{"gene":"TEAD1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1991,"finding":"TEF-1 (TEAD1) was cloned and shown to specifically bind the SV40 GT-IIC and Sph enhansons. Its trans-activation function is mediated by a highly limiting, cell-specific, titratable transcriptional intermediary factor(s), demonstrated by squelching/repression assays and GAL4 chimera experiments in HeLa and MPC11 cells. Translation initiates exclusively at an AUU codon in vivo.","method":"cDNA cloning, in vitro/in vivo transcription assays, GAL4 chimera squelching experiments, cell-free transcription","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — original cloning paper with in vitro reconstitution, mutagenesis-equivalent chimera experiments, and multiple orthogonal assays; foundational and replicated across subsequent work","pmids":["1851669"],"is_preprint":false},{"year":1994,"finding":"Muscle-enriched TEF-1 (TEAD1) isoforms TEF-1A and TEF-1B bind M-CAT elements from muscle-specific promoters with high affinity and in a sequence-specific manner. The C-terminal exon unique to TEF-1B confers transcriptional activation ability, whereas the equivalent domain of TEF-1A cannot activate transcription when linked to a heterologous DNA-binding domain.","method":"cDNA cloning from chick heart, electrophoretic mobility shift assay (EMSA), transient transfection with GAL4 chimera reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro DNA-binding assays plus functional chimera reporter experiments in a single rigorous study establishing isoform-specific transcriptional activity","pmids":["8106348"],"is_preprint":false},{"year":2002,"finding":"TEF-1 (TEAD1) physically interacts with the MADS domain of MEF2 transcription factors, requiring additional sequences in both proteins' activation domains beyond the MADS domain alone for in vivo association. This interaction functionally co-activates muscle-specific promoters.","method":"Co-immunoprecipitation, GST pull-down assay, mammalian two-hybrid assay, transient transfection reporter assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down plus functional reporter assays, single lab with multiple orthogonal methods","pmids":["12061776"],"is_preprint":false},{"year":2004,"finding":"A missense mutation Y421H in TEAD1 is the causative allele in Sveinsson's chorioretinal atrophy (SCRA). Y421 lies in a conserved C-terminal region that is a potential binding site for the co-factor YAP65, which is expressed in human retina along with TEAD1.","method":"Genome-wide linkage analysis, sequencing, LOD score analysis, RT-PCR expression analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — genetic mapping with high LOD score identifies causative mutation; molecular mechanism inferred from sequence conservation and co-factor binding site prediction without direct biochemical confirmation of binding disruption in this paper","pmids":["15016762"],"is_preprint":false},{"year":2005,"finding":"TEAD1 (TEF-1) interacts with the transcriptional co-activator TAZ both in vitro and in vivo. TAZ interacts with TEAD1 while TEAD1 is bound to MCAT DNA. TAZ interacts more efficiently with TEF-1 (TEAD1) than with RTEF-1 (TEAD4), demonstrating differential co-activator association among TEAD family members.","method":"GST pull-down assay, co-immunoprecipitation, modified mammalian two-hybrid assay, EMSA with purified proteins","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP, GST pull-down, EMSA, and two-hybrid assays in one study; multiple orthogonal methods establishing direct interaction","pmids":["15628970"],"is_preprint":false},{"year":2007,"finding":"The SCRA-associated missense mutation Y410H in mouse Tead1 (corresponding to human Y421H) abolishes direct interaction between Tead1 and co-factors YAP and TAZ, but not with Vgl-1, -2, or -3. The mutation eliminates the transcriptional activity of Tead1 when co-expressed with YAP or TAZ, establishing that Y421 is essential for YAP/TAZ binding.","method":"Mammalian two-hybrid assay, GST pull-down with purified proteins, site-directed mutagenesis, transcriptional reporter assays in RPE-J cells","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct reconstitution of binding disruption by mutagenesis, GST pull-down plus functional reporter assays, multiple orthogonal methods in single study","pmids":["17689488"],"is_preprint":false},{"year":2008,"finding":"Tead1 and Tead2 are functionally redundant in mouse development; double-knockout embryos die at E9.5 with severe growth defects including absence of notochord, closed neural tube, and somites. Genetic interaction experiments demonstrate that Tead1/Tead2 use YAP as a major co-activator in vivo. Tead1/Tead2 double-knockout embryos show reduced cell proliferation and increased apoptosis.","method":"Generation of Tead1 and Tead2 knockout mice, genetic epistasis with Yap mutants, embryo phenotyping, cell proliferation/apoptosis assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic loss-of-function with defined cellular phenotypes and genetic epistasis with YAP, replicated across multiple mutant combinations","pmids":["18332127"],"is_preprint":false},{"year":2010,"finding":"Taz and its co-activator Tead1 regulate expression of the EMT transcription factor Zeb1 in RPE cells. Nuclear translocation of Taz-TEAD1 coincides with loss of cell-cell contact and onset of Zeb1 expression. shRNA knockdown of Taz prevents Zeb1 overexpression and blocks proliferation, repression of Mitf, and EMT. Taz directly binds the Zeb1 promoter in vivo.","method":"shRNA knockdown, real-time PCR, immunofluorescence for subcellular localization, chromatin immunoprecipitation (ChIP)","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms in vivo promoter binding, functional KD with defined phenotypic readouts, single lab with multiple methods","pmids":["20207963"],"is_preprint":false},{"year":2011,"finding":"TEAD1 directly regulates FoxO3a transcription in skeletal muscle by binding to the M-CAT element in the foxo3a promoter, as demonstrated by ChIP-on-chip, independent ChIP-PCR, EMSA, and luciferase reporter assays. Overexpression and inhibition experiments confirm FoxO3a is positively regulated by TEAD1.","method":"ChIP-on-chip, ChIP-PCR, EMSA, luciferase reporter assay, overexpression/knockdown experiments","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, reporter) confirming direct promoter binding and transcriptional regulation, single lab","pmids":["21211055"],"is_preprint":false},{"year":2012,"finding":"TEAD1 overexpression arrests the C2C12 myoblast cell cycle and promotes differentiation. TEAD1 directly regulates three novel target genes: Mrpl21 and Ndufa6 (upregulated during differentiation) and Ccne1 (downregulated). Regulation was confirmed by promoter activity assays.","method":"Overexpression experiments, expression analysis, promoter activity measurement assay, cell cycle analysis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional overexpression with defined cellular phenotypes and promoter activity validation, single lab","pmids":["23220227"],"is_preprint":false},{"year":2016,"finding":"Tead1 and co-activators Yap and Taz are required for PMP22 expression in Schwann cells, as well as for expression of Egr2. Tead1 directly binds PMP22 and Egr2 enhancers early in development and its binding is induced during myelination, correlating with PMP22 expression.","method":"ChIP, analysis of enhancer histone modifications, KD/KO with gene expression readouts, developmental binding analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct enhancer binding in vivo, functional requirement established by knockdown, single lab with multiple methods","pmids":["27288457"],"is_preprint":false},{"year":2016,"finding":"Myofiber-specific TEAD1 overexpression in transgenic mice causes non-cell-autonomous hyperplasia of satellite cells (muscle stem cells) without affecting muscle tissue size, establishing that TEAD1 in myofibers activates a signaling pathway that determines satellite cell pool size.","method":"Transgenic mouse overexpression model, satellite cell quantification, regeneration assays, muscle injury models","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean transgenic gain-of-function with defined cellular phenotype and non-cell-autonomous mechanism established, single lab","pmids":["27725085"],"is_preprint":false},{"year":2016,"finding":"TEAD1 enhances CRC cell proliferation by directly binding the SP1 promoter and activating SP1 expression, as demonstrated by luciferase assay and ChIP assay.","method":"Luciferase reporter assay, ChIP assay, siRNA knockdown, overexpression, cell proliferation assays","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ChIP and reporter assays but limited mechanistic follow-up beyond promoter binding","pmids":["27434865"],"is_preprint":false},{"year":2017,"finding":"Tead1 is a cell-autonomous direct transcriptional activator of SERCA2a and the SR-associated protein phosphatase 1 regulatory subunit Inhibitor-1 (I-1) in adult cardiomyocytes. Tead1 deletion causes lethal dilated cardiomyopathy, decreasing SERCA2a and I-1 protein levels, increasing PP1 activity, accumulating dephosphorylated phospholamban, and impairing excitation-contraction coupling.","method":"Tamoxifen-inducible CM-specific Tead1 knockout, global transcriptomic analysis, mechanistic biochemical assays (PP1 activity, phospholamban phosphorylation), iPSC-derived CM validation","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible conditional KO with defined molecular mechanism, multiple orthogonal readouts, validated in human iPSC-CMs","pmids":["28878117"],"is_preprint":false},{"year":2018,"finding":"TEAD1 occupies chromatin at AQP4, EGFR, and CDH4 loci in glioblastoma stem cells, validated by ChIP-PCR. CRISPR-Cas9 knockout of TEAD1 robustly diminishes GBM cell migration in vitro and in vivo, with consistent downregulation of its target AQP4. TEAD1 overexpression restores AQP4 expression and rescues migratory deficits in TEAD1-KO cells.","method":"ATAC-seq, ChIP-PCR, CRISPR-Cas9 KO, in vitro and in vivo migration assays, transcriptome analysis, overexpression rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with defined in vitro and in vivo phenotype, ChIP validation of direct target, rescue experiment, multiple orthogonal methods","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 fails to bind TEAD1 attenuates these effects.","method":"siRNA knockdown, YAP1 mutant constructs (S127A/S94A), in vitro angiogenesis sprouting assay, in vivo fibrin gel vascular morphogenesis, oxygen consumption measurement","journal":"Microvascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutant strategy distinguishes TEAD1-dependent from independent YAP1 effects, single lab with multiple functional readouts","pmids":["29680477"],"is_preprint":false},{"year":2019,"finding":"VGLL3 binds TEAD1, TEAD3, and TEAD4 in myoblasts and/or myotubes, as identified by interaction proteomics. VGLL3 mainly represses gene expression, regulating similar genes to those regulated by YAP and TAZ. siRNA-mediated Vgll3 knockdown suppresses myoblast proliferation, and Vgll3 overexpression promotes myogenic differentiation.","method":"Interaction proteomics (pulldown/MS), siRNA knockdown, overexpression, gene expression analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction proteomics plus functional KD/OE with defined phenotypic readouts, single lab","pmids":["31138678"],"is_preprint":false},{"year":2019,"finding":"TEAD1 is essential for vascular smooth muscle cell (VSMC) differentiation and cardiovascular development. CMC/VSMC-specific Tead1 deletion causes embryonic lethality by E14.5 due to hypoplastic cardiac and vascular walls and impaired proliferation. TEAD1 transcriptionally activates Pitx2c as a novel target gene, and Pitx2c and myocardin rescue TEAD1-dependent defects in VSMC differentiation. Pitx2c directly interacts with myocardin to augment VSMC differentiation.","method":"Conditional Tead1 KO mice, whole transcriptome analysis, in vitro rescue experiments, identification of Pitx2c as transcriptional target, co-IP for Pitx2c-myocardin interaction","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined lethal phenotype, transcriptome analysis, novel target identification, rescue experiments, multiple orthogonal methods","pmids":["31024075"],"is_preprint":false},{"year":2019,"finding":"TEAD1 directly activates the miR-222 promoter by physically binding to it (validated by ChIP assay) in gastric cancer cells. TEAD1 knockdown decreases miR-222 expression and increases VGLL4 expression, establishing a miR-222/VGLL4/YAP-TEAD1 regulatory loop.","method":"ChIP assay, siRNA knockdown, luciferase assay, expression analysis","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP assay with limited mechanistic follow-up, single lab","pmids":["26045994"],"is_preprint":false},{"year":2019,"finding":"Tead1 is required for perinatal cardiomyocyte proliferation. Perinatal CM-specific deletion of Tead1 (Myh6-Cre) leads to lethal dilated cardiomyopathy by postnatal day 9 due to significantly decreased CM proliferation. Cell-autonomous Tead1 function is required for normal CM proliferation, associated with decreased levels of cell cycle-promoting proteins.","method":"Perinatal CM-specific conditional KO (Myh6-Cre), echocardiography, histology, proliferation assays, HL-1 cell line KO confirmation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined lethal phenotype and cell-autonomous validation in cell line, single lab","pmids":["30811446"],"is_preprint":false},{"year":2020,"finding":"YAP-TEAD1 complex targets key genes encoding proteins involved in cytoskeleton dynamics in human pluripotent stem cells, controlling focal adhesion gene transcription and intracellular tension. YAP-TEAD1 inactivation is needed to adjust PSC mechanical properties in response to physiological substrate stiffness during germ layer specification.","method":"Tankyrase inhibition (AMOT/YAP axis), TEAD1 reporter assays, gene expression analysis, mechanobiology assays","journal":"Cell death and differentiation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — limited direct mechanistic evidence for TEAD1-specific role; YAP-TEAD1 complex activity inferred from inhibitor studies without direct TEAD1 KO/KI","pmids":["33116297"],"is_preprint":false},{"year":2020,"finding":"Tead1 directly suppresses Apln (apelin) transcription in myogenic cells; Tead1 knockdown stimulates Apln secretion in vitro and myofiber-specific Tead1 overexpression suppresses Apln secretion in vivo. Secreted apelin acts on endothelial Aplnr to stimulate endothelial cell expansion, establishing a Tead1-Apln paracrine axis from myogenic to endothelial cells.","method":"Yeast one-hybrid screen, single-cell RNA-seq, siRNA knockdown, myofiber-specific overexpression in vivo, co-culture assays, Apln peptide supplementation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast one-hybrid identifies binding, in vitro KD and in vivo OE confirm secretion regulation, single lab with multiple orthogonal approaches","pmids":["35789856"],"is_preprint":false},{"year":2021,"finding":"Tead1 deletion in adult cardiomyocytes activates necroptosis (not apoptosis) and causes lethal dilated cardiomyopathy. Mechanistically, Tead1 directly activates nuclear DNA-encoded mitochondrial genes required for electron transport chain assembly and ATP production (genome-wide ChIP-seq). Loss of Tead1 increases mitochondrial ROS, disrupts mitochondrial structure, and reduces complex I–IV oxygen consumption. Necrostatin-1 blocks necroptosis and rescues Tead1-deletion-induced heart failure.","method":"CM-specific and ubiquitous Tead1 KO, RNA-seq, ChIP-seq, mitochondrial function assays, necrostatin-1 rescue, inflammatory marker quantification","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide ChIP-seq establishes direct targets, ChIP confirmed by orthogonal KO phenotype, pharmacological rescue, multiple independent methods in single rigorous study","pmids":["33469230"],"is_preprint":false},{"year":2021,"finding":"VGLL1 co-activates TEAD1-mediated transcription of HPV early genes. TEAD1 binds 11 sites in the HPV16 long control region (LCR) identified by in vitro DNA pulldown; 8 contribute to early promoter activation. VGLL1 is recruited to the HPV16 LCR via its interaction with TEAD1 both in vitro and in vivo. Knockdown of VGLL1 and/or TEAD1 decreases viral early gene expression.","method":"In vitro DNA pulldown, luciferase reporter assays, ChIP, siRNA knockdown, co-IP","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays, ChIP confirming in vivo recruitment, functional KD experiments, single lab with multiple orthogonal methods","pmids":["32132238"],"is_preprint":false},{"year":2021,"finding":"YAP/TEAD1 complex directly represses cardiac TLR genes. TEAD1 directly binds genomic regions adjacent to Tlr1–7 and Tlr9 in cardiomyocytes. YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near its transcription start site (luciferase reporter). Cardiomyocyte-specific YAP depletion increases TLR gene expression, pro-inflammatory cytokines, and cardiac susceptibility to LPS.","method":"ChIP-seq/ChIP, luciferase reporter assay, CM-specific YAP KO, gene expression analysis, LPS challenge","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays confirm direct binding and repression, functional KO phenotype, single lab","pmids":["34206257"],"is_preprint":false},{"year":2021,"finding":"Tead1 overexpression (replacing TBX5 in a GMT cocktail) nearly 3-fold increases cardiac troponin T expression in fibroblasts compared to GMT alone, increases H3K4me3 at cardio-differentiation and mitochondrial biogenesis gene promoters, and enables cell contractility (beating). YAP and TAZ failed to enhance cTnT expression.","method":"Fibroblast reprogramming assay, immunofluorescence for cTnT/sarcomere, ChIP for H3K4me3, beating cell assay","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gain-of-function with specific epigenetic readout (H3K4me3 ChIP), specific TEAD1 vs YAP/TAZ comparison, single lab","pmids":["34889103"],"is_preprint":false},{"year":2022,"finding":"TEAD1 has a pocket region-independent direct transcriptional repression mechanism controlling cell proliferation. TEAD1 directly represses a class of target genes by interfering with RNA polymerase II (POLII) binding to target promoters, independently of YAP/TAZ/VGLL4 co-factor binding to the TEAD1 hydrophobic pocket. TEAD1 overexpression represses tumor cell proliferation; β cell-specific TEAD1 KO increases cell-autonomous β cell proliferation. TEAD1 controls transcription in a motif-dependent, orientation-independent manner.","method":"Conditional KO, transcriptomic profiling, cistromic analysis (ChIP-seq), overexpression in cancer cell lines, POLII ChIP, promoter orientation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide ChIP-seq plus transcriptomics, POLII ChIP mechanistically distinguishes repression mode from co-factor-mediated activation, multiple orthogonal methods, single rigorous study","pmids":["36484096"],"is_preprint":false},{"year":2022,"finding":"RBFOX2 promotes inclusion of TEAD1 exon 6 via binding to a conserved GCAUG element in the downstream intron, generating full-length TEAD1. The full-length isoform has greater transcriptional activity and oncogenic properties than the TEAD1ΔE6 isoform, with the difference attributable to differential YAP interaction.","method":"Alternative splicing analysis, public database correlation, isoform-specific functional assays, RBFOX2 KD, RNA-binding motif analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RBFOX2 KD and functional isoform comparison with YAP interaction assays, single lab","pmids":["35699208"],"is_preprint":false},{"year":2022,"finding":"VGLL4 and MENIN function as TEAD1 co-repressors in pancreatic β cells. Both proteins bind TEAD1 and repress expression of its target genes FZD7 and CCN2, leading to inhibition of β cell proliferation. β cell-specific TEAD1 deletion results in cell-autonomous increase in β cell proliferation, while deletion of canonical co-activators YAP and TAZ does not affect proliferation.","method":"Improved split-GFP system, yeast two-hybrid, conditional KO (TEAD1, YAP, TAZ in β cells), gene expression analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel co-repressor identification by split-GFP and yeast two-hybrid, validated by conditional KO phenotypes, single lab","pmids":["36662616"],"is_preprint":false},{"year":2023,"finding":"Mutant Lamin A/C (Q353R) traps TEAD1 at the nuclear membrane in cardiomyocytes, preventing it from activating cardiac developmental gene targets, causing dilated cardiomyopathy. Inhibition of the Hippo pathway rescued dysregulation of cardiac developmental genes caused by TEAD1 trapping in LMNA-mutant cardiomyocytes.","method":"Single-cell RNA-seq, ATAC-seq, protein array, electron microscopy, Hippo pathway inhibitor rescue experiments, human DCM patient tissue validation","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal omics methods, mechanistic protein-interaction mechanism, pharmacological rescue, human patient tissue confirmation","pmids":["37058558"],"is_preprint":false},{"year":2024,"finding":"TEAD1 is SUMOylated at lysine 173 by SUMO1, a modification regulated by SENP1-mediated deSUMOylation during cardiac hypertrophy. SUMOylation affects TEAD1 protein stability, nuclear localization, DNA-binding ability, and enhances its interaction with YAP1. DeSUMOylation of TEAD1 (K173R mutant) markedly exacerbates cardiomyocyte enlargement in vitro and in hypertrophy mouse models.","method":"SUMOylation assays, site-directed mutagenesis (K173R), co-IP, nuclear localization imaging, AAV9-mediated in vivo cardiac expression, mouse hypertrophy model","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific mutagenesis identifies SUMOylation site, multiple functional readouts, in vivo AAV rescue/phenotype model, identifies writer (SUMO1) and eraser (SENP1)","pmids":["38225750"],"is_preprint":false},{"year":2024,"finding":"TM7SF3 controls alternative splicing of TEAD1 by maintaining the splicing factor hnRNPU. TM7SF3 deletion inhibits hnRNPU, causing exclusion of inhibitory exon 5 and generating a more transcriptionally active TEAD1 isoform that promotes hepatic stellate cell (HSC) activation and liver fibrosis. An antisense oligomer (ASO) that blocks TEAD1 alternative splicing deactivates HSCs in vitro and reduces MASH-induced liver fibrosis in vivo.","method":"Genetic deletion (TM7SF3 KO), liver organoids, primary human HSCs, in vivo MASH mouse model, splicing analysis, ASO intervention","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — TM7SF3-hnRNPU-TEAD1 splicing axis established by genetic and molecular methods, in vitro and in vivo validation, ASO pharmacological rescue","pmids":["38670107"],"is_preprint":false},{"year":2024,"finding":"TEAD1 promotes cardiac fibroblast-to-myofibroblast transition through the BRD4/Wnt4 signaling pathway. Wnt4 is a novel direct TEAD1 transcriptional target identified by RNA-seq and ChIP-seq. TEAD1 interacts with BET protein BRD4 (demonstrated by Co-IP/mass spectrometry and ChIP), leading to binding and activation of the Wnt4 promoter. CFs-specific TEAD1 KO and TEAD1 inhibitor VT103 ameliorate TAC-induced cardiac remodeling.","method":"Conditional CF/myofibroblast-specific TEAD1 KO, RNA-seq, ChIP-seq, Co-IP with mass spectrometry, luciferase assay, TAC and Ang-II mouse models, pharmacological inhibition with VT103","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-seq establishes direct target, Co-IP/MS identifies BRD4 interaction, multiple orthogonal methods, in vivo conditional KO and pharmacological rescue","pmids":["38374140"],"is_preprint":false},{"year":2024,"finding":"TEAD1 is essential for Schwann cell developmental myelination and nerve regeneration. TEAD1 promotes myelination by positively and negatively 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 TEAD1 KO mice, SC-specific phenotyping, gene expression analysis, electron microscopy","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional and inducible KO with defined cellular and molecular phenotypes at multiple developmental stages, multiple orthogonal methods","pmids":["38456457"],"is_preprint":false},{"year":2024,"finding":"Endothelial YAP/TEAD1 complex promotes CXCL17 transcription in hepatic endothelial cells during ischemia-reperfusion. Hypoxia-reoxygenation activates the YAP/TEAD1 complex to upregulate CXCL17, which recruits myeloid-derived suppressor cells (MDSCs) via GPR35 to attenuate liver injury.","method":"Bulk RNA-seq, in vivo YAP/TEAD1 manipulation, CXCL17 reporter, adoptive transfer experiments, mouse IRI model","journal":"Hepatology","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — RNA-seq and in vivo experiments identify pathway but direct TEAD1 binding to CXCL17 promoter not directly demonstrated in this abstract; mechanism relies on YAP/TEAD1 complex activity inference","pmids":["38407233"],"is_preprint":false}],"current_model":"TEAD1 (TEF-1) is a TEA-domain transcription factor that binds MCAT and GT-IIC DNA elements and requires co-activators (YAP, TAZ, VGLL proteins) or co-repressors (VGLL4, MENIN) that dock at its hydrophobic pocket to regulate target gene transcription; it also possesses a pocket-independent direct repression mechanism via interference with RNA polymerase II binding; its activity is modulated by SUMOylation at K173 (by SUMO1/SENP1) affecting stability, nuclear localization, and YAP interaction, and by alternative splicing (regulated by RBFOX2 and hnRNPU/TM7SF3); in the heart, TEAD1 directly activates SERCA2a, Inhibitor-1, and nuclear-encoded mitochondrial genes essential for oxidative phosphorylation, and its loss causes necroptotic dilated cardiomyopathy, while in development it acts redundantly with TEAD2 using YAP as a major co-activator to support notochord maintenance, cardiomyocyte proliferation, VSMC differentiation (via Pitx2c/myocardin), and Schwann cell myelination (via Egr2/PMP22/FDPS/IDI1)."},"narrative":{"mechanistic_narrative":"TEAD1 (TEF-1) is a sequence-specific TEA-domain transcription factor that binds MCAT/GT-IIC enhansons and depends on a cell-limiting transcriptional intermediary factor to activate transcription [PMID:1851669, PMID:8106348]. Its output is set by docking of co-regulators at a conserved C-terminal surface: the co-activators YAP and TAZ bind through residue Y421, whose mutation (Y421H/Y410H) abolishes YAP/TAZ binding and underlies Sveinsson's chorioretinal atrophy [PMID:15016762, PMID:17689488, PMID:15628970], while VGLL family proteins and MENIN act as co-repressors at the same axis [PMID:31138678, PMID:36662616, PMID:32132238]. Beyond co-factor-dependent control, TEAD1 also directly represses a class of genes by interfering with RNA polymerase II recruitment independently of its hydrophobic pocket, a mode that restrains proliferation [PMID:36484096]. TEAD1 activity is further tuned by SUMOylation at K173 (by SUMO1, reversed by SENP1), which governs its stability, nuclear localization, DNA binding, and YAP interaction [PMID:38225750], and by alternative splicing controlled by RBFOX2 and the TM7SF3/hnRNPU axis, which switch TEAD1 between isoforms of differing transcriptional strength [PMID:35699208, PMID:38670107]. In the heart, TEAD1 is a cell-autonomous activator of SERCA2a, Inhibitor-1, and nuclear-encoded mitochondrial/electron-transport-chain genes; its loss collapses calcium handling and oxidative phosphorylation and triggers necroptotic dilated cardiomyopathy rescuable by necrostatin-1 [PMID:28878117, PMID:33469230], and its mislocalization by mutant Lamin A/C similarly causes cardiomyopathy [PMID:37058558]. Across development TEAD1 acts redundantly with TEAD2 using YAP as a major co-activator to support notochord and embryonic growth [PMID:18332127], cardiomyocyte and vascular smooth muscle proliferation/differentiation (via Pitx2c/myocardin) [PMID:31024075, PMID:30811446], and Schwann cell myelination (via Egr2 and cholesterol enzymes FDPS/IDI1) [PMID:38456457], and it drives pro-fibrotic and oncogenic programs in fibroblasts, glioblastoma, and other cancers [PMID:38374140, PMID:30275445].","teleology":[{"year":1991,"claim":"Established TEAD1 as a sequence-specific enhancer-binding factor whose activation depends on a limiting cellular cofactor rather than an intrinsic strong activation domain, framing the central question of co-factor dependence.","evidence":"cDNA cloning with in vitro/in vivo transcription and GAL4 chimera squelching in HeLa and MPC11 cells","pmids":["1851669"],"confidence":"High","gaps":["Identity of the limiting transcriptional intermediary factor not defined","No structural basis for cofactor docking"]},{"year":1994,"claim":"Showed that TEAD1 isoforms bind muscle MCAT elements with high affinity and that a single C-terminal exon confers activation capacity, linking isoform structure to transcriptional output.","evidence":"cDNA cloning from chick heart, EMSA, GAL4 chimera reporter assays","pmids":["8106348"],"confidence":"High","gaps":["Mechanism by which the C-terminal exon recruits coactivators not defined","Tissue distribution of isoforms not mapped"]},{"year":2002,"claim":"Identified MEF2 as a direct partner that co-activates muscle promoters, expanding TEAD1's combinatorial control beyond Hippo coactivators.","evidence":"Co-IP, GST pull-down, mammalian two-hybrid, reporter assays","pmids":["12061776"],"confidence":"Medium","gaps":["Interaction surface not mapped","In vivo requirement of TEAD1-MEF2 cooperation not tested"]},{"year":2004,"claim":"Connected TEAD1 to human Mendelian disease by mapping the Y421H mutation as causative for Sveinsson's chorioretinal atrophy, implicating a YAP65-binding region.","evidence":"Genome-wide linkage, sequencing, LOD analysis, RT-PCR","pmids":["15016762"],"confidence":"Medium","gaps":["Direct biochemical disruption of binding not shown in this study","Retinal target genes not identified"]},{"year":2005,"claim":"Demonstrated TAZ as a direct DNA-bound co-activator with TEAD-family selectivity, refining which Hippo effectors engage TEAD1.","evidence":"GST pull-down, Co-IP, modified two-hybrid, EMSA with purified proteins","pmids":["15628970"],"confidence":"High","gaps":["Structural basis of differential TEAD1 vs TEAD4 affinity not resolved","In vivo consequences of TAZ-TEAD1 selectivity not tested"]},{"year":2007,"claim":"Established Y421 as the essential YAP/TAZ-binding residue, mechanistically explaining the SCRA mutation as a coactivator-binding defect distinct from VGLL binding.","evidence":"Two-hybrid, GST pull-down, site-directed mutagenesis, reporter assays in RPE-J cells","pmids":["17689488"],"confidence":"High","gaps":["Does not address pocket-independent TEAD1 functions","No structural model of the disrupted interface in this study"]},{"year":2008,"claim":"Defined TEAD1/TEAD2 functional redundancy and YAP as the major in vivo coactivator, establishing the developmental requirement for TEAD-YAP signaling.","evidence":"Tead1/Tead2 knockout mice, genetic epistasis with Yap, embryo phenotyping","pmids":["18332127"],"confidence":"High","gaps":["TEAD1-specific (non-redundant) targets not separated from TEAD2","Direct target genes underlying notochord/somite defects not defined"]},{"year":2010,"claim":"Linked TAZ-TEAD1 to EMT control through direct activation of Zeb1, connecting mechanotransduction to epithelial state changes.","evidence":"shRNA knockdown, qPCR, immunofluorescence, ChIP in RPE cells","pmids":["20207963"],"confidence":"Medium","gaps":["ChIP demonstrated TAZ binding; direct TEAD1 promoter occupancy at Zeb1 not separately resolved","In vivo relevance not tested"]},{"year":2011,"claim":"Identified FoxO3a as a direct MCAT-element target of TEAD1 in skeletal muscle, broadening its direct regulon.","evidence":"ChIP-on-chip, ChIP-PCR, EMSA, luciferase, overexpression/knockdown","pmids":["21211055"],"confidence":"Medium","gaps":["Cofactor dependence of FoxO3a activation not defined","Physiological phenotype of the TEAD1-FoxO3a axis not established"]},{"year":2012,"claim":"Showed TEAD1 couples myoblast cell-cycle exit to differentiation through direct mitochondrial (Ndufa6, Mrpl21) and cell-cycle (Ccne1) targets, foreshadowing its mitochondrial gene control.","evidence":"Overexpression, expression analysis, promoter activity assays, cell-cycle analysis in C2C12","pmids":["23220227"],"confidence":"Medium","gaps":["Direct binding shown only by promoter activity, not genome-wide ChIP","Cofactor requirement unresolved"]},{"year":2016,"claim":"Established TEAD1 (with YAP/TAZ) as a direct regulator of Schwann cell myelination genes PMP22 and Egr2, with developmentally induced enhancer binding.","evidence":"ChIP, enhancer histone modification analysis, KD/KO expression readouts","pmids":["27288457"],"confidence":"Medium","gaps":["Mechanism of developmentally timed binding not defined","Distinction from cofactor recruitment kinetics unresolved"]},{"year":2016,"claim":"Revealed a non-cell-autonomous role: myofiber TEAD1 sets satellite-cell pool size via a secreted signal, decoupling TEAD1 transcriptional output from autonomous growth.","evidence":"Myofiber-specific transgenic overexpression, satellite-cell quantification, regeneration/injury assays","pmids":["27725085"],"confidence":"Medium","gaps":["Secreted effector not identified in this study","Receiving-cell signaling pathway undefined"]},{"year":2016,"claim":"Implicated TEAD1 in colorectal cancer proliferation via direct activation of SP1.","evidence":"Luciferase, ChIP, siRNA, overexpression, proliferation assays","pmids":["27434865"],"confidence":"Low","gaps":["Single lab with limited mechanistic follow-up beyond promoter binding","Cofactor and in vivo relevance not established"]},{"year":2017,"claim":"Identified TEAD1 as a cell-autonomous activator of calcium-handling genes SERCA2a and Inhibitor-1 in adult cardiomyocytes, defining a direct mechanism for excitation-contraction coupling and dilated cardiomyopathy on its loss.","evidence":"Inducible CM-specific KO, transcriptomics, PP1/phospholamban biochemistry, iPSC-CM validation","pmids":["28878117"],"confidence":"High","gaps":["Cofactor partners driving SERCA2a/I-1 activation not defined","Direct ChIP at these promoters not shown here"]},{"year":2018,"claim":"Showed TEAD1 directly drives glioblastoma stem-cell migration through AQP4/EGFR/CDH4, with rescue establishing AQP4 as a key effector.","evidence":"ATAC-seq, ChIP-PCR, CRISPR KO, in vitro/in vivo migration, overexpression rescue","pmids":["30275445"],"confidence":"High","gaps":["Cofactor dependence in GBM not dissected","Upstream signals activating TEAD1 in GBM undefined"]},{"year":2018,"claim":"Linked YAP1-TEAD1 to mitochondrial biogenesis and angiogenesis via PGC1α in endothelial cells, reinforcing TEAD1's metabolic regulatory role.","evidence":"siRNA, YAP1 S94A/S127A mutants, sprouting and vascular morphogenesis assays, oxygen consumption","pmids":["29680477"],"confidence":"Medium","gaps":["Direct TEAD1 binding at PGC1α not shown","Distinction from YAP1-independent effects partial"]},{"year":2019,"claim":"Defined VGLL3 as a TEAD-binding co-repressor in muscle that regulates a YAP/TAZ-overlapping gene set, expanding the repressive arm of TEAD1 control.","evidence":"Interaction proteomics, siRNA, overexpression, expression analysis in myoblasts/myotubes","pmids":["31138678"],"confidence":"Medium","gaps":["TEAD1-specific (vs TEAD3/4) repressive targets not separated","Mechanism of repression not defined"]},{"year":2019,"claim":"Established TEAD1 as essential for VSMC differentiation and cardiovascular development, identifying Pitx2c as a direct target acting with myocardin.","evidence":"Conditional KO mice, transcriptomics, in vitro rescue, Co-IP for Pitx2c-myocardin","pmids":["31024075"],"confidence":"High","gaps":["Cofactor dependence of Pitx2c activation not defined","Direct ChIP at Pitx2c in vivo not shown here"]},{"year":2019,"claim":"Showed cell-autonomous TEAD1 is required for perinatal cardiomyocyte proliferation, distinguishing a proliferative program from the later metabolic/contractile one.","evidence":"Perinatal CM-specific KO (Myh6-Cre), echocardiography, histology, HL-1 KO","pmids":["30811446"],"confidence":"Medium","gaps":["Direct proliferative target genes not identified","Cofactor identity not defined"]},{"year":2019,"claim":"Placed TEAD1 in a miR-222/VGLL4/YAP-TEAD1 feedback loop in gastric cancer via direct miR-222 promoter activation.","evidence":"ChIP, siRNA, luciferase, expression analysis","pmids":["26045994"],"confidence":"Low","gaps":["Single ChIP with limited follow-up","In vivo relevance untested"]},{"year":2020,"claim":"Connected YAP-TEAD1 to cytoskeletal/focal-adhesion gene control and mechanosensing during stem-cell germ-layer specification.","evidence":"Tankyrase inhibition, TEAD1 reporter, expression analysis, mechanobiology assays","pmids":["33116297"],"confidence":"Low","gaps":["TEAD1-specific role inferred from inhibitor studies without direct TEAD1 KO/KI","Direct target binding not shown"]},{"year":2020,"claim":"Identified a TEAD1-Apln paracrine axis: direct repression of apelin in myofibers controls endothelial expansion, mechanistically explaining non-cell-autonomous vascular effects.","evidence":"Yeast one-hybrid, scRNA-seq, siRNA, myofiber-specific overexpression, co-culture, peptide supplementation","pmids":["35789856"],"confidence":"Medium","gaps":["Cofactor mediating Apln repression not defined","Relation to pocket-independent repression mode unresolved"]},{"year":2021,"claim":"Defined the mechanism of TEAD1-loss cardiomyopathy as necroptosis driven by failure to activate nuclear-encoded mitochondrial ETC genes, with pharmacological rescue by necrostatin-1.","evidence":"CM-specific/ubiquitous KO, RNA-seq, ChIP-seq, mitochondrial assays, necrostatin-1 rescue","pmids":["33469230"],"confidence":"High","gaps":["Cofactor requirement for mitochondrial gene activation not defined","Trigger linking ETC failure to necroptosis machinery incompletely mapped"]},{"year":2021,"claim":"Showed VGLL1 co-activates TEAD1 at the HPV16 control region to drive viral early gene expression, demonstrating viral hijacking of TEAD1.","evidence":"In vitro DNA pulldown, luciferase, ChIP, siRNA, Co-IP","pmids":["32132238"],"confidence":"Medium","gaps":["Structural basis of VGLL1-TEAD1 recruitment not resolved","In vivo viral life-cycle relevance not tested"]},{"year":2021,"claim":"Revealed a YAP/TEAD1 repressive function silencing cardiac TLR genes to restrain innate immunity, broadening the repressive regulon.","evidence":"ChIP-seq/ChIP, luciferase, CM-specific YAP KO, LPS challenge","pmids":["34206257"],"confidence":"Medium","gaps":["Mechanism of YAP-dependent repression vs canonical activation unresolved","Cofactor switch determining repression undefined"]},{"year":2021,"claim":"Demonstrated TEAD1 can replace TBX5 in cardiac reprogramming and uniquely deposit H3K4me3 at cardiac/mitochondrial genes, an activity not reproduced by YAP/TAZ.","evidence":"Fibroblast reprogramming, cTnT/sarcomere IF, H3K4me3 ChIP, beating assay","pmids":["34889103"],"confidence":"Medium","gaps":["Chromatin-modifying partner mediating H3K4me3 not identified here","Mechanism distinguishing TEAD1 from YAP/TAZ unresolved"]},{"year":2022,"claim":"Established a pocket-independent direct repression mode in which TEAD1 blocks POLII recruitment to restrain proliferation, separating it mechanistically from cofactor-dependent activation.","evidence":"Conditional KO, transcriptomics, ChIP-seq, POLII ChIP, promoter-orientation assays","pmids":["36484096"],"confidence":"High","gaps":["Structural basis of POLII interference not defined","Determinants selecting genes for repression vs activation unresolved"]},{"year":2022,"claim":"Showed RBFOX2-dependent inclusion of exon 6 generates a full-length, more oncogenic TEAD1 isoform with enhanced YAP interaction, linking splicing to transcriptional strength.","evidence":"Splicing analysis, isoform functional assays, RBFOX2 KD, motif analysis","pmids":["35699208"],"confidence":"Medium","gaps":["Structural basis of isoform-dependent YAP affinity not resolved","In vivo splicing control not tested here"]},{"year":2022,"claim":"Identified VGLL4 and MENIN as TEAD1 co-repressors in β cells controlling FZD7/CCN2 and showed TEAD1 (not YAP/TAZ) restrains β-cell proliferation, demonstrating cofactor-context-specific output.","evidence":"Split-GFP, yeast two-hybrid, conditional KO of TEAD1/YAP/TAZ, expression analysis","pmids":["36662616"],"confidence":"Medium","gaps":["Whether MENIN/VGLL4 repression uses the pocket or POLII-interference mode not separated","Direct ChIP at FZD7/CCN2 not shown here"]},{"year":2023,"claim":"Demonstrated that mutant Lamin A/C sequesters TEAD1 at the nuclear membrane to block cardiac developmental gene activation, with Hippo inhibition rescuing the defect, linking TEAD1 localization to cardiomyopathy.","evidence":"scRNA-seq, ATAC-seq, protein array, EM, Hippo inhibitor rescue, human DCM tissue","pmids":["37058558"],"confidence":"High","gaps":["Direct LMNA-TEAD1 interaction interface not mapped","Generality across other LMNA mutations untested"]},{"year":2024,"claim":"Established SUMOylation at K173 (SUMO1/SENP1) as a post-translational switch controlling TEAD1 stability, localization, DNA binding, and YAP interaction during cardiac hypertrophy.","evidence":"SUMOylation assays, K173R mutagenesis, Co-IP, localization imaging, AAV9 in vivo hypertrophy model","pmids":["38225750"],"confidence":"High","gaps":["Signals controlling SENP1 activity on TEAD1 not defined","Interplay with splicing/cofactor regulation unresolved"]},{"year":2024,"claim":"Defined a TM7SF3/hnRNPU splicing axis that controls TEAD1 exon-5 inclusion, with the active isoform driving hepatic stellate cell activation and fibrosis, and an ASO providing therapeutic correction.","evidence":"TM7SF3 KO, liver organoids, primary human HSCs, MASH mouse model, splicing analysis, ASO intervention","pmids":["38670107"],"confidence":"High","gaps":["Direct fibrotic target genes of the active isoform not fully defined","Relationship to RBFOX2-controlled exon 6 splicing unresolved"]},{"year":2024,"claim":"Showed TEAD1 drives cardiac fibroblast-to-myofibroblast transition via a BRD4/Wnt4 axis, identifying BRD4 as a chromatin partner and Wnt4 as a direct target, with VT103 inhibition rescuing remodeling.","evidence":"CF-specific KO, RNA-seq, ChIP-seq, Co-IP/MS, luciferase, TAC/Ang-II models, VT103","pmids":["38374140"],"confidence":"High","gaps":["Whether BRD4 recruitment is pocket-dependent unresolved","Generality of TEAD1-BRD4 cooperation beyond cardiac fibroblasts untested"]},{"year":2024,"claim":"Implicated endothelial YAP/TEAD1 in CXCL17-mediated MDSC recruitment protecting against hepatic ischemia-reperfusion injury.","evidence":"Bulk RNA-seq, in vivo YAP/TEAD1 manipulation, CXCL17 reporter, adoptive transfer, IRI model","pmids":["38407233"],"confidence":"Low","gaps":["Direct TEAD1 binding to CXCL17 promoter not demonstrated","TEAD1-specific contribution vs YAP-complex inference unresolved"]},{"year":null,"claim":"How TEAD1 selects between cofactor-dependent activation, pocket-independent POLII-interference repression, and cofactor-mediated repression at individual loci, and how splicing, SUMOylation, and localization integrate to set these choices, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying model linking PTMs/isoforms to activation-vs-repression choice","Locus-level determinants of cofactor recruitment undefined","No structural account of pocket-independent POLII interference"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,13,22,26]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,8,22,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,29,30]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[29]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,22,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,15,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,17,33]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[22]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13,22,15]}],"complexes":["YAP-TEAD1 complex","TAZ-TEAD1 complex"],"partners":["YAP1","TAZ","VGLL1","VGLL3","VGLL4","MENIN","MEF2","BRD4"],"other_free_text":[]}},"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":"1851669","id":"PMC_1851669","title":"Cloning, expression, and transcriptional properties of the human enhancer factor TEF-1.","date":"1991","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1851669","citation_count":382,"is_preprint":false},{"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":231,"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":203,"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":"18332127","id":"PMC_18332127","title":"Redundant roles of Tead1 and Tead2 in notochord development and the regulation of cell proliferation and survival.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18332127","citation_count":151,"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":146,"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":142,"is_preprint":false},{"pmid":"3293363","id":"PMC_3293363","title":"Cerebral arteriovenous malformations (C. 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specifically bind the SV40 GT-IIC and Sph enhansons. Its trans-activation function is mediated by a highly limiting, cell-specific, titratable transcriptional intermediary factor(s), demonstrated by squelching/repression assays and GAL4 chimera experiments in HeLa and MPC11 cells. Translation initiates exclusively at an AUU codon in vivo.\",\n      \"method\": \"cDNA cloning, in vitro/in vivo transcription assays, GAL4 chimera squelching experiments, cell-free transcription\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original cloning paper with in vitro reconstitution, mutagenesis-equivalent chimera experiments, and multiple orthogonal assays; foundational and replicated across subsequent work\",\n      \"pmids\": [\"1851669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Muscle-enriched TEF-1 (TEAD1) isoforms TEF-1A and TEF-1B bind M-CAT elements from muscle-specific promoters with high affinity and in a sequence-specific manner. The C-terminal exon unique to TEF-1B confers transcriptional activation ability, whereas the equivalent domain of TEF-1A cannot activate transcription when linked to a heterologous DNA-binding domain.\",\n      \"method\": \"cDNA cloning from chick heart, electrophoretic mobility shift assay (EMSA), transient transfection with GAL4 chimera reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro DNA-binding assays plus functional chimera reporter experiments in a single rigorous study establishing isoform-specific transcriptional activity\",\n      \"pmids\": [\"8106348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TEF-1 (TEAD1) physically interacts with the MADS domain of MEF2 transcription factors, requiring additional sequences in both proteins' activation domains beyond the MADS domain alone for in vivo association. This interaction functionally co-activates muscle-specific promoters.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down assay, mammalian two-hybrid assay, transient transfection reporter assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pull-down plus functional reporter assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12061776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A missense mutation Y421H in TEAD1 is the causative allele in Sveinsson's chorioretinal atrophy (SCRA). Y421 lies in a conserved C-terminal region that is a potential binding site for the co-factor YAP65, which is expressed in human retina along with TEAD1.\",\n      \"method\": \"Genome-wide linkage analysis, sequencing, LOD score analysis, RT-PCR expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — genetic mapping with high LOD score identifies causative mutation; molecular mechanism inferred from sequence conservation and co-factor binding site prediction without direct biochemical confirmation of binding disruption in this paper\",\n      \"pmids\": [\"15016762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TEAD1 (TEF-1) interacts with the transcriptional co-activator TAZ both in vitro and in vivo. TAZ interacts with TEAD1 while TEAD1 is bound to MCAT DNA. TAZ interacts more efficiently with TEF-1 (TEAD1) than with RTEF-1 (TEAD4), demonstrating differential co-activator association among TEAD family members.\",\n      \"method\": \"GST pull-down assay, co-immunoprecipitation, modified mammalian two-hybrid assay, EMSA with purified proteins\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP, GST pull-down, EMSA, and two-hybrid assays in one study; multiple orthogonal methods establishing direct interaction\",\n      \"pmids\": [\"15628970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The SCRA-associated missense mutation Y410H in mouse Tead1 (corresponding to human Y421H) abolishes direct interaction between Tead1 and co-factors YAP and TAZ, but not with Vgl-1, -2, or -3. The mutation eliminates the transcriptional activity of Tead1 when co-expressed with YAP or TAZ, establishing that Y421 is essential for YAP/TAZ binding.\",\n      \"method\": \"Mammalian two-hybrid assay, GST pull-down with purified proteins, site-directed mutagenesis, transcriptional reporter assays in RPE-J cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct reconstitution of binding disruption by mutagenesis, GST pull-down plus functional reporter assays, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17689488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tead1 and Tead2 are functionally redundant in mouse development; double-knockout embryos die at E9.5 with severe growth defects including absence of notochord, closed neural tube, and somites. Genetic interaction experiments demonstrate that Tead1/Tead2 use YAP as a major co-activator in vivo. Tead1/Tead2 double-knockout embryos show reduced cell proliferation and increased apoptosis.\",\n      \"method\": \"Generation of Tead1 and Tead2 knockout mice, genetic epistasis with Yap mutants, embryo phenotyping, cell proliferation/apoptosis assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic loss-of-function with defined cellular phenotypes and genetic epistasis with YAP, replicated across multiple mutant combinations\",\n      \"pmids\": [\"18332127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Taz and its co-activator Tead1 regulate expression of the EMT transcription factor Zeb1 in RPE cells. Nuclear translocation of Taz-TEAD1 coincides with loss of cell-cell contact and onset of Zeb1 expression. shRNA knockdown of Taz prevents Zeb1 overexpression and blocks proliferation, repression of Mitf, and EMT. Taz directly binds the Zeb1 promoter in vivo.\",\n      \"method\": \"shRNA knockdown, real-time PCR, immunofluorescence for subcellular localization, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms in vivo promoter binding, functional KD with defined phenotypic readouts, single lab with multiple methods\",\n      \"pmids\": [\"20207963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TEAD1 directly regulates FoxO3a transcription in skeletal muscle by binding to the M-CAT element in the foxo3a promoter, as demonstrated by ChIP-on-chip, independent ChIP-PCR, EMSA, and luciferase reporter assays. Overexpression and inhibition experiments confirm FoxO3a is positively regulated by TEAD1.\",\n      \"method\": \"ChIP-on-chip, ChIP-PCR, EMSA, luciferase reporter assay, overexpression/knockdown experiments\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, reporter) confirming direct promoter binding and transcriptional regulation, single lab\",\n      \"pmids\": [\"21211055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TEAD1 overexpression arrests the C2C12 myoblast cell cycle and promotes differentiation. TEAD1 directly regulates three novel target genes: Mrpl21 and Ndufa6 (upregulated during differentiation) and Ccne1 (downregulated). Regulation was confirmed by promoter activity assays.\",\n      \"method\": \"Overexpression experiments, expression analysis, promoter activity measurement assay, cell cycle analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional overexpression with defined cellular phenotypes and promoter activity validation, single lab\",\n      \"pmids\": [\"23220227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tead1 and co-activators Yap and Taz are required for PMP22 expression in Schwann cells, as well as for expression of Egr2. Tead1 directly binds PMP22 and Egr2 enhancers early in development and its binding is induced during myelination, correlating with PMP22 expression.\",\n      \"method\": \"ChIP, analysis of enhancer histone modifications, KD/KO with gene expression readouts, developmental binding analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct enhancer binding in vivo, functional requirement established by knockdown, single lab with multiple methods\",\n      \"pmids\": [\"27288457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Myofiber-specific TEAD1 overexpression in transgenic mice causes non-cell-autonomous hyperplasia of satellite cells (muscle stem cells) without affecting muscle tissue size, establishing that TEAD1 in myofibers activates a signaling pathway that determines satellite cell pool size.\",\n      \"method\": \"Transgenic mouse overexpression model, satellite cell quantification, regeneration assays, muscle injury models\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean transgenic gain-of-function with defined cellular phenotype and non-cell-autonomous mechanism established, single lab\",\n      \"pmids\": [\"27725085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TEAD1 enhances CRC cell proliferation by directly binding the SP1 promoter and activating SP1 expression, as demonstrated by luciferase assay and ChIP assay.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, siRNA knockdown, overexpression, cell proliferation assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ChIP and reporter assays but limited mechanistic follow-up beyond promoter binding\",\n      \"pmids\": [\"27434865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tead1 is a cell-autonomous direct transcriptional activator of SERCA2a and the SR-associated protein phosphatase 1 regulatory subunit Inhibitor-1 (I-1) in adult cardiomyocytes. Tead1 deletion causes lethal dilated cardiomyopathy, decreasing SERCA2a and I-1 protein levels, increasing PP1 activity, accumulating dephosphorylated phospholamban, and impairing excitation-contraction coupling.\",\n      \"method\": \"Tamoxifen-inducible CM-specific Tead1 knockout, global transcriptomic analysis, mechanistic biochemical assays (PP1 activity, phospholamban phosphorylation), iPSC-derived CM validation\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible conditional KO with defined molecular mechanism, multiple orthogonal readouts, validated in human iPSC-CMs\",\n      \"pmids\": [\"28878117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TEAD1 occupies chromatin at AQP4, EGFR, and CDH4 loci in glioblastoma stem cells, validated by ChIP-PCR. CRISPR-Cas9 knockout of TEAD1 robustly diminishes GBM cell migration in vitro and in vivo, with consistent downregulation of its target AQP4. TEAD1 overexpression restores AQP4 expression and rescues migratory deficits in TEAD1-KO cells.\",\n      \"method\": \"ATAC-seq, ChIP-PCR, CRISPR-Cas9 KO, in vitro and in vivo migration assays, transcriptome analysis, overexpression rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with defined in vitro and in vivo phenotype, ChIP validation of direct target, rescue experiment, multiple orthogonal methods\",\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 fails to bind TEAD1 attenuates these effects.\",\n      \"method\": \"siRNA knockdown, YAP1 mutant constructs (S127A/S94A), in vitro angiogenesis sprouting assay, in vivo fibrin gel vascular morphogenesis, oxygen consumption measurement\",\n      \"journal\": \"Microvascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutant strategy distinguishes TEAD1-dependent from independent YAP1 effects, single lab with multiple functional readouts\",\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, as identified by interaction proteomics. VGLL3 mainly represses gene expression, regulating similar genes to those regulated by YAP and TAZ. siRNA-mediated Vgll3 knockdown suppresses myoblast proliferation, and Vgll3 overexpression promotes myogenic differentiation.\",\n      \"method\": \"Interaction proteomics (pulldown/MS), siRNA knockdown, overexpression, gene expression analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction proteomics plus functional KD/OE with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"31138678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEAD1 is essential for vascular smooth muscle cell (VSMC) differentiation and cardiovascular development. CMC/VSMC-specific Tead1 deletion causes embryonic lethality by E14.5 due to hypoplastic cardiac and vascular walls and impaired proliferation. TEAD1 transcriptionally activates Pitx2c as a novel target gene, and Pitx2c and myocardin rescue TEAD1-dependent defects in VSMC differentiation. Pitx2c directly interacts with myocardin to augment VSMC differentiation.\",\n      \"method\": \"Conditional Tead1 KO mice, whole transcriptome analysis, in vitro rescue experiments, identification of Pitx2c as transcriptional target, co-IP for Pitx2c-myocardin interaction\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined lethal phenotype, transcriptome analysis, novel target identification, rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"31024075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEAD1 directly activates the miR-222 promoter by physically binding to it (validated by ChIP assay) in gastric cancer cells. TEAD1 knockdown decreases miR-222 expression and increases VGLL4 expression, establishing a miR-222/VGLL4/YAP-TEAD1 regulatory loop.\",\n      \"method\": \"ChIP assay, siRNA knockdown, luciferase assay, expression analysis\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP assay with limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"26045994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tead1 is required for perinatal cardiomyocyte proliferation. Perinatal CM-specific deletion of Tead1 (Myh6-Cre) leads to lethal dilated cardiomyopathy by postnatal day 9 due to significantly decreased CM proliferation. Cell-autonomous Tead1 function is required for normal CM proliferation, associated with decreased levels of cell cycle-promoting proteins.\",\n      \"method\": \"Perinatal CM-specific conditional KO (Myh6-Cre), echocardiography, histology, proliferation assays, HL-1 cell line KO confirmation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined lethal phenotype and cell-autonomous validation in cell line, single lab\",\n      \"pmids\": [\"30811446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YAP-TEAD1 complex targets key genes encoding proteins involved in cytoskeleton dynamics in human pluripotent stem cells, controlling focal adhesion gene transcription and intracellular tension. YAP-TEAD1 inactivation is needed to adjust PSC mechanical properties in response to physiological substrate stiffness during germ layer specification.\",\n      \"method\": \"Tankyrase inhibition (AMOT/YAP axis), TEAD1 reporter assays, gene expression analysis, mechanobiology assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — limited direct mechanistic evidence for TEAD1-specific role; YAP-TEAD1 complex activity inferred from inhibitor studies without direct TEAD1 KO/KI\",\n      \"pmids\": [\"33116297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tead1 directly suppresses Apln (apelin) transcription in myogenic cells; Tead1 knockdown stimulates Apln secretion in vitro and myofiber-specific Tead1 overexpression suppresses Apln secretion in vivo. Secreted apelin acts on endothelial Aplnr to stimulate endothelial cell expansion, establishing a Tead1-Apln paracrine axis from myogenic to endothelial cells.\",\n      \"method\": \"Yeast one-hybrid screen, single-cell RNA-seq, siRNA knockdown, myofiber-specific overexpression in vivo, co-culture assays, Apln peptide supplementation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast one-hybrid identifies binding, in vitro KD and in vivo OE confirm secretion regulation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"35789856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tead1 deletion in adult cardiomyocytes activates necroptosis (not apoptosis) and causes lethal dilated cardiomyopathy. Mechanistically, Tead1 directly activates nuclear DNA-encoded mitochondrial genes required for electron transport chain assembly and ATP production (genome-wide ChIP-seq). Loss of Tead1 increases mitochondrial ROS, disrupts mitochondrial structure, and reduces complex I–IV oxygen consumption. Necrostatin-1 blocks necroptosis and rescues Tead1-deletion-induced heart failure.\",\n      \"method\": \"CM-specific and ubiquitous Tead1 KO, RNA-seq, ChIP-seq, mitochondrial function assays, necrostatin-1 rescue, inflammatory marker quantification\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide ChIP-seq establishes direct targets, ChIP confirmed by orthogonal KO phenotype, pharmacological rescue, multiple independent methods in single rigorous study\",\n      \"pmids\": [\"33469230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VGLL1 co-activates TEAD1-mediated transcription of HPV early genes. TEAD1 binds 11 sites in the HPV16 long control region (LCR) identified by in vitro DNA pulldown; 8 contribute to early promoter activation. VGLL1 is recruited to the HPV16 LCR via its interaction with TEAD1 both in vitro and in vivo. Knockdown of VGLL1 and/or TEAD1 decreases viral early gene expression.\",\n      \"method\": \"In vitro DNA pulldown, luciferase reporter assays, ChIP, siRNA knockdown, co-IP\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays, ChIP confirming in vivo recruitment, functional KD experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32132238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YAP/TEAD1 complex directly represses cardiac TLR genes. TEAD1 directly binds genomic regions adjacent to Tlr1–7 and Tlr9 in cardiomyocytes. YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near its transcription start site (luciferase reporter). Cardiomyocyte-specific YAP depletion increases TLR gene expression, pro-inflammatory cytokines, and cardiac susceptibility to LPS.\",\n      \"method\": \"ChIP-seq/ChIP, luciferase reporter assay, CM-specific YAP KO, gene expression analysis, LPS challenge\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays confirm direct binding and repression, functional KO phenotype, single lab\",\n      \"pmids\": [\"34206257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tead1 overexpression (replacing TBX5 in a GMT cocktail) nearly 3-fold increases cardiac troponin T expression in fibroblasts compared to GMT alone, increases H3K4me3 at cardio-differentiation and mitochondrial biogenesis gene promoters, and enables cell contractility (beating). YAP and TAZ failed to enhance cTnT expression.\",\n      \"method\": \"Fibroblast reprogramming assay, immunofluorescence for cTnT/sarcomere, ChIP for H3K4me3, beating cell assay\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gain-of-function with specific epigenetic readout (H3K4me3 ChIP), specific TEAD1 vs YAP/TAZ comparison, single lab\",\n      \"pmids\": [\"34889103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TEAD1 has a pocket region-independent direct transcriptional repression mechanism controlling cell proliferation. TEAD1 directly represses a class of target genes by interfering with RNA polymerase II (POLII) binding to target promoters, independently of YAP/TAZ/VGLL4 co-factor binding to the TEAD1 hydrophobic pocket. TEAD1 overexpression represses tumor cell proliferation; β cell-specific TEAD1 KO increases cell-autonomous β cell proliferation. TEAD1 controls transcription in a motif-dependent, orientation-independent manner.\",\n      \"method\": \"Conditional KO, transcriptomic profiling, cistromic analysis (ChIP-seq), overexpression in cancer cell lines, POLII ChIP, promoter orientation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide ChIP-seq plus transcriptomics, POLII ChIP mechanistically distinguishes repression mode from co-factor-mediated activation, multiple orthogonal methods, single rigorous study\",\n      \"pmids\": [\"36484096\"],\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, generating full-length TEAD1. The full-length isoform has greater transcriptional activity and oncogenic properties than the TEAD1ΔE6 isoform, with the difference attributable to differential YAP interaction.\",\n      \"method\": \"Alternative splicing analysis, public database correlation, isoform-specific functional assays, RBFOX2 KD, RNA-binding motif analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RBFOX2 KD and functional isoform comparison with YAP interaction assays, single lab\",\n      \"pmids\": [\"35699208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VGLL4 and MENIN function as TEAD1 co-repressors in pancreatic β cells. Both proteins bind TEAD1 and repress expression of its target genes FZD7 and CCN2, leading to inhibition of β cell proliferation. β cell-specific TEAD1 deletion results in cell-autonomous increase in β cell proliferation, while deletion of canonical co-activators YAP and TAZ does not affect proliferation.\",\n      \"method\": \"Improved split-GFP system, yeast two-hybrid, conditional KO (TEAD1, YAP, TAZ in β cells), gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel co-repressor identification by split-GFP and yeast two-hybrid, validated by conditional KO phenotypes, single lab\",\n      \"pmids\": [\"36662616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mutant Lamin A/C (Q353R) traps TEAD1 at the nuclear membrane in cardiomyocytes, preventing it from activating cardiac developmental gene targets, causing dilated cardiomyopathy. Inhibition of the Hippo pathway rescued dysregulation of cardiac developmental genes caused by TEAD1 trapping in LMNA-mutant cardiomyocytes.\",\n      \"method\": \"Single-cell RNA-seq, ATAC-seq, protein array, electron microscopy, Hippo pathway inhibitor rescue experiments, human DCM patient tissue validation\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal omics methods, mechanistic protein-interaction mechanism, pharmacological rescue, human patient tissue confirmation\",\n      \"pmids\": [\"37058558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD1 is SUMOylated at lysine 173 by SUMO1, a modification regulated by SENP1-mediated deSUMOylation during cardiac hypertrophy. SUMOylation affects TEAD1 protein stability, nuclear localization, DNA-binding ability, and enhances its interaction with YAP1. DeSUMOylation of TEAD1 (K173R mutant) markedly exacerbates cardiomyocyte enlargement in vitro and in hypertrophy mouse models.\",\n      \"method\": \"SUMOylation assays, site-directed mutagenesis (K173R), co-IP, nuclear localization imaging, AAV9-mediated in vivo cardiac expression, mouse hypertrophy model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific mutagenesis identifies SUMOylation site, multiple functional readouts, in vivo AAV rescue/phenotype model, identifies writer (SUMO1) and eraser (SENP1)\",\n      \"pmids\": [\"38225750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TM7SF3 controls alternative splicing of TEAD1 by maintaining the splicing factor hnRNPU. TM7SF3 deletion inhibits hnRNPU, causing exclusion of inhibitory exon 5 and generating a more transcriptionally active TEAD1 isoform that promotes hepatic stellate cell (HSC) activation and liver fibrosis. An antisense oligomer (ASO) that blocks TEAD1 alternative splicing deactivates HSCs in vitro and reduces MASH-induced liver fibrosis in vivo.\",\n      \"method\": \"Genetic deletion (TM7SF3 KO), liver organoids, primary human HSCs, in vivo MASH mouse model, splicing analysis, ASO intervention\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — TM7SF3-hnRNPU-TEAD1 splicing axis established by genetic and molecular methods, in vitro and in vivo validation, ASO pharmacological rescue\",\n      \"pmids\": [\"38670107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD1 promotes cardiac fibroblast-to-myofibroblast transition through the BRD4/Wnt4 signaling pathway. Wnt4 is a novel direct TEAD1 transcriptional target identified by RNA-seq and ChIP-seq. TEAD1 interacts with BET protein BRD4 (demonstrated by Co-IP/mass spectrometry and ChIP), leading to binding and activation of the Wnt4 promoter. CFs-specific TEAD1 KO and TEAD1 inhibitor VT103 ameliorate TAC-induced cardiac remodeling.\",\n      \"method\": \"Conditional CF/myofibroblast-specific TEAD1 KO, RNA-seq, ChIP-seq, Co-IP with mass spectrometry, luciferase assay, TAC and Ang-II mouse models, pharmacological inhibition with VT103\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-seq establishes direct target, Co-IP/MS identifies BRD4 interaction, multiple orthogonal methods, in vivo conditional KO and pharmacological rescue\",\n      \"pmids\": [\"38374140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD1 is essential for Schwann cell developmental myelination and nerve regeneration. TEAD1 promotes myelination by positively and negatively 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 TEAD1 KO mice, SC-specific phenotyping, gene expression analysis, electron microscopy\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional and inducible KO with defined cellular and molecular phenotypes at multiple developmental stages, multiple orthogonal methods\",\n      \"pmids\": [\"38456457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Endothelial YAP/TEAD1 complex promotes CXCL17 transcription in hepatic endothelial cells during ischemia-reperfusion. Hypoxia-reoxygenation activates the YAP/TEAD1 complex to upregulate CXCL17, which recruits myeloid-derived suppressor cells (MDSCs) via GPR35 to attenuate liver injury.\",\n      \"method\": \"Bulk RNA-seq, in vivo YAP/TEAD1 manipulation, CXCL17 reporter, adoptive transfer experiments, mouse IRI model\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA-seq and in vivo experiments identify pathway but direct TEAD1 binding to CXCL17 promoter not directly demonstrated in this abstract; mechanism relies on YAP/TEAD1 complex activity inference\",\n      \"pmids\": [\"38407233\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEAD1 (TEF-1) is a TEA-domain transcription factor that binds MCAT and GT-IIC DNA elements and requires co-activators (YAP, TAZ, VGLL proteins) or co-repressors (VGLL4, MENIN) that dock at its hydrophobic pocket to regulate target gene transcription; it also possesses a pocket-independent direct repression mechanism via interference with RNA polymerase II binding; its activity is modulated by SUMOylation at K173 (by SUMO1/SENP1) affecting stability, nuclear localization, and YAP interaction, and by alternative splicing (regulated by RBFOX2 and hnRNPU/TM7SF3); in the heart, TEAD1 directly activates SERCA2a, Inhibitor-1, and nuclear-encoded mitochondrial genes essential for oxidative phosphorylation, and its loss causes necroptotic dilated cardiomyopathy, while in development it acts redundantly with TEAD2 using YAP as a major co-activator to support notochord maintenance, cardiomyocyte proliferation, VSMC differentiation (via Pitx2c/myocardin), and Schwann cell myelination (via Egr2/PMP22/FDPS/IDI1).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TEAD1 (TEF-1) is a sequence-specific TEA-domain transcription factor that binds MCAT/GT-IIC enhansons and depends on a cell-limiting transcriptional intermediary factor to activate transcription [#0, #1]. Its output is set by docking of co-regulators at a conserved C-terminal surface: the co-activators YAP and TAZ bind through residue Y421, whose mutation (Y421H/Y410H) abolishes YAP/TAZ binding and underlies Sveinsson's chorioretinal atrophy [#3, #5, #4], while VGLL family proteins and MENIN act as co-repressors at the same axis [#16, #28, #23]. Beyond co-factor-dependent control, TEAD1 also directly represses a class of genes by interfering with RNA polymerase II recruitment independently of its hydrophobic pocket, a mode that restrains proliferation [#26]. TEAD1 activity is further tuned by SUMOylation at K173 (by SUMO1, reversed by SENP1), which governs its stability, nuclear localization, DNA binding, and YAP interaction [#30], and by alternative splicing controlled by RBFOX2 and the TM7SF3/hnRNPU axis, which switch TEAD1 between isoforms of differing transcriptional strength [#27, #31]. In the heart, TEAD1 is a cell-autonomous activator of SERCA2a, Inhibitor-1, and nuclear-encoded mitochondrial/electron-transport-chain genes; its loss collapses calcium handling and oxidative phosphorylation and triggers necroptotic dilated cardiomyopathy rescuable by necrostatin-1 [#13, #22], and its mislocalization by mutant Lamin A/C similarly causes cardiomyopathy [#29]. Across development TEAD1 acts redundantly with TEAD2 using YAP as a major co-activator to support notochord and embryonic growth [#6], cardiomyocyte and vascular smooth muscle proliferation/differentiation (via Pitx2c/myocardin) [#17, #19], and Schwann cell myelination (via Egr2 and cholesterol enzymes FDPS/IDI1) [#33], and it drives pro-fibrotic and oncogenic programs in fibroblasts, glioblastoma, and other cancers [#32, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established TEAD1 as a sequence-specific enhancer-binding factor whose activation depends on a limiting cellular cofactor rather than an intrinsic strong activation domain, framing the central question of co-factor dependence.\",\n      \"evidence\": \"cDNA cloning with in vitro/in vivo transcription and GAL4 chimera squelching in HeLa and MPC11 cells\",\n      \"pmids\": [\"1851669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the limiting transcriptional intermediary factor not defined\", \"No structural basis for cofactor docking\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showed that TEAD1 isoforms bind muscle MCAT elements with high affinity and that a single C-terminal exon confers activation capacity, linking isoform structure to transcriptional output.\",\n      \"evidence\": \"cDNA cloning from chick heart, EMSA, GAL4 chimera reporter assays\",\n      \"pmids\": [\"8106348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the C-terminal exon recruits coactivators not defined\", \"Tissue distribution of isoforms not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified MEF2 as a direct partner that co-activates muscle promoters, expanding TEAD1's combinatorial control beyond Hippo coactivators.\",\n      \"evidence\": \"Co-IP, GST pull-down, mammalian two-hybrid, reporter assays\",\n      \"pmids\": [\"12061776\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction surface not mapped\", \"In vivo requirement of TEAD1-MEF2 cooperation not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected TEAD1 to human Mendelian disease by mapping the Y421H mutation as causative for Sveinsson's chorioretinal atrophy, implicating a YAP65-binding region.\",\n      \"evidence\": \"Genome-wide linkage, sequencing, LOD analysis, RT-PCR\",\n      \"pmids\": [\"15016762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical disruption of binding not shown in this study\", \"Retinal target genes not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated TAZ as a direct DNA-bound co-activator with TEAD-family selectivity, refining which Hippo effectors engage TEAD1.\",\n      \"evidence\": \"GST pull-down, Co-IP, modified two-hybrid, EMSA with purified proteins\",\n      \"pmids\": [\"15628970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of differential TEAD1 vs TEAD4 affinity not resolved\", \"In vivo consequences of TAZ-TEAD1 selectivity not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established Y421 as the essential YAP/TAZ-binding residue, mechanistically explaining the SCRA mutation as a coactivator-binding defect distinct from VGLL binding.\",\n      \"evidence\": \"Two-hybrid, GST pull-down, site-directed mutagenesis, reporter assays in RPE-J cells\",\n      \"pmids\": [\"17689488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address pocket-independent TEAD1 functions\", \"No structural model of the disrupted interface in this study\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined TEAD1/TEAD2 functional redundancy and YAP as the major in vivo coactivator, establishing the developmental requirement for TEAD-YAP signaling.\",\n      \"evidence\": \"Tead1/Tead2 knockout mice, genetic epistasis with Yap, embryo phenotyping\",\n      \"pmids\": [\"18332127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TEAD1-specific (non-redundant) targets not separated from TEAD2\", \"Direct target genes underlying notochord/somite defects not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked TAZ-TEAD1 to EMT control through direct activation of Zeb1, connecting mechanotransduction to epithelial state changes.\",\n      \"evidence\": \"shRNA knockdown, qPCR, immunofluorescence, ChIP in RPE cells\",\n      \"pmids\": [\"20207963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ChIP demonstrated TAZ binding; direct TEAD1 promoter occupancy at Zeb1 not separately resolved\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified FoxO3a as a direct MCAT-element target of TEAD1 in skeletal muscle, broadening its direct regulon.\",\n      \"evidence\": \"ChIP-on-chip, ChIP-PCR, EMSA, luciferase, overexpression/knockdown\",\n      \"pmids\": [\"21211055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactor dependence of FoxO3a activation not defined\", \"Physiological phenotype of the TEAD1-FoxO3a axis not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed TEAD1 couples myoblast cell-cycle exit to differentiation through direct mitochondrial (Ndufa6, Mrpl21) and cell-cycle (Ccne1) targets, foreshadowing its mitochondrial gene control.\",\n      \"evidence\": \"Overexpression, expression analysis, promoter activity assays, cell-cycle analysis in C2C12\",\n      \"pmids\": [\"23220227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding shown only by promoter activity, not genome-wide ChIP\", \"Cofactor requirement unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established TEAD1 (with YAP/TAZ) as a direct regulator of Schwann cell myelination genes PMP22 and Egr2, with developmentally induced enhancer binding.\",\n      \"evidence\": \"ChIP, enhancer histone modification analysis, KD/KO expression readouts\",\n      \"pmids\": [\"27288457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of developmentally timed binding not defined\", \"Distinction from cofactor recruitment kinetics unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a non-cell-autonomous role: myofiber TEAD1 sets satellite-cell pool size via a secreted signal, decoupling TEAD1 transcriptional output from autonomous growth.\",\n      \"evidence\": \"Myofiber-specific transgenic overexpression, satellite-cell quantification, regeneration/injury assays\",\n      \"pmids\": [\"27725085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Secreted effector not identified in this study\", \"Receiving-cell signaling pathway undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Implicated TEAD1 in colorectal cancer proliferation via direct activation of SP1.\",\n      \"evidence\": \"Luciferase, ChIP, siRNA, overexpression, proliferation assays\",\n      \"pmids\": [\"27434865\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single lab with limited mechanistic follow-up beyond promoter binding\", \"Cofactor and in vivo relevance not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified TEAD1 as a cell-autonomous activator of calcium-handling genes SERCA2a and Inhibitor-1 in adult cardiomyocytes, defining a direct mechanism for excitation-contraction coupling and dilated cardiomyopathy on its loss.\",\n      \"evidence\": \"Inducible CM-specific KO, transcriptomics, PP1/phospholamban biochemistry, iPSC-CM validation\",\n      \"pmids\": [\"28878117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor partners driving SERCA2a/I-1 activation not defined\", \"Direct ChIP at these promoters not shown here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed TEAD1 directly drives glioblastoma stem-cell migration through AQP4/EGFR/CDH4, with rescue establishing AQP4 as a key effector.\",\n      \"evidence\": \"ATAC-seq, ChIP-PCR, CRISPR KO, in vitro/in vivo migration, overexpression rescue\",\n      \"pmids\": [\"30275445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor dependence in GBM not dissected\", \"Upstream signals activating TEAD1 in GBM undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked YAP1-TEAD1 to mitochondrial biogenesis and angiogenesis via PGC1\\u03b1 in endothelial cells, reinforcing TEAD1's metabolic regulatory role.\",\n      \"evidence\": \"siRNA, YAP1 S94A/S127A mutants, sprouting and vascular morphogenesis assays, oxygen consumption\",\n      \"pmids\": [\"29680477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TEAD1 binding at PGC1\\u03b1 not shown\", \"Distinction from YAP1-independent effects partial\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined VGLL3 as a TEAD-binding co-repressor in muscle that regulates a YAP/TAZ-overlapping gene set, expanding the repressive arm of TEAD1 control.\",\n      \"evidence\": \"Interaction proteomics, siRNA, overexpression, expression analysis in myoblasts/myotubes\",\n      \"pmids\": [\"31138678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TEAD1-specific (vs TEAD3/4) repressive targets not separated\", \"Mechanism of repression not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established TEAD1 as essential for VSMC differentiation and cardiovascular development, identifying Pitx2c as a direct target acting with myocardin.\",\n      \"evidence\": \"Conditional KO mice, transcriptomics, in vitro rescue, Co-IP for Pitx2c-myocardin\",\n      \"pmids\": [\"31024075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor dependence of Pitx2c activation not defined\", \"Direct ChIP at Pitx2c in vivo not shown here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed cell-autonomous TEAD1 is required for perinatal cardiomyocyte proliferation, distinguishing a proliferative program from the later metabolic/contractile one.\",\n      \"evidence\": \"Perinatal CM-specific KO (Myh6-Cre), echocardiography, histology, HL-1 KO\",\n      \"pmids\": [\"30811446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct proliferative target genes not identified\", \"Cofactor identity not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed TEAD1 in a miR-222/VGLL4/YAP-TEAD1 feedback loop in gastric cancer via direct miR-222 promoter activation.\",\n      \"evidence\": \"ChIP, siRNA, luciferase, expression analysis\",\n      \"pmids\": [\"26045994\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single ChIP with limited follow-up\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected YAP-TEAD1 to cytoskeletal/focal-adhesion gene control and mechanosensing during stem-cell germ-layer specification.\",\n      \"evidence\": \"Tankyrase inhibition, TEAD1 reporter, expression analysis, mechanobiology assays\",\n      \"pmids\": [\"33116297\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"TEAD1-specific role inferred from inhibitor studies without direct TEAD1 KO/KI\", \"Direct target binding not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a TEAD1-Apln paracrine axis: direct repression of apelin in myofibers controls endothelial expansion, mechanistically explaining non-cell-autonomous vascular effects.\",\n      \"evidence\": \"Yeast one-hybrid, scRNA-seq, siRNA, myofiber-specific overexpression, co-culture, peptide supplementation\",\n      \"pmids\": [\"35789856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactor mediating Apln repression not defined\", \"Relation to pocket-independent repression mode unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the mechanism of TEAD1-loss cardiomyopathy as necroptosis driven by failure to activate nuclear-encoded mitochondrial ETC genes, with pharmacological rescue by necrostatin-1.\",\n      \"evidence\": \"CM-specific/ubiquitous KO, RNA-seq, ChIP-seq, mitochondrial assays, necrostatin-1 rescue\",\n      \"pmids\": [\"33469230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor requirement for mitochondrial gene activation not defined\", \"Trigger linking ETC failure to necroptosis machinery incompletely mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed VGLL1 co-activates TEAD1 at the HPV16 control region to drive viral early gene expression, demonstrating viral hijacking of TEAD1.\",\n      \"evidence\": \"In vitro DNA pulldown, luciferase, ChIP, siRNA, Co-IP\",\n      \"pmids\": [\"32132238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of VGLL1-TEAD1 recruitment not resolved\", \"In vivo viral life-cycle relevance not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a YAP/TEAD1 repressive function silencing cardiac TLR genes to restrain innate immunity, broadening the repressive regulon.\",\n      \"evidence\": \"ChIP-seq/ChIP, luciferase, CM-specific YAP KO, LPS challenge\",\n      \"pmids\": [\"34206257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of YAP-dependent repression vs canonical activation unresolved\", \"Cofactor switch determining repression undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated TEAD1 can replace TBX5 in cardiac reprogramming and uniquely deposit H3K4me3 at cardiac/mitochondrial genes, an activity not reproduced by YAP/TAZ.\",\n      \"evidence\": \"Fibroblast reprogramming, cTnT/sarcomere IF, H3K4me3 ChIP, beating assay\",\n      \"pmids\": [\"34889103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chromatin-modifying partner mediating H3K4me3 not identified here\", \"Mechanism distinguishing TEAD1 from YAP/TAZ unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a pocket-independent direct repression mode in which TEAD1 blocks POLII recruitment to restrain proliferation, separating it mechanistically from cofactor-dependent activation.\",\n      \"evidence\": \"Conditional KO, transcriptomics, ChIP-seq, POLII ChIP, promoter-orientation assays\",\n      \"pmids\": [\"36484096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of POLII interference not defined\", \"Determinants selecting genes for repression vs activation unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RBFOX2-dependent inclusion of exon 6 generates a full-length, more oncogenic TEAD1 isoform with enhanced YAP interaction, linking splicing to transcriptional strength.\",\n      \"evidence\": \"Splicing analysis, isoform functional assays, RBFOX2 KD, motif analysis\",\n      \"pmids\": [\"35699208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of isoform-dependent YAP affinity not resolved\", \"In vivo splicing control not tested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified VGLL4 and MENIN as TEAD1 co-repressors in \\u03b2 cells controlling FZD7/CCN2 and showed TEAD1 (not YAP/TAZ) restrains \\u03b2-cell proliferation, demonstrating cofactor-context-specific output.\",\n      \"evidence\": \"Split-GFP, yeast two-hybrid, conditional KO of TEAD1/YAP/TAZ, expression analysis\",\n      \"pmids\": [\"36662616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MENIN/VGLL4 repression uses the pocket or POLII-interference mode not separated\", \"Direct ChIP at FZD7/CCN2 not shown here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that mutant Lamin A/C sequesters TEAD1 at the nuclear membrane to block cardiac developmental gene activation, with Hippo inhibition rescuing the defect, linking TEAD1 localization to cardiomyopathy.\",\n      \"evidence\": \"scRNA-seq, ATAC-seq, protein array, EM, Hippo inhibitor rescue, human DCM tissue\",\n      \"pmids\": [\"37058558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct LMNA-TEAD1 interaction interface not mapped\", \"Generality across other LMNA mutations untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established SUMOylation at K173 (SUMO1/SENP1) as a post-translational switch controlling TEAD1 stability, localization, DNA binding, and YAP interaction during cardiac hypertrophy.\",\n      \"evidence\": \"SUMOylation assays, K173R mutagenesis, Co-IP, localization imaging, AAV9 in vivo hypertrophy model\",\n      \"pmids\": [\"38225750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling SENP1 activity on TEAD1 not defined\", \"Interplay with splicing/cofactor regulation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a TM7SF3/hnRNPU splicing axis that controls TEAD1 exon-5 inclusion, with the active isoform driving hepatic stellate cell activation and fibrosis, and an ASO providing therapeutic correction.\",\n      \"evidence\": \"TM7SF3 KO, liver organoids, primary human HSCs, MASH mouse model, splicing analysis, ASO intervention\",\n      \"pmids\": [\"38670107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct fibrotic target genes of the active isoform not fully defined\", \"Relationship to RBFOX2-controlled exon 6 splicing unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed TEAD1 drives cardiac fibroblast-to-myofibroblast transition via a BRD4/Wnt4 axis, identifying BRD4 as a chromatin partner and Wnt4 as a direct target, with VT103 inhibition rescuing remodeling.\",\n      \"evidence\": \"CF-specific KO, RNA-seq, ChIP-seq, Co-IP/MS, luciferase, TAC/Ang-II models, VT103\",\n      \"pmids\": [\"38374140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRD4 recruitment is pocket-dependent unresolved\", \"Generality of TEAD1-BRD4 cooperation beyond cardiac fibroblasts untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated endothelial YAP/TEAD1 in CXCL17-mediated MDSC recruitment protecting against hepatic ischemia-reperfusion injury.\",\n      \"evidence\": \"Bulk RNA-seq, in vivo YAP/TEAD1 manipulation, CXCL17 reporter, adoptive transfer, IRI model\",\n      \"pmids\": [\"38407233\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct TEAD1 binding to CXCL17 promoter not demonstrated\", \"TEAD1-specific contribution vs YAP-complex inference unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TEAD1 selects between cofactor-dependent activation, pocket-independent POLII-interference repression, and cofactor-mediated repression at individual loci, and how splicing, SUMOylation, and localization integrate to set these choices, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unifying model linking PTMs/isoforms to activation-vs-repression choice\", \"Locus-level determinants of cofactor recruitment undefined\", \"No structural account of pocket-independent POLII interference\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 13, 22, 26]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 8, 22, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 29, 30]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 22, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 15, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 17, 33]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 22, 15]}\n    ],\n    \"complexes\": [\n      \"YAP-TEAD1 complex\",\n      \"TAZ-TEAD1 complex\"\n    ],\n    \"partners\": [\n      \"YAP1\",\n      \"TAZ\",\n      \"VGLL1\",\n      \"VGLL3\",\n      \"VGLL4\",\n      \"MENIN\",\n      \"MEF2\",\n      \"BRD4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}