoblasts and/or myotubes (identified by interaction proteomics); unlike YAP and TAZ, VGLL3 does not interact with components of the Hippo kinase cascade; VGLL3 overexpression reduces Hippo negative-feedback loop activity and promotes myogenic differentiation, while siRNA-mediated Vgll3 knockdown suppresses myoblast proliferation.\",\n      \"method\": \"Interaction proteomics (pull-down/MS), siRNA knockdown, overexpression, gene expression profiling\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — interaction proteomics identifying TEAD1 as binding partner, combined with functional KD/OE phenotypes\",\n      \"pmids\": [\"31138678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TEAD1 directly regulates FoxO3a transcription in skeletal muscle by binding to an M-CAT element in the foxo3a promoter, demonstrated by ChIP-on-chip, independent ChIP-PCR, EMSA, and luciferase reporter assay; overexpression and inhibition experiments confirm that foxo3a is positively regulated by TEAD1.\",\n      \"method\": \"ChIP-on-chip, ChIP-PCR, EMSA, luciferase reporter assay, overexpression/knockdown\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods for direct target validation\",\n      \"pmids\": [\"21211055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TEAD1 knockdown in prostate cell lines (PC3 and RWPE1) leads to decreased cell growth and disrupted acinar formation in 3D culture, establishing a cell-autonomous role for TEAD1 in prostate epithelial cell proliferation and glandular architecture.\",\n      \"method\": \"siRNA knockdown, cell growth assay, 3D culture acinar formation assay\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean siRNA KD with specific cellular phenotype, single lab\",\n      \"pmids\": [\"19002168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Myofiber-specific TEAD1 overexpression in transgenic mice causes dramatic hyperplasia of muscle satellite cells (SCs) without affecting muscle size; hyperplastic SCs are normally quiescent, accelerate regeneration, and are accumulated non-cell-autonomously via signals from TEAD1-expressing myofibers; TEAD1 transgene also ameliorates dystrophic muscle pathology.\",\n      \"method\": \"Transgenic mouse overexpression, satellite cell quantification, injury-induced regeneration assays, transplantation/non-cell-autonomous signal analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic model with defined non-cell-autonomous signaling mechanism and functional rescue in disease model\",\n      \"pmids\": [\"27725085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TEAD1 acts as a direct transcriptional activator of the HPV early promoter and cooperates with VGLL1 cofactor to drive HPV early gene expression; 11 TEAD1 target sites were identified in the HPV16 long control region (LCR) by in vitro DNA pulldown, 8 of which activate the early promoter in luciferase assays; VGLL1 binds to the LCR via its interaction with TEAD1 in vitro and in vivo; knockdown of VGLL1 and/or TEAD1 decreases viral early gene expression.\",\n      \"method\": \"In vitro DNA pulldown, luciferase reporter assay, ChIP, siRNA knockdown\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding identification, ChIP validation, luciferase reporters, and functional siRNA knockdown\",\n      \"pmids\": [\"32132238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TEAD1 regulates C-MYC and GLUT1 expression in human leukemia cells through the MST1-YAP1-TEAD1 axis; YAP1 positively regulates C-MYC mRNA in complex with TEAD1; specific depletion of TEAD1 decreases lactate production; TEAD-binding motifs in C-MYC and GLUT1 promoters were identified bioinformatically, supporting direct transcriptional regulation.\",\n      \"method\": \"RNAi knockdown, lactate production assay, bioinformatics promoter analysis, shikonin-mediated MST1 activation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional RNAi with metabolic readout, bioinformatic support for direct binding, single lab\",\n      \"pmids\": [\"27793648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The YAP/TEAD1 complex acts as a default repressor of cardiac Toll-like receptor genes; TEAD1 directly binds genomic regions adjacent to Tlr1-7 and Tlr9 (by ChIP); in vitro luciferase assays show YAP/TEAD1 repression of Tlr4 requires a conserved TEAD1 binding motif near the Tlr4 TSS; cardiomyocyte-specific YAP depletion in vivo increases expression of most examined TLR genes and activates pro-inflammatory cytokine synthesis.\",\n      \"method\": \"ChIP, luciferase reporter assay with TEAD1 binding motif mutation, cardiomyocyte-specific YAP KO mouse, cytokine profiling\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assay with motif mutagenesis and in vivo KO validation\",\n      \"pmids\": [\"34206257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBFOX2 promotes inclusion of TEAD1 exon 6 via binding to a conserved GCAUG element in the downstream intron; the full-length TEAD1 isoform (with exon 6) has greater transcriptional activity and oncogenic properties than TEAD1ΔE6, with the difference in transcription related to YAP interaction; expression of YAP-TEAD target genes negatively correlates with TEAD1ΔE6 expression.\",\n      \"method\": \"Alternative splicing analysis, RNA binding assay (RBFOX2-GCAUG), transcriptional activity assays, YAP interaction assays, bioinformatics\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic splicing regulation identified with functional consequences on YAP interaction and transcriptional activity\",\n      \"pmids\": [\"35699208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TM7SF3 deletion promotes alternative splicing of TEAD1 by inhibiting the splicing factor hnRNPU, resulting in exclusion of inhibitory exon 5 and generation of a more transcriptionally active TEAD1 isoform that triggers hepatic stellate cell (HSC) activation and liver fibrosis; inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis in vivo.\",\n      \"method\": \"Conditional TM7SF3 KO, alternative splicing analysis, hnRNPU manipulation, ASO treatment, in vitro HSC activation assay, in vivo MASH model\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — causal chain established from upstream regulator (TM7SF3→hnRNPU→TEAD1 splicing→HSC activation), with in vivo ASO rescue\",\n      \"pmids\": [\"38670107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TEAD1 exerts a pocket region-independent direct transcriptional repression mechanism by interfering with RNA Polymerase II binding to target promoters; conditional pancreatic β-cell TEAD1 knockout leads to cell-autonomous increase in β-cell proliferation independently of YAP/TAZ; genome-wide ChIP-seq and transcriptomics identified direct TEAD1-repressed target genes in a motif-dependent, orientation-independent manner.\",\n      \"method\": \"Conditional β-cell KO mice, ChIP-seq, RNA-seq, cancer cell line overexpression, POLII binding assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq cistromics, transcriptomics, in vivo KO, and mechanistic POLII assay\",\n      \"pmids\": [\"36484096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VGLL4 and MENIN function as TEAD1 corepressors in pancreatic β cells; using split-GFP and yeast two-hybrid platforms, VGLL4 and MENIN were shown to bind TEAD1 and repress expression of target genes FZD7 and CCN2, thereby inhibiting β cell proliferation; β cell-specific deletion of TEAD1 (but not YAP/TAZ) increases β cell proliferation, confirming a YAP/TAZ-independent repressive mechanism.\",\n      \"method\": \"Split-GFP system, yeast two-hybrid, conditional β-cell KO mice (TEAD1, YAP, TAZ), gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — novel corepressor identification with multiple interaction platforms, corroborated by selective in vivo KO phenotypes\",\n      \"pmids\": [\"36662616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tead1 induces cardiac fibroblast-to-cardiomyocyte reprogramming; Tead1 overexpression (substituting for TBX5 in GMT cocktail) nearly triples cardiomyocyte marker cTnT expression in mouse embryonic and adult rat fibroblasts, enables sarcomere organization and contractility (beating) in reprogrammed cells; mechanistically, GMTd increases H3K4me3 marks at promoters of cardio-differentiation and mitochondrial biogenesis genes.\",\n      \"method\": \"Fibroblast reprogramming assay, flow cytometry for cTnT, sarcomere organization imaging, contractility measurement, ChIP for H3K4me3\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reprogramming with epigenetic mechanism (H3K4me3 ChIP), single lab\",\n      \"pmids\": [\"34889103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TEAD1 positively activates transcription of the NAIP (neuronal apoptosis inhibitory protein) gene through an intronic regulatory region; this activation requires interaction with the endogenous YAP cofactor, as demonstrated by reporter assays and co-expression experiments.\",\n      \"method\": \"Reporter assay, co-expression with YAP, intronic regulatory region mapping\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter assay plus co-expression, single lab, no direct binding assay for this target\",\n      \"pmids\": [\"23994529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD1 promotes cardiac fibroblast-to-myofibroblast transition through a BRD4/Wnt4 signaling pathway; co-IP combined with mass spectrometry identified BRD4 as a TEAD1 interactor; ChIP-seq and luciferase assays showed TEAD1 and BRD4 bind and activate the Wnt4 promoter; genetic Wnt4 knockdown inhibited the pro-transformation phenotype in cardiac fibroblasts with TEAD1 overexpression; CF/myofibroblast-specific TEAD1 KO and TEAD1 inhibitor VT103 both ameliorated TAC-induced cardiac remodeling in vivo.\",\n      \"method\": \"Co-IP with mass spectrometry, ChIP-seq, luciferase assay, RNA-seq, conditional KO mice, pharmacological inhibition (VT103), echocardiography\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mass spectrometry-identified interaction, ChIP-seq, in vivo KO and pharmacological rescue with multiple orthogonal methods\",\n      \"pmids\": [\"38374140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SUMOylation of TEAD1 at lysine 173 by SUMO1 (deSUMOylation regulated by SENP1) affects TEAD1 protein stability, nuclear localization, and DNA-binding ability, and enhances interaction between TEAD1 and YAP1; deSUMOylation of TEAD1 (KR mutant) exacerbates cardiomyocyte hypertrophy in vitro and in a mouse cardiac hypertrophy model (AAV9 delivery).\",\n      \"method\": \"Site-directed mutagenesis of K173, SUMOylation assay, nuclear localization analysis, co-IP (TEAD1-YAP1), DNA-binding assay, AAV9 in vivo delivery, echocardiography\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of SUMOylation site with multiple functional readouts (stability, localization, binding, transcription) and in vivo validation\",\n      \"pmids\": [\"38225750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD1 is essential for Schwann cell myelination; conditional TEAD1 KO abolishes SC myelination development and regeneration; TEAD1 promotes myelination by regulating SC proliferation, enabling Krox20/Egr2 to upregulate myelin proteins, and upregulating cholesterol biosynthetic enzymes FDPS and IDI1; non-myelinating SCs uniquely require TEAD1 to enwrap nociceptive axons in Remak bundles.\",\n      \"method\": \"Conditional and inducible Schwann cell-specific KO mice, electron microscopy, gene expression analysis, functional nerve assessments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined mechanistic targets (Krox20/Egr2, FDPS, IDI1) and cell-type-specific functional readouts\",\n      \"pmids\": [\"38456457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TEAD1 and YAP1 co-localize in trophectoderm and primitive endoderm precursor cells during human preimplantation development, suggesting roles in both first (ICM vs TE) and second (EPI vs PrE) lineage segregation events; TEAD1 displays a distinct spatial pattern coinciding with YAP1/GATA3 co-localization in outer/TE cells, with lower levels in ICM cells.\",\n      \"method\": \"Immunofluorescence/confocal imaging of human preimplantation embryos, co-localization analysis\",\n      \"journal\": \"Human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — descriptive localization study without functional manipulation, but with systematic staging across 188 embryos\",\n      \"pmids\": [\"37295962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD1 interacts with PGC-1α (peroxisomal proliferator-γ coactivator-1α) to promote mitochondrial function in proximal tubule cells; proximal tubule-specific TEAD1 KO enhances necroptosis, inflammatory response, and mitochondrial dysfunction (increased ROS, reduced ATP) in cisplatin-induced acute kidney injury.\",\n      \"method\": \"Proximal tubule conditional KO mice, co-immunoprecipitation (TEAD1-PGC1α), mitochondrial bioenergetics assays, necroptosis pathway analysis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — conditional KO with functional mitochondrial readouts and Co-IP for interaction, single lab\",\n      \"pmids\": [\"39781453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YAP-TEAD1 complex targets key genes encoding proteins involved in cytoskeleton dynamics and focal adhesion stability in human pluripotent stem cells (PSCs); inactivation of YAP-TEAD1 is required for adjustment of PSC mechanical properties during germ layer specification; aberrant YAP-TEAD1 activation alters PSC potency by inhibiting cytoskeleton dynamics.\",\n      \"method\": \"Tankyrase inhibitor to modulate AMOT/YAP, gene expression analysis, mechanobiology assays on substrates of defined stiffness\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological modulation with transcriptome and mechanobiology readouts, no direct TEAD1 KO\",\n      \"pmids\": [\"33116297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TEAD1 knockdown in mouse skin fibroblasts attenuates SA-β-Gal activity and partially alters the replicative senescence-associated transcriptome, identifying TEAD1 as a transcriptional regulator of the senescence program.\",\n      \"method\": \"siRNA knockdown, ATAC-seq/RRBS/RNA-seq multi-omics, SA-β-Gal activity assay\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multi-omics with functional KD phenotype, single lab\",\n      \"pmids\": [\"35023014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RGS12 negatively regulates the transcriptional activity of the YAP/TEAD1 complex through its PDZ domain to inhibit expression of the osteosarcoma marker Ezrin; RGS12 knockdown upregulates Ezrin via GNA12/13-RhoA-YAP pathway and TEAD1 complex activity.\",\n      \"method\": \"siRNA knockdown, PDZ domain peptide competition, luciferase reporter assay, orthotopic xenograft mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — PDZ domain-based mechanistic dissection with in vivo xenograft, single lab\",\n      \"pmids\": [\"33686240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD1 directly regulates ITGA1 and ITGA2 integrin gene expression in prostate cancer cells; TEAD1 loss phenocopies dual ITGA1/ITGA2 loss by inducing EMT via enhanced TGFβ1 secretion and nuclear YAP1 targeting in vitro and in vivo.\",\n      \"method\": \"Genome-wide co-expression analysis, TEAD1 loss-of-function, in vitro EMT assays, in vivo tumor model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo and in vitro functional studies with pathway placement, single lab\",\n      \"pmids\": [\"38169150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TEAD1 positively feedback regulates miR-222 transcription in gastric cancer cells by physically binding to the miR-222 promoter (demonstrated by ChIP assay); miR-222 in turn suppresses VGLL4 (a TEAD1 co-repressor), maintaining over-activated YAP-TEAD1 signaling in a regulatory loop.\",\n      \"method\": \"ChIP assay for TEAD1 at miR-222 promoter, siRNA knockdown, luciferase reporter assay\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP plus reporter assay, single lab\",\n      \"pmids\": [\"26045994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Endothelial YAP/TEAD1-CXCL17 signaling recruits myeloid-derived suppressor cells (MDSCs) during liver ischemia-reperfusion injury; hypoxia-reoxygenation stimulation activates the YAP/TEAD1 complex in hepatic endothelial cells to promote CXCL17 transcription, and CXCL17 recruits MDSCs via GPR35.\",\n      \"method\": \"Single-cell RNA-seq, bulk RNA-seq, in vivo YAP/TEAD1 modulation, adoptive MDSC transfer, mechanistic in vitro experiments\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic pathway established by RNA-seq and in vivo experiments, single lab\",\n      \"pmids\": [\"38407233\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEAD1 is a TEA domain transcription factor that binds M-CAT DNA elements and functions as the primary transcriptional effector of Hippo signaling by associating with co-activators (YAP, TAZ, VGLL1/2/3) or co-repressors (VGLL4, MENIN) through its conserved C-terminal YAP-binding pocket (disrupted by the SCRA-causing Y421H mutation) and a TBP-interacting proline-rich domain for repression; it drives organ-specific programs in the heart (directly activating SERCA2a, Inhibitor-1, and nuclear DNA-encoded mitochondrial genes to prevent necroptosis and maintain contractility), vasculature (upstream of Pitx2c/myocardin for smooth muscle differentiation), skeletal muscle (regulating satellite cell pool size non-cell-autonomously and activating FoxO3a), peripheral nerve (enabling Schwann cell myelination via Krox20/Egr2 and cholesterol biosynthetic enzymes), and various cancer contexts (promoting migration via AQP4 in GBM and driving fibroblast activation via BRD4/Wnt4 in cardiac fibrosis); its activity is further modulated by alternative splicing of exon 6 (regulated by RBFOX2 and hnRNPU/TM7SF3) and SUMOylation at K173, which controls protein stability, nuclear localization, and YAP interaction.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TEAD1 is a TEA domain transcription factor that binds M-CAT DNA elements to regulate tissue-specific gene programs governing cardiac contractility, vascular smooth muscle differentiation, skeletal muscle homeostasis, Schwann cell myelination, and cell proliferation across multiple lineages. It functions as the principal nuclear effector of Hippo pathway signaling by partnering with co-activators YAP, TAZ, and VGLL family members through a conserved C-terminal binding pocket, while also exerting YAP/TAZ-independent transcriptional repression—recruiting co-repressors VGLL4 and MENIN or directly interfering with RNA Polymerase II loading at target promoters [PMID:36484096, PMID:36662616, PMID:15628970, PMID:12376544]. In cardiomyocytes, TEAD1 directly activates SERCA2a, Inhibitor-1, and nuclear-encoded mitochondrial genes; its loss triggers mitochondrial dysfunction and necroptosis-driven dilated cardiomyopathy [PMID:28878117, PMID:33469230]. A Y421H missense mutation that selectively abolishes YAP/TAZ binding causes Sveinsson's chorioretinal atrophy, and TEAD1 activity is further tuned by RBFOX2/hnRNPU-regulated alternative splicing of exon 5/6 and by SUMO1 conjugation at K173, which modulates protein stability, nuclear retention, and YAP interaction strength [PMID:15016762, PMID:17689488, PMID:35699208, PMID:38670107, PMID:38225750].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that TEAD1 isoforms bind M-CAT elements with high affinity but differ in transcriptional activation capacity resolved how a single gene could produce both activating and non-activating forms.\",\n      \"evidence\": \"Binding assays and heterologous DBD-fusion activation assays of chicken TEF-1A vs TEF-1B isoforms\",\n      \"pmids\": [\"8106348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of isoform-specific activation not tested in vivo\", \"Upstream splicing regulators not identified\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating that TEAD1 represses transcription by physically sequestering TBP away from TATA boxes revealed a cofactor-independent repression mechanism distinct from its activation function.\",\n      \"evidence\": \"GST pull-down of TBP, in vitro TBP-TATA competition assay, and co-transfection relief experiment in BeWo cells\",\n      \"pmids\": [\"8621623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide extent of TBP-dependent repression unknown\", \"Whether this mechanism operates in non-placental contexts untested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Cross-species rescue of Drosophila Scalloped mutants by human TEAD1 established deep evolutionary conservation of its DNA-binding and transcriptional activation functions.\",\n      \"evidence\": \"Transgenic Drosophila complementation of sd loss-of-function alleles\",\n      \"pmids\": [\"9099715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian cofactors (YAP/TAZ/VGLL) also complement Yki/Vg not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of VGLL2 as a nuclear-translocating TEAD1 co-activator during myogenesis provided the first vertebrate Vestigial-like cofactor and linked TEAD1 to skeletal muscle differentiation.\",\n      \"evidence\": \"Mammalian two-hybrid, in vitro binding, reporter assays, and subcellular fractionation during C2C12 differentiation\",\n      \"pmids\": [\"12376544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement of VGLL2 for TEAD1-driven myogenesis not demonstrated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping the SCRA-causing Y421H mutation to TEAD1's C-terminal domain linked a human retinal dystrophy to loss of the YAP-binding interface, providing the first disease gene assignment for TEAD1.\",\n      \"evidence\": \"Genome-wide linkage (LOD 18.9) in Icelandic SCRA families, sequencing, segregation in 81 patients/502 controls\",\n      \"pmids\": [\"15016762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which YAP-binding loss causes selective chorioretinal degeneration unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that TAZ physically engages TEAD1 on M-CAT DNA and activates TEAD1-dependent transcription established the second major Hippo effector–TEAD1 partnership and showed preferential TAZ binding to TEAD1 over TEAD4.\",\n      \"evidence\": \"GST pull-down, co-IP, mammalian two-hybrid, EMSA, and reporter assays\",\n      \"pmids\": [\"15628970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for TEAD1-vs-TEAD4 selectivity of TAZ unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mutagenesis of the SCRA residue (Y410H in mouse) selectively ablated YAP/TAZ but not VGLL binding, defining two mechanistically separable cofactor interfaces on TEAD1.\",\n      \"evidence\": \"GST pull-down and reporter assays comparing wild-type and Y410H TEAD1 with YAP, TAZ, and VGLL1-3\",\n      \"pmids\": [\"17689488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural resolution of separate VGLL vs YAP/TAZ binding surfaces not provided\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of FoxO3a as a direct TEAD1 target in skeletal muscle connected TEAD1 to proteostasis and atrophy signaling beyond its known role in muscle-specific gene activation.\",\n      \"evidence\": \"ChIP-on-chip, ChIP-PCR, EMSA, luciferase reporter, and overexpression/knockdown in muscle cells\",\n      \"pmids\": [\"21211055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of TEAD1-FoxO3a axis for muscle atrophy not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Myofiber-specific TEAD1 overexpression revealed a non-cell-autonomous mechanism by which TEAD1-expressing fibers expand the satellite cell pool, linking TEAD1 to muscle regenerative capacity.\",\n      \"evidence\": \"Transgenic mouse overexpression, satellite cell quantification, injury regeneration, transplantation analysis\",\n      \"pmids\": [\"27725085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the secreted signal(s) mediating non-cell-autonomous satellite cell expansion unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cardiomyocyte-specific Tead1 deletion causing lethal dilated cardiomyopathy via SERCA2a and Inhibitor-1 loss established TEAD1 as an essential regulator of cardiac calcium handling.\",\n      \"evidence\": \"Tamoxifen-inducible cardiac-specific KO mice, transcriptome analysis, validation in human iPS-cardiomyocytes\",\n      \"pmids\": [\"28878117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TEAD1 cofactors YAP or VGLL mediate cardiac-specific target selection not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ChIP-validated TEAD1 occupancy at AQP4, EGFR, and CDH4 loci in glioblastoma, combined with CRISPR KO and rescue experiments, established TEAD1 as a driver of GBM cell migration through AQP4.\",\n      \"evidence\": \"ATAC-seq, ChIP-PCR, CRISPR-Cas9 KO, migration assays in vitro and in vivo, overexpression rescue\",\n      \"pmids\": [\"30275445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AQP4-mediated migration requires YAP as cofactor not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"VSMC-specific Tead1 KO embryonic lethality and identification of Pitx2c as a direct target—synergizing with myocardin—placed TEAD1 upstream of the core vascular smooth muscle differentiation cascade.\",\n      \"evidence\": \"Conditional KO mice (lethal E14.5), transcriptome analysis, rescue experiments\",\n      \"pmids\": [\"31024075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TEAD1-Pitx2c axis operates in postnatal vascular remodeling not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genome-wide ChIP-seq in cardiomyocytes revealed that TEAD1 directly activates nuclear-encoded mitochondrial genes, and that its loss triggers necroptosis (rescuable by necrostatin-1), unifying the cardiac phenotype under a mitochondrial dysfunction mechanism.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, mitochondrial functional assays, necrostatin-1 rescue in conditional KO mice\",\n      \"pmids\": [\"33469230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TEAD1 coordinates mitochondrial gene regulation with SERCA2a/calcium targets unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of RBFOX2-mediated inclusion of TEAD1 exon 6 and its effect on YAP interaction strength provided the first upstream splicing code controlling TEAD1 transcriptional potency.\",\n      \"evidence\": \"Alternative splicing analysis, RBFOX2-GCAUG RNA binding, transcriptional and YAP interaction assays\",\n      \"pmids\": [\"35699208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific RBFOX2 regulation of TEAD1 splicing not mapped in vivo\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that TEAD1 represses target genes in pancreatic β cells by blocking RNA Pol II loading—independently of its YAP-binding pocket—established a second, cofactor-independent repression mode beyond TBP sequestration.\",\n      \"evidence\": \"Conditional β-cell KO, ChIP-seq, RNA-seq, Pol II occupancy assays in cancer cell lines\",\n      \"pmids\": [\"36484096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for pocket-independent Pol II interference unknown\", \"Whether this mechanism operates in cardiomyocytes untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of VGLL4 and MENIN as TEAD1 corepressors in β cells, repressing FZD7 and CCN2 independently of YAP/TAZ, revealed that TEAD1's role as a proliferation brake in endocrine cells uses a distinct cofactor repertoire.\",\n      \"evidence\": \"Split-GFP, yeast two-hybrid, conditional TEAD1/YAP/TAZ β-cell KO mice\",\n      \"pmids\": [\"36662616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MENIN binding competes with or is simultaneous to VGLL4 not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Characterization of TM7SF3/hnRNPU-controlled exclusion of TEAD1 exon 5 in hepatic stellate cells, with ASO-mediated splice correction reducing liver fibrosis in vivo, identified a second regulated splicing event and a therapeutic strategy.\",\n      \"evidence\": \"Conditional TM7SF3 KO, hnRNPU manipulation, ASO treatment, in vivo MASH model\",\n      \"pmids\": [\"38670107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether exon 5 and exon 6 splicing events interact or are independently regulated unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SUMOylation at K173 was shown to stabilize TEAD1 protein, promote nuclear retention, and enhance YAP interaction, with deSUMOylation exacerbating cardiac hypertrophy in vivo, adding a post-translational layer of TEAD1 regulation.\",\n      \"evidence\": \"K173 mutagenesis, SUMOylation assay, co-IP, DNA-binding assay, AAV9 delivery in mouse hypertrophy model\",\n      \"pmids\": [\"38225750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal-dependent regulation of SENP1/SUMO1 balance at TEAD1 unknown\", \"Whether SUMOylation affects VGLL4/MENIN co-repressor binding untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Schwann cell-specific TEAD1 KO abolishing myelination and Remak bundle formation, via Krox20/Egr2 and cholesterol biosynthesis gene regulation, extended TEAD1's essential roles to the peripheral nervous system.\",\n      \"evidence\": \"Conditional and inducible SC-specific KO mice, electron microscopy, gene expression analysis, nerve function assays\",\n      \"pmids\": [\"38456457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TEAD1 acts with YAP or VGLL cofactors in Schwann cells not determined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of BRD4 as a TEAD1 interactor driving Wnt4-dependent cardiac fibroblast activation, with both genetic KO and pharmacological TEAD1 inhibition (VT103) rescuing cardiac fibrosis, provided a druggable mechanism.\",\n      \"evidence\": \"Co-IP/MS, ChIP-seq, luciferase, conditional KO, VT103 treatment in TAC model\",\n      \"pmids\": [\"38374140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRD4-TEAD1 interaction is direct or bridged by chromatin context not resolved\", \"Selectivity of VT103 for TEAD1 vs other TEAD family members unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis for TEAD1's dual activation/repression switching, how tissue-specific cofactor selection (YAP/TAZ vs VGLL vs VGLL4/MENIN) is determined, and the interplay between alternative splicing (exon 5 vs exon 6) and post-translational modifications (SUMOylation, palmitoylation) in controlling TEAD1 output in different cell types.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length TEAD1 with cofactor switching intermediates\", \"Integrated model of splicing and PTM regulation across tissues absent\", \"Mechanistic basis for non-cell-autonomous signaling from TEAD1-expressing myofibers remains unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 5, 10, 13, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 5, 7, 9, 10, 13, 16, 21, 22, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 26, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 5, 7, 9, 10, 13, 16, 21, 22, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 11, 17, 22, 25, 32]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 8, 15, 27]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"YAP-TEAD1\",\n      \"TAZ-TEAD1\",\n      \"TEAD1-BRD4\"\n    ],\n    \"partners\": [\n      \"YAP1\",\n      \"WWTR1\",\n      \"VGLL2\",\n      \"VGLL3\",\n      \"VGLL4\",\n      \"MEN1\",\n      \"BRD4\",\n      \"VGLL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}