{"gene":"TEAD4","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2007,"finding":"TEAD4 is required for specification of the trophectoderm lineage in preimplantation mouse embryos; Tead4-/- embryos fail to express trophectoderm-specific genes (Cdx2, Eomes, Fgfr2) while expressing ICM-specific genes (Oct4, Nanog) in all blastomeres, demonstrating TEAD4 acts upstream of Cdx2 in TE specification.","method":"Gene knockout (Tead4-/- mice), immunofluorescence, gene expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined molecular phenotype, independently replicated across two labs (PMIDs 17913785 and 18083014) with concordant findings","pmids":["17913785","18083014"],"is_preprint":false},{"year":2009,"finding":"The Hippo pathway components Lats kinase and Yap regulate TEAD4 activity to distinguish trophectoderm from ICM: in outside cells, Yap localizes to nuclei and co-activates TEAD4 to induce Cdx2 and trophoblast genes; in inside cells, Lats-mediated phosphorylation retains Yap in the cytoplasm, suppressing TEAD4 transcriptional activity.","method":"Genetic epistasis, immunofluorescence of Yap localization, modulation of Tead4/Yap activity in embryos and ES cells, Cdx2 expression readout","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic and cell-biological experiments with defined pathway epistasis, replicated across multiple labs","pmids":["19289085"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the YAP-interacting C-terminal domain of TEAD4 in complex with the N-terminal domain of YAP reveals an immunoglobulin-like fold in TEAD4; YAP interacts mainly through two short helices flanking a PXXPhiP motif-containing loop. Point mutations in TEAD4 at the interface abolish YAP interaction and transforming activity.","method":"X-ray crystallography, site-directed mutagenesis, functional transformation assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis with functional validation in a single rigorous study","pmids":["20123908"],"is_preprint":false},{"year":2010,"finding":"Gata3 expression in trophoblast is regulated downstream of Tead4 (and in parallel with Cdx2): Gata3 and Cdx2 act in parallel downstream of Tead4 to promote trophoblast fate, as shown by loss of both Gata3 and Cdx2 in Tead4-null embryos.","method":"Bioinformatic and functional genomic strategies, genetic epistasis in mouse embryos, ES cell differentiation assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with defined downstream transcriptional targets, independently consistent with other TE specification studies","pmids":["20081188"],"is_preprint":false},{"year":2012,"finding":"Differential nuclear versus cytoplasmic localization of TEAD4 in outer versus inner blastomeres dictates first mammalian cell fate: TEAD4 lacks nuclear localization in inner cells, impairing TE-specific transcription. Forced nuclear restoration of TEAD4 in inner blastomeres maintains the TE transcriptional program and prevents ICM/TE segregation.","method":"ChIP-sequencing for genome-wide target identification, subcellular localization manipulation, loss-of-function in preimplantation embryos","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus direct localization manipulation with functional consequences, single lab but multiple orthogonal methods","pmids":["22529382"],"is_preprint":false},{"year":2013,"finding":"TEAD4 is not required for trophectoderm specification per se but is essential for preventing oxidative stress during blastocoel formation: Tead4-/- embryos can form blastocysts and express TE genes under low-oxidative-stress culture conditions. TEAD4 suppresses reactive oxygen species (ROS) and maintains mitochondrial membrane potential. Ectopically expressed TEAD4 can localize to mitochondria as well as the nucleus—a property unique to TEAD4 among TEAD family members.","method":"Genetic knockout under altered culture conditions (low O2/antioxidant), ROS measurement, mitochondrial membrane potential assay, subcellular fractionation/localization","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in one rigorous study demonstrating novel mitochondrial localization and ROS-suppression mechanism","pmids":["23903192"],"is_preprint":false},{"year":2013,"finding":"TEAD4 binds the palmitoylation-binding hydrophobic cavity of its C-terminal domain. The YAP and TAZ co-activators bind essentially the same site on TEAD4 with similar affinities but use different residues for key contacts, as shown by biochemical and biophysical assays with peptides and molecular modeling.","method":"Biochemical binding assays (peptide affinity), biophysical assays, molecular modeling, structural biology","journal":"Chembiochem : a European journal of chemical biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding and structural data from single lab without full mutagenesis validation","pmids":["23780915"],"is_preprint":false},{"year":2014,"finding":"VGLL1-derived peptides bind TEAD4 with nanomolar affinity via a β-strand:loop:α-helix motif, binding the same site used by YAP and TAZ but without the secondary structural element required by the latter two coactivators.","method":"Biochemical peptide binding assays, structural biology/molecular analysis","journal":"Chembiochem : a European journal of chemical biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro peptide binding assay with structural characterization, single lab","pmids":["24504694"],"is_preprint":false},{"year":2011,"finding":"TEAD4 occupies promoters of myogenic genes (including Myogenin, CDKN1A, Caveolin 3) in C2C12 myoblasts as shown by ChIP-chip, and is required for normal myotube differentiation; TEAD4 knockdown results in shortened myotubes and reduced expression of structural, regulatory, and unfolded protein response genes; TEAD4 represses CTGF to promote differentiation.","method":"shRNA knockdown, ChIP coupled to array hybridization (ChIP-chip), RNA-seq, dominant-negative TEAD expression","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-chip, RNA-seq, and functional knockdown with specific phenotypic readouts, single lab with multiple orthogonal methods","pmids":["21701496"],"is_preprint":false},{"year":2017,"finding":"TEAD4 forms a complex with TCF4 (TCF7L2) and co-binds target genes; VGLL4 disrupts this TEAD4-TCF4 complex to suppress TCF4 transactivation, directly linking Hippo-YAP and Wnt/β-catenin signaling at the transcription factor level in colorectal cancer.","method":"Co-immunoprecipitation, ChIP, genome-wide co-binding analysis, functional assays, VGLL4 peptide mimetic in mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP demonstrating physical complex, ChIP for co-binding, and in vivo functional validation in single study with multiple orthogonal methods","pmids":["28051067"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of the TEAD4 TEA domain in complex with a muscle-CAT (MCAT) DNA element reveals that the α3 recognition helix determines DNA-binding specificity, interacting with both major and minor grooves. Mutations at two major binding-site residues substantially reduce promoter occupancy and impair YAP-induced transcription and cancer cell growth.","method":"X-ray crystallography, site-directed mutagenesis, ChIP-qPCR, colony formation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis with functional validation, single lab","pmids":["28368398"],"is_preprint":false},{"year":2016,"finding":"The tumor suppressor RBM4 facilitates alternative splicing of TEAD4 to produce a truncated isoform TEAD4-S lacking the N-terminal DNA-binding domain but retaining the YAP-interaction domain; TEAD4-S localizes to both nucleus and cytoplasm and acts as a dominant-negative inhibitor of YAP activity, suppressing cancer cell proliferation and migration.","method":"Alternative splicing analysis, subcellular fractionation/localization, dominant-negative functional assay, xenograft mouse models, knockdown/rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (localization, dominant-negative, in vivo xenograft) in single lab","pmids":["27291620"],"is_preprint":false},{"year":2018,"finding":"TEAD4 localizes to mitochondria in trophoblast stem cells, binds mitochondrial DNA (mtDNA), and facilitates mitochondrial transcription by recruiting mitochondrial RNA polymerase (POLRMT). Loss of TEAD4 impairs POLRMT recruitment, reduces expression of mtDNA-encoded electron transport chain components, and inhibits oxidative phosphorylation.","method":"Mitochondrial fractionation, mtDNA ChIP, POLRMT co-immunoprecipitation, loss-of-function in trophoblast stem cells, metabolic assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct biochemical demonstration of mitochondrial TEAD4 binding to mtDNA and POLRMT interaction, multiple orthogonal methods, single lab","pmids":["30201685"],"is_preprint":false},{"year":2018,"finding":"TEAD4 acylation (palmitoylation) is not required for YAP or TAZ binding in biochemical and cellular assays; however, TEAD4 acylation significantly enhances its protein stability, suggesting palmitoylation helps maintain its active conformation rather than directly mediating co-activator binding. NMR studies further confirm mTEAD4 can catalyze autopalmitoylation, and flufenamic acid inhibits this reaction.","method":"NMR spectroscopy, biochemical binding assays, palmitoylation mutagenesis (C360S), in vitro autopalmitoylation assay, fragment screening","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR plus in vitro enzymatic assay plus mutagenesis, single lab with multiple orthogonal methods","pmids":["29760238"],"is_preprint":false},{"year":2017,"finding":"Acylation (palmitoylation) of TEAD4 does not serve as a prerequisite for YAP or TAZ binding (shown by biochemical and cellular assays comparing acylated vs. non-acylated TEAD4), but significantly enhances TEAD4 stability.","method":"Biochemical binding assays, cellular assays with acylated/non-acylated TEAD4","journal":"Protein science : a publication of the Protein Society","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assays from single lab without structural validation","pmids":["28960584"],"is_preprint":false},{"year":2018,"finding":"TEAD4 forms a complex with VGLL4 and CtBP2 to repress adipogenesis in 3T3-L1 preadipocytes; VGLL4 acts as an adaptor bridging TEAD4 and CtBP2; this ternary complex occupies promoters of PPARγ and Adipoq to suppress their transcription. This repression of adipogenesis is YAP/TAZ-independent.","method":"Co-immunoprecipitation, ChIP, promoter luciferase assay, siRNA knockdown with adipogenic differentiation readouts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional knockdown with multiple orthogonal methods in single lab","pmids":["30209132"],"is_preprint":false},{"year":2019,"finding":"VGLL3 physically interacts with TEAD1, TEAD3, and TEAD4 in myoblasts and myotubes (as shown by interaction proteomics); unlike YAP/TAZ, VGLL3 does not interact with Hippo kinase cascade proteins. VGLL3 mainly represses gene expression in a TEAD-dependent manner to regulate myogenesis.","method":"Interaction proteomics (affinity purification-MS), functional overexpression/knockdown with myogenic differentiation readouts","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — interaction proteomics (single method for physical interaction) with functional follow-up, single lab","pmids":["31138678"],"is_preprint":false},{"year":2016,"finding":"RAC-TRIO signaling inhibits LATS1/2-mediated YAP phosphorylation, causing YAP to dissociate from RUNX3 and associate with TEAD4. RUNX3 contributes to both formation and dissociation of the YAP-TEAD4 complex, likely through formation of a YAP-TEAD4-RUNX3 ternary complex, functioning as a molecular switch between proliferative and tumor-suppressive states.","method":"Genetic epistasis in Drosophila, co-immunoprecipitation in mammalian cells, phosphorylation-deficient YAP mutants, cancer cell tumorigenicity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combined Drosophila epistasis and mammalian Co-IP with functional validation, single lab","pmids":["27425596"],"is_preprint":false},{"year":2019,"finding":"Glucocorticoid receptor (GR) interacts with TEAD4 upon glucocorticoid treatment, forming a complex recruited to the TEAD4 promoter to boost its own transcription (positive autoregulatory loop). GR facilitates nuclear accumulation of TEAD4.","method":"Co-immunoprecipitation, ChIP, promoter reporter assay, nuclear fractionation, knockdown/overexpression with functional assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ChIP on TEAD4 promoter, multiple methods, single lab","pmids":["31289134"],"is_preprint":false},{"year":2021,"finding":"Arginine acts as an epigenetic regulator that retains TEAD4 in the nucleus in a YAP1-independent but mTOR-dependent manner in prostate cancer cells. Nuclear TEAD4 is recruited to promoter/enhancer regions of nuclear-encoded OXPHOS genes and mediates their coordinated upregulation. Arginine also activates lysine acetyltransferases, increasing acetyl-CoA and histone acetylation to facilitate TEAD4 chromatin recruitment.","method":"ChIP-seq, amino acid deprivation experiments, mTOR pathway inhibition, siRNA knockdown, metabolic assays, xenograft model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with metabolic and signaling pathway validation using multiple orthogonal methods in single lab","pmids":["33893278"],"is_preprint":false},{"year":2019,"finding":"Metformin inhibits BLCA cell proliferation via the AMPKα/YAP1/TEAD4/CCNE1/2 axis; YAP1 positively regulates CCNE1 and CCNE2 expression by forming a complex with TEAD4 (confirmed by Co-IP); TEAD4 is the only TEAD family member precipitated by YAP1 in bladder cancer cells.","method":"Co-immunoprecipitation, dual-luciferase reporter, bioinformatics, siRNA, xenograft model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and luciferase reporter with functional follow-up, single lab","pmids":["31455378"],"is_preprint":false},{"year":2015,"finding":"TEAD4 promotes cell adhesion, EMT, and vimentin expression in colorectal cancer cells through a YAP-independent mechanism; a YAP-binding-defective TEAD4 mutant (Y429H) retains full ability to reverse mesenchymal-to-epithelial transition and increase vimentin expression, confirming YAP-independent transcriptional activity of TEAD4.","method":"Knockdown/rescue with TEAD4 mutant defective in YAP binding, microarray analysis, in vivo metastasis model, YAP knockdown negative control","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis rescue experiment establishing YAP-independence, multiple methods, single lab","pmids":["26387538"],"is_preprint":false},{"year":2016,"finding":"AP-1 (FOS/JUN) factors are required for de novo binding of TEAD4 to regulatory chromatin regions during vascular/hematopoietic development; AP-1 and TEAD4 co-occupy cis-regulatory hubs that regulate the balance between smooth muscle and hemogenic cell fates.","method":"Genome-wide ChIP-seq, dominant-negative FOS inhibition, ES cell differentiation assays","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with functional perturbation, single lab","pmids":["27802171"],"is_preprint":false},{"year":2020,"finding":"TEAD4 ensures trophoblast progenitor self-renewal postimplantation; in both mouse and human, TEAD4 directly regulates cell cycle gene expression in trophoblast stem cells (TSCs). TEAD4 and its cofactor YAP1 are specifically expressed in cytotrophoblast progenitors of the first-trimester human placenta.","method":"Conditional trophoblast-specific Tead4 knockout in mouse, human TSC derivation from RPL patients, RNA-seq, ChIP-seq, functional rescue of TEAD4 expression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with defined phenotype, human patient-derived TSC model, and multiple genomics methods in a single rigorous study","pmids":["32669432"],"is_preprint":false},{"year":2018,"finding":"TEAD4 functions as a master regulator in a positive feedback loop with MYCN in high-risk neuroblastoma; silencing either gene collapses MYCN-amplified neuroblastoma transcriptional hallmarks and abrogates viability in vitro and in vivo. TEAD4 activity in this context is independent of the canonical Hippo coactivators YAP and TAZ.","method":"Transcriptional regulatory network analysis, gene silencing, in vitro and in vivo viability assays, multi-cohort analysis","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gene silencing with in vivo validation and network analysis; mechanistic independence of YAP/TAZ demonstrated functionally","pmids":["29510988"],"is_preprint":false},{"year":2022,"finding":"CK2 (casein kinase 2) phosphorylates HHEX and enhances its interaction with TEAD4; HHEX associates with and stabilizes the YAP-TEAD4 complex at regulatory genomic loci to co-regulate YAP/TEAD target genes. A CK2 inhibitor (CX-4945) diminishes the HHEX-TEAD4 interaction, reducing target gene expression.","method":"Co-immunoprecipitation, ChIP-seq, kinase assay, CK2 inhibitor treatment, serum stimulation experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, and kinase assay with pharmacological validation, single lab","pmids":["36008411"],"is_preprint":false},{"year":2024,"finding":"NF2 directly interacts with TEAD4 through its FERM domain and C-terminal tail, decreasing TEAD4 protein stability independently of LATS1/2 and YAP. NF2 inhibits TEAD4 palmitoylation and induces cytoplasmic translocation of TEAD4, leading to its ubiquitination and functional inactivation. NF2-TEAD4 interaction is required for NF2's cell proliferation-suppressing activity.","method":"Co-immunoprecipitation, domain-mapping experiments, palmitoylation assay, subcellular fractionation, ubiquitination assay, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (Co-IP, palmitoylation, ubiquitination, localization) establishing a direct physical interaction with functional consequence, single lab","pmids":["38522513"],"is_preprint":false},{"year":2024,"finding":"TEAD4 and TFAP2C promote embryo polarization and accelerate loss of totipotency in mouse embryos; they paradoxically promote and inhibit Hippo signaling before lineage diversification, driving expression of multiple Hippo regulators while also promoting apical domain formation that inactivates Hippo. Asymmetric apical domain segregation resolves these opposing activities into TE (Hippo OFF) versus ICM (Hippo ON) fates.","method":"Genetic manipulation of TFAP2C and TEAD4, embryo polarization assays, Hippo pathway component expression analysis, live imaging","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation with multiple functional readouts, single lab","pmids":["38789684"],"is_preprint":false},{"year":2022,"finding":"TEAD4 directly binds the TEAD4 promoter to activate its own transcription, forming a positive feedback loop with NT5DC2 in leiomyosarcoma; NT5DC2 interacts with unpalmitoylated TEAD4 and reduces its degradation via the ubiquitin-proteasome pathway. The E3 ubiquitin ligase TRIM27 induces K27/K48-linked ubiquitination of unpalmitoylated TEAD4 at Lys278.","method":"Dual-luciferase assay, co-immunoprecipitation, ubiquitination assay, cell proliferation and in vivo xenograft assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays identifying specific ubiquitination site and binding partner, single lab","pmids":["33993634"],"is_preprint":false},{"year":2015,"finding":"TEAD4 binds KLF5 and together they repress the CDK inhibitor p27 (CDKN1B) gene promoter, promoting triple-negative breast cancer cell proliferation; depletion of either TEAD4 or KLF5 activates p27 promoter and increases p27 mRNA levels.","method":"Co-immunoprecipitation, promoter reporter assay, siRNA knockdown, xenograft model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and promoter assay with functional rescue experiments, single lab","pmids":["25970772"],"is_preprint":false},{"year":1998,"finding":"RTEF-1 (TEAD4) transactivates both the beta-myosin heavy chain and skeletal alpha-actin promoters through MCAT elements in cardiac myocytes and potentiates alpha1-adrenergic signaling responses, unlike TEF-1 which only activates betaMyHC. RTEF-1 can activate the SKA promoter through a mechanism independent of its MCAT element, suggesting promoter-specific cofactors.","method":"Cotransfection with promoter/reporter constructs in neonatal rat cardiac myocytes, MCAT mutation analysis, gel shift competition assay","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assays with mutagenesis in primary cells, single lab, multiple target genes tested","pmids":["9670917"],"is_preprint":false},{"year":2000,"finding":"The C-terminal domain of RTEF-1 (TEAD4) mediates the alpha1-adrenergic response in cardiac myocytes; a single serine residue (Ser-322), not present in TEF-1, accounts for ~70% of the alpha1-adrenergic activation as demonstrated by site-directed mutagenesis, suggesting direct phosphorylation at Ser-322 by alpha1-adrenergic-dependent kinases.","method":"Chimeric protein analysis, site-directed mutagenesis of serine residues, cotransfection reporter assays in cardiac myocytes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional validation identifying specific phosphorylation site, single lab","pmids":["10764782"],"is_preprint":false},{"year":2004,"finding":"RTEF-1 (TEAD4) transcriptionally activates VEGF by binding to the first Sp1 element (-97 to -87) in the VEGF promoter GC-rich region, confirmed by EMSA and ChIP. This is distinct from HIF-1alpha binding and does not require MCAT elements. RTEF-1-driven VEGF activation promotes endothelial cell proliferation and vascular structure formation.","method":"Sequential deletion analysis, site-directed mutagenesis of VEGF promoter, EMSA, ChIP, endothelial cell functional assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and EMSA with mutagenesis establishing direct DNA binding, single lab","pmids":["15073166"],"is_preprint":false},{"year":2011,"finding":"RTEF-1 (TEAD4) transcriptionally regulates the HIF-1alpha gene by binding an MCAT-like element in the HIF-1alpha promoter (confirmed by ChIP). In VE-cadherin/RTEF-1 transgenic mice subjected to hindlimb ischemia, RTEF-1-driven HIF-1alpha upregulation accelerates blood flow recovery and increases capillary density.","method":"Sequential deletion of HIF-1alpha promoter, ChIP, siRNA knockdown, transgenic mouse hindlimb ischemia model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-validated direct promoter binding plus in vivo transgenic model with functional outcome, single lab","pmids":["21540178"],"is_preprint":false},{"year":2023,"finding":"TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, impairing the binding of Smad2/3 to the histone acetyltransferase p300, thereby suppressing TGF-β/Smad target gene transcription and HCC cell proliferation/migration. This function is independent of YAP (shown by point mutagenesis disrupting TEAD4-YAP interaction and by YAP/TAZ depletion).","method":"Co-immunoprecipitation, YAP-binding-defective mutagenesis, siRNA knockdown, xenograft model, luciferase reporter","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis establishing YAP-independence, multiple functional assays, single lab","pmids":["36806855"],"is_preprint":false},{"year":2023,"finding":"TEAD4 m6A methylation (mediated by WTAP) is recognized by YTHDF2, which stabilizes TEAD4 protein and leads to its aberrant upregulation in nasopharyngeal carcinoma. Upregulated TEAD4 drives NPC progression by transcriptionally activating BZW2, which induces the AKT oncogenic pathway; this activity is independent of YAP/TAZ.","method":"m6A methylation assay, YTHDF2/WTAP Co-IP and functional knockdown, ChIP and luciferase reporter for BZW2 transcription, AKT pathway analysis","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods establishing m6A modification and downstream transcriptional target, single lab","pmids":["36608137"],"is_preprint":false},{"year":2024,"finding":"VGLL1 partners with TEAD4 to regulate chromatin accessibility at target gene loci through histone acetylation during human trophectoderm specification and trophoblast stem cell self-renewal; VGLL1 cooperates with GATA3 and TFAP2C in this process.","method":"ChIP-seq/ATAC-seq for chromatin accessibility, histone acetylation assays, loss-of-function in human TELCs/TSCs","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide chromatin and acetylation assays with functional validation, single lab","pmids":["38233381"],"is_preprint":false},{"year":2020,"finding":"A trophoblast-specific inter-chromosomal enhancer on chromosome 19 physically interacts with the Tead4 promoter on chromosome 6 and is required for appropriate Tead4 expression level in mouse blastocysts, as shown by chromatin conformation capture and deletion of a 1.5 kb genomic interval causing a 42% decrease in Tead4 expression.","method":"Chromatin conformation capture (3C), luciferase reporter assay, CRISPR/Cas9 enhancer deletion mouse lines, quantitative RT-PCR and RNA-seq","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional deletion of enhancer with quantitative expression readout in vivo, single lab","pmids":["31777916"],"is_preprint":false},{"year":2022,"finding":"TEAD4 in TEAD4 in Tead4 knockout mouse embryos shows a dramatic decrease in nuclear YAP in outside cells of the morula, suggesting that TEAD4 directly regulates Hippo signaling (nuclear YAP localization) and trophectoderm epithelium integrity through Krt8 regulation. Bovine TEAD4 depletion does not affect CDX2, GATA3, or SOX2 expression, confirming species-specific role.","method":"Base editing for Tead4 knockout in mouse, RNA-seq, immunofluorescence for nuclear YAP and KRT8","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — base editing with RNA-seq and immunofluorescence, multiple readouts, single lab","pmids":["38206180"],"is_preprint":false},{"year":2018,"finding":"TEAD4 promotes colorectal tumorigenesis by directly binding the YAP1 gene promoter and transcriptionally activating YAP1 expression, establishing a TEAD4→YAP1 positive regulatory axis in CRC.","method":"ChIP-qPCR, luciferase reporter assay, RNA-seq/GSEA, siRNA knockdown with in vivo tumor growth","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and luciferase reporter validating direct transcriptional activation, single lab","pmids":["29157094"],"is_preprint":false},{"year":2012,"finding":"RTEF-1 (TEAD4) upregulates IGFBP-1 transcription by binding the insulin response element in the IGFBP-1 promoter; endothelium-specific RTEF-1 knockout mice show increased blood glucose and insulin resistance with decreased serum IGFBP-1, while RTEF-1 transgenic mice show improved glucose clearance.","method":"Transgenic/knockout mice, ChIP, promoter reporter assay with insulin response element, metabolic phenotyping","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-validated direct binding plus bidirectional transgenic/knockout mouse models with metabolic phenotype, single lab","pmids":["22843786"],"is_preprint":false},{"year":2025,"finding":"PKCζ phosphorylates SP1 and enhances its interaction with TEAD4; SP1 physically interacts with and stabilizes the YAP/TEAD4 complex at regulatory genomic loci to co-regulate YAP/TEAD target genes including VISTA (an immune checkpoint gene); TEAD4-SP1-YAP co-occupancy of the VISTA enhancer drives VISTA expression and CD8+ T cell suppression.","method":"Co-immunoprecipitation, ChIP-seq, kinase assay (PKCζ), luciferase reporter, T cell functional assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, kinase assay with functional immune validation, single lab","pmids":["39875519"],"is_preprint":false},{"year":2022,"finding":"TEAD4 promotes YAP/TAZ-TEAD4-BRD4 complex-dependent transcriptional upregulation of CCBE1 by directly binding the CCBE1 enhancer region in CRC cells and cancer-associated fibroblasts, promoting VEGFC proteolysis and tumor lymphangiogenesis.","method":"ChIP, luciferase reporter, Co-IP, in vitro and in vivo lymphangiogenesis assays, BET inhibitor (JQ1) treatment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter validating direct enhancer binding with in vivo functional validation, single lab","pmids":["36781122"],"is_preprint":false},{"year":2019,"finding":"TEAD4 (RTEF-1) inhibits beta-glycerophosphate-induced vascular smooth muscle cell calcification by suppressing the Wnt/β-catenin signaling pathway; RTEF-1 overexpression reduces Wnt3a and p-β-catenin (Ser675) levels while increasing phospho-β-catenin (Ser33/37), and a Wnt agonist (LiCl) reverses RTEF-1's protective effects.","method":"Overexpression/siRNA knockdown, alizarin red staining, calcium content assay, western blot pathway analysis, pharmacological rescue","journal":"Calcified tissue international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional overexpression/knockdown with pharmacological rescue, multiple labs corroborate RTEF-1/TEAD4 cardiovascular role, single lab for this specific mechanism","pmids":["33713163"],"is_preprint":false}],"current_model":"TEAD4 is a TEA-domain transcription factor that functions as the DNA-binding effector of the Hippo pathway, forming complexes with the co-activators YAP/TAZ (whose nuclear localization is controlled by LATS kinases) and alternative co-factors (VGLL1, VGLL3, VGLL4, KLF5, RUNX3, GR, HHEX, SP1, TCF4, CtBP2, Smad2/3/4) to regulate diverse transcriptional programs; its activity is controlled at multiple levels including palmitoylation-dependent stability and conformation, subcellular localization (nuclear vs. cytoplasmic vs. mitochondrial), NF2-mediated ubiquitination, m6A methylation-YTHDF2 stability, and alpha1-adrenergic/mTOR/PKC signaling, enabling context-specific outputs ranging from trophectoderm specification, mitochondrial transcription, OXPHOS regulation, and angiogenesis to cancer-promoting EMT, metabolic reprogramming, and immune evasion."},"narrative":{"mechanistic_narrative":"TEAD4 is a TEA-domain sequence-specific transcription factor that serves as the DNA-binding effector of the Hippo pathway, partnering with the co-activators YAP/TAZ to drive transcriptional programs governing cell fate, proliferation, and metabolism [PMID:19289085, PMID:20123908]. Its TEA domain recognizes MCAT DNA elements through an α3 recognition helix that contacts both major and minor grooves [PMID:28368398], while a separate immunoglobulin-like C-terminal domain binds YAP/TAZ through a shared hydrophobic interface, with point mutations at this surface abolishing co-activator binding and transforming activity [PMID:20123908, PMID:23780915]. This same C-terminal cavity harbors an autopalmitoylation activity; acylation is dispensable for YAP/TAZ binding but stabilizes the active conformation of the protein [PMID:29760238]. The earliest defined biological role is in preimplantation development, where TEAD4 acts upstream of Cdx2/Gata3 to specify the trophectoderm lineage, with outer-versus-inner cell fate decided by nuclear-versus-cytoplasmic TEAD4 localization and by Lats-controlled nuclear YAP availability [PMID:17913785, PMID:18083014, PMID:20123908, PMID:20081188, PMID:22529382]; postimplantation, TEAD4 sustains trophoblast progenitor self-renewal in mouse and human placenta by directly regulating cell-cycle genes [PMID:32669432]. Beyond canonical nuclear transcription, TEAD4 uniquely localizes to mitochondria where it binds mtDNA and recruits POLRMT to drive mitochondrial transcription and oxidative phosphorylation, and it suppresses reactive oxygen species during blastocoel formation [PMID:23903192, PMID:30201685]. TEAD4 activity is tuned by combinatorial cofactor exchange — VGLL1/3/4, KLF5, RUNX3, glucocorticoid receptor, HHEX, SP1, TCF4, CtBP2, and Smad2/3/4 — many engagements occurring through the same co-activator pocket and producing context-specific activation or repression, frequently independent of YAP/TAZ [PMID:24504694, PMID:28051067, PMID:30209132, PMID:27425596, PMID:31289134, PMID:36008411, PMID:25970772, PMID:36806855, PMID:39875519]. Stability and localization are further controlled negatively by NF2, which inhibits palmitoylation and drives cytoplasmic translocation and ubiquitination of TEAD4 independently of LATS/YAP [PMID:38522513], and positively by m6A-YTHDF2-mediated protein stabilization [PMID:36608137]. In its first-described context as cardiac/endothelial RTEF-1, TEAD4 transactivates MCAT- and Sp1-element targets including β-MyHC, VEGF, and HIF-1α, mediating α1-adrenergic responses through phosphorylation at Ser-322 and promoting angiogenesis and metabolic control [PMID:9670917, PMID:10764782, PMID:15073166, PMID:21540178]. Across cancers TEAD4 promotes EMT, proliferation, lymphangiogenesis, metabolic reprogramming, and immune evasion, often via YAP-independent transcriptional outputs and feed-forward autoregulation of its own and YAP1 expression [PMID:33893278, PMID:26387538, PMID:29510988, PMID:29157094, PMID:39875519, PMID:36781122].","teleology":[{"year":2007,"claim":"Established TEAD4 as a required upstream determinant of the trophectoderm lineage, defining its first concrete developmental function.","evidence":"Tead4-/- mouse knockout with lineage-marker expression analysis","pmids":["17913785","18083014"],"confidence":"High","gaps":["Did not define the cofactor driving TE-specific transcription","Did not address how the same factor is restricted to outer cells"]},{"year":2009,"claim":"Placed TEAD4 downstream of Hippo signaling, showing Lats/YAP control of TEAD4 transcriptional output distinguishes TE from ICM.","evidence":"Genetic epistasis and YAP localization in embryos and ES cells","pmids":["19289085"],"confidence":"High","gaps":["Mechanism positioning TEAD4 itself differently in inner vs outer cells not resolved","Direct target gene set not yet mapped"]},{"year":2010,"claim":"Defined the structural basis of TEAD4-YAP coactivation and parallel downstream effectors, explaining how the complex drives transforming and trophoblast programs.","evidence":"X-ray crystallography with interface mutagenesis; genetic epistasis identifying Gata3 parallel to Cdx2","pmids":["20123908","20081188"],"confidence":"High","gaps":["DNA-binding specificity not yet structurally defined","Other coactivators using the same interface not characterized"]},{"year":2012,"claim":"Showed that subcellular localization of TEAD4 itself, not just YAP, dictates the first cell-fate decision.","evidence":"ChIP-seq and forced nuclear restoration in preimplantation embryos","pmids":["22529382"],"confidence":"High","gaps":["Molecular signal controlling TEAD4 nuclear import not identified","Relationship to YAP localization not fully separated"]},{"year":2013,"claim":"Revealed a non-canonical mitochondrial/ROS-suppressing role and reframed TEAD4 as essential for redox protection rather than strictly TE specification.","evidence":"Knockout under low-oxidative-stress conditions, ROS and mitochondrial membrane potential assays, subcellular localization; parallel biochemical mapping of the palmitoylation cavity","pmids":["23903192","23780915"],"confidence":"High","gaps":["Mitochondrial import mechanism unknown","How nuclear and mitochondrial pools are partitioned not resolved"]},{"year":2014,"claim":"Demonstrated that diverse cofactors (VGLL1) engage the same TEAD4 surface as YAP/TAZ but with distinct structural requirements, foreshadowing combinatorial regulation.","evidence":"Biochemical peptide-binding and structural analysis","pmids":["24504694"],"confidence":"Medium","gaps":["In-cell functional consequences of VGLL1 binding not shown here","Selectivity determinants among cofactors not fully mapped"]},{"year":2017,"claim":"Resolved the DNA-recognition mechanism and established functional consequences of disrupting promoter occupancy, and connected TEAD4 to Wnt signaling via TCF4.","evidence":"Crystal structure of TEA domain on MCAT DNA with mutagenesis; Co-IP/ChIP showing TEAD4-TCF4 complex disrupted by VGLL4","pmids":["28368398","28051067"],"confidence":"High","gaps":["Genome-wide cofactor switching not quantified","How DNA binding integrates with cofactor pocket occupancy not addressed"]},{"year":2018,"claim":"Defined TEAD4 as a direct mitochondrial transcription factor and clarified that palmitoylation governs stability/conformation rather than coactivator binding.","evidence":"mtDNA ChIP and POLRMT Co-IP in trophoblast stem cells; NMR autopalmitoylation and C360S mutagenesis; VGLL4-CtBP2 repressor complex by Co-IP/ChIP","pmids":["30201685","29760238","30209132","28960584"],"confidence":"High","gaps":["Whether mitochondrial TEAD4 requires palmitoylation not tested","Acyltransferase regulating TEAD4 in vivo not identified"]},{"year":2019,"claim":"Expanded the cofactor repertoire and signaling inputs, showing GR, VGLL3, and AMPK/YAP axes route TEAD4 into distinct transcriptional and proliferative programs.","evidence":"Co-IP/ChIP for GR autoregulatory loop; interaction proteomics for VGLL3; Co-IP and reporter for YAP1/TEAD4/CCNE axis","pmids":["31289134","31138678","31455378"],"confidence":"Medium","gaps":["Single-method interaction evidence for several partners","Hierarchy among competing cofactors at shared sites unresolved"]},{"year":2021,"claim":"Established a metabolite-driven, YAP-independent mode in which arginine/mTOR retains TEAD4 in the nucleus to coordinately upregulate OXPHOS genes.","evidence":"ChIP-seq, amino acid deprivation, mTOR inhibition and metabolic assays in prostate cancer cells","pmids":["33893278"],"confidence":"High","gaps":["Direct sensor linking arginine to TEAD4 retention not identified","Generalizability beyond prostate cancer not tested"]},{"year":2024,"claim":"Identified NF2 as a direct LATS/YAP-independent negative regulator controlling TEAD4 palmitoylation, localization, and ubiquitin-mediated turnover.","evidence":"Co-IP, domain mapping, palmitoylation/ubiquitination assays and localization in proliferation assays; VGLL1-chromatin accessibility and TEAD4/TFAP2C polarization studies","pmids":["38522513","38233381","38789684"],"confidence":"High","gaps":["E3 ligase acting in the NF2 axis not defined here","Integration of NF2 control with mitochondrial pool unknown"]},{"year":2025,"claim":"Linked TEAD4 to immune evasion by showing PKCζ-phosphorylated SP1 stabilizes a TEAD4-SP1-YAP complex driving the VISTA immune checkpoint.","evidence":"Co-IP, ChIP-seq, PKCζ kinase assay and CD8+ T cell functional assays","pmids":["39875519"],"confidence":"Medium","gaps":["Reciprocal validation of the ternary complex limited to one system","In vivo immune-checkpoint relevance not fully established"]},{"year":null,"claim":"How TEAD4 partitions between nuclear, cytoplasmic, and mitochondrial pools and how competing cofactors are selected at shared interfaces to specify opposing transcriptional outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of localization control across compartments","Determinants of YAP-dependent vs YAP-independent activity not predictable","Quantitative cofactor competition at the C-terminal pocket not measured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,8,10,24,39]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10,12,32,33]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,18,19,34]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,11,26]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,10,12,39]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,3,4,23]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,19,40]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21,24,35,39,42]}],"complexes":["TEAD4-YAP/TAZ","TEAD4-VGLL4-CtBP2","YAP-TEAD4-RUNX3","YAP/TAZ-TEAD4-BRD4"],"partners":["YAP1","TAZ","VGLL4","VGLL1","TCF4","NF2","RUNX3","SP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15561","full_name":"Transcriptional enhancer factor TEF-3","aliases":["TEA domain family member 4","TEAD-4","Transcription factor 13-like 1","Transcription factor RTEF-1"],"length_aa":434,"mass_kda":48.3,"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 non-cooperatively to the Sph and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription. Binds to the M-CAT motif","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15561/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEAD4","classification":"Not Classified","n_dependent_lines":108,"n_total_lines":1208,"dependency_fraction":0.08940397350993377},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TEAD4","total_profiled":1310},"omim":[{"mim_id":"619589","title":"BRAF-ACTIVATED NONCODING RNA; BANCR","url":"https://www.omim.org/entry/619589"},{"mim_id":"603170","title":"TEA DOMAIN FAMILY MEMBER 3; TEAD3","url":"https://www.omim.org/entry/603170"},{"mim_id":"601714","title":"TEA DOMAIN FAMILY MEMBER 4; TEAD4","url":"https://www.omim.org/entry/601714"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":122.6}],"url":"https://www.proteinatlas.org/search/TEAD4"},"hgnc":{"alias_symbol":["TEF-3","TEFR-1","EFTR-2","RTEF-1"],"prev_symbol":["TCF13L1"]},"alphafold":{"accession":"Q15561","domains":[{"cath_id":"-","chopping":"43-133","consensus_level":"medium","plddt":77.5119,"start":43,"end":133},{"cath_id":"2.70.50.80","chopping":"226-433","consensus_level":"high","plddt":92.3848,"start":226,"end":433}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15561","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15561-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15561-F1-predicted_aligned_error_v6.png","plddt_mean":75.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEAD4","jax_strain_url":"https://www.jax.org/strain/search?query=TEAD4"},"sequence":{"accession":"Q15561","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15561.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15561/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15561"}},"corpus_meta":[{"pmid":"19289085","id":"PMC_19289085","title":"The 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mice), immunofluorescence, gene expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined molecular phenotype, independently replicated across two labs (PMIDs 17913785 and 18083014) with concordant findings\",\n      \"pmids\": [\"17913785\", \"18083014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The Hippo pathway components Lats kinase and Yap regulate TEAD4 activity to distinguish trophectoderm from ICM: in outside cells, Yap localizes to nuclei and co-activates TEAD4 to induce Cdx2 and trophoblast genes; in inside cells, Lats-mediated phosphorylation retains Yap in the cytoplasm, suppressing TEAD4 transcriptional activity.\",\n      \"method\": \"Genetic epistasis, immunofluorescence of Yap localization, modulation of Tead4/Yap activity in embryos and ES cells, Cdx2 expression readout\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic and cell-biological experiments with defined pathway epistasis, replicated across multiple labs\",\n      \"pmids\": [\"19289085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the YAP-interacting C-terminal domain of TEAD4 in complex with the N-terminal domain of YAP reveals an immunoglobulin-like fold in TEAD4; YAP interacts mainly through two short helices flanking a PXXPhiP motif-containing loop. Point mutations in TEAD4 at the interface abolish YAP interaction and transforming activity.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, functional transformation assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis with functional validation in a single rigorous study\",\n      \"pmids\": [\"20123908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Gata3 expression in trophoblast is regulated downstream of Tead4 (and in parallel with Cdx2): Gata3 and Cdx2 act in parallel downstream of Tead4 to promote trophoblast fate, as shown by loss of both Gata3 and Cdx2 in Tead4-null embryos.\",\n      \"method\": \"Bioinformatic and functional genomic strategies, genetic epistasis in mouse embryos, ES cell differentiation assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with defined downstream transcriptional targets, independently consistent with other TE specification studies\",\n      \"pmids\": [\"20081188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Differential nuclear versus cytoplasmic localization of TEAD4 in outer versus inner blastomeres dictates first mammalian cell fate: TEAD4 lacks nuclear localization in inner cells, impairing TE-specific transcription. Forced nuclear restoration of TEAD4 in inner blastomeres maintains the TE transcriptional program and prevents ICM/TE segregation.\",\n      \"method\": \"ChIP-sequencing for genome-wide target identification, subcellular localization manipulation, loss-of-function in preimplantation embryos\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus direct localization manipulation with functional consequences, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22529382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TEAD4 is not required for trophectoderm specification per se but is essential for preventing oxidative stress during blastocoel formation: Tead4-/- embryos can form blastocysts and express TE genes under low-oxidative-stress culture conditions. TEAD4 suppresses reactive oxygen species (ROS) and maintains mitochondrial membrane potential. Ectopically expressed TEAD4 can localize to mitochondria as well as the nucleus—a property unique to TEAD4 among TEAD family members.\",\n      \"method\": \"Genetic knockout under altered culture conditions (low O2/antioxidant), ROS measurement, mitochondrial membrane potential assay, subcellular fractionation/localization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in one rigorous study demonstrating novel mitochondrial localization and ROS-suppression mechanism\",\n      \"pmids\": [\"23903192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TEAD4 binds the palmitoylation-binding hydrophobic cavity of its C-terminal domain. The YAP and TAZ co-activators bind essentially the same site on TEAD4 with similar affinities but use different residues for key contacts, as shown by biochemical and biophysical assays with peptides and molecular modeling.\",\n      \"method\": \"Biochemical binding assays (peptide affinity), biophysical assays, molecular modeling, structural biology\",\n      \"journal\": \"Chembiochem : a European journal of chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding and structural data from single lab without full mutagenesis validation\",\n      \"pmids\": [\"23780915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VGLL1-derived peptides bind TEAD4 with nanomolar affinity via a β-strand:loop:α-helix motif, binding the same site used by YAP and TAZ but without the secondary structural element required by the latter two coactivators.\",\n      \"method\": \"Biochemical peptide binding assays, structural biology/molecular analysis\",\n      \"journal\": \"Chembiochem : a European journal of chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro peptide binding assay with structural characterization, single lab\",\n      \"pmids\": [\"24504694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TEAD4 occupies promoters of myogenic genes (including Myogenin, CDKN1A, Caveolin 3) in C2C12 myoblasts as shown by ChIP-chip, and is required for normal myotube differentiation; TEAD4 knockdown results in shortened myotubes and reduced expression of structural, regulatory, and unfolded protein response genes; TEAD4 represses CTGF to promote differentiation.\",\n      \"method\": \"shRNA knockdown, ChIP coupled to array hybridization (ChIP-chip), RNA-seq, dominant-negative TEAD expression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-chip, RNA-seq, and functional knockdown with specific phenotypic readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21701496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TEAD4 forms a complex with TCF4 (TCF7L2) and co-binds target genes; VGLL4 disrupts this TEAD4-TCF4 complex to suppress TCF4 transactivation, directly linking Hippo-YAP and Wnt/β-catenin signaling at the transcription factor level in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, genome-wide co-binding analysis, functional assays, VGLL4 peptide mimetic in mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP demonstrating physical complex, ChIP for co-binding, and in vivo functional validation in single study with multiple orthogonal methods\",\n      \"pmids\": [\"28051067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of the TEAD4 TEA domain in complex with a muscle-CAT (MCAT) DNA element reveals that the α3 recognition helix determines DNA-binding specificity, interacting with both major and minor grooves. Mutations at two major binding-site residues substantially reduce promoter occupancy and impair YAP-induced transcription and cancer cell growth.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, ChIP-qPCR, colony formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis with functional validation, single lab\",\n      \"pmids\": [\"28368398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The tumor suppressor RBM4 facilitates alternative splicing of TEAD4 to produce a truncated isoform TEAD4-S lacking the N-terminal DNA-binding domain but retaining the YAP-interaction domain; TEAD4-S localizes to both nucleus and cytoplasm and acts as a dominant-negative inhibitor of YAP activity, suppressing cancer cell proliferation and migration.\",\n      \"method\": \"Alternative splicing analysis, subcellular fractionation/localization, dominant-negative functional assay, xenograft mouse models, knockdown/rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (localization, dominant-negative, in vivo xenograft) in single lab\",\n      \"pmids\": [\"27291620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TEAD4 localizes to mitochondria in trophoblast stem cells, binds mitochondrial DNA (mtDNA), and facilitates mitochondrial transcription by recruiting mitochondrial RNA polymerase (POLRMT). Loss of TEAD4 impairs POLRMT recruitment, reduces expression of mtDNA-encoded electron transport chain components, and inhibits oxidative phosphorylation.\",\n      \"method\": \"Mitochondrial fractionation, mtDNA ChIP, POLRMT co-immunoprecipitation, loss-of-function in trophoblast stem cells, metabolic assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical demonstration of mitochondrial TEAD4 binding to mtDNA and POLRMT interaction, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30201685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TEAD4 acylation (palmitoylation) is not required for YAP or TAZ binding in biochemical and cellular assays; however, TEAD4 acylation significantly enhances its protein stability, suggesting palmitoylation helps maintain its active conformation rather than directly mediating co-activator binding. NMR studies further confirm mTEAD4 can catalyze autopalmitoylation, and flufenamic acid inhibits this reaction.\",\n      \"method\": \"NMR spectroscopy, biochemical binding assays, palmitoylation mutagenesis (C360S), in vitro autopalmitoylation assay, fragment screening\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR plus in vitro enzymatic assay plus mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29760238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Acylation (palmitoylation) of TEAD4 does not serve as a prerequisite for YAP or TAZ binding (shown by biochemical and cellular assays comparing acylated vs. non-acylated TEAD4), but significantly enhances TEAD4 stability.\",\n      \"method\": \"Biochemical binding assays, cellular assays with acylated/non-acylated TEAD4\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assays from single lab without structural validation\",\n      \"pmids\": [\"28960584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TEAD4 forms a complex with VGLL4 and CtBP2 to repress adipogenesis in 3T3-L1 preadipocytes; VGLL4 acts as an adaptor bridging TEAD4 and CtBP2; this ternary complex occupies promoters of PPARγ and Adipoq to suppress their transcription. This repression of adipogenesis is YAP/TAZ-independent.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, promoter luciferase assay, siRNA knockdown with adipogenic differentiation readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional knockdown with multiple orthogonal methods in single lab\",\n      \"pmids\": [\"30209132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VGLL3 physically interacts with TEAD1, TEAD3, and TEAD4 in myoblasts and myotubes (as shown by interaction proteomics); unlike YAP/TAZ, VGLL3 does not interact with Hippo kinase cascade proteins. VGLL3 mainly represses gene expression in a TEAD-dependent manner to regulate myogenesis.\",\n      \"method\": \"Interaction proteomics (affinity purification-MS), functional overexpression/knockdown with myogenic differentiation readouts\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — interaction proteomics (single method for physical interaction) with functional follow-up, single lab\",\n      \"pmids\": [\"31138678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RAC-TRIO signaling inhibits LATS1/2-mediated YAP phosphorylation, causing YAP to dissociate from RUNX3 and associate with TEAD4. RUNX3 contributes to both formation and dissociation of the YAP-TEAD4 complex, likely through formation of a YAP-TEAD4-RUNX3 ternary complex, functioning as a molecular switch between proliferative and tumor-suppressive states.\",\n      \"method\": \"Genetic epistasis in Drosophila, co-immunoprecipitation in mammalian cells, phosphorylation-deficient YAP mutants, cancer cell tumorigenicity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combined Drosophila epistasis and mammalian Co-IP with functional validation, single lab\",\n      \"pmids\": [\"27425596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Glucocorticoid receptor (GR) interacts with TEAD4 upon glucocorticoid treatment, forming a complex recruited to the TEAD4 promoter to boost its own transcription (positive autoregulatory loop). GR facilitates nuclear accumulation of TEAD4.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, promoter reporter assay, nuclear fractionation, knockdown/overexpression with functional assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ChIP on TEAD4 promoter, multiple methods, single lab\",\n      \"pmids\": [\"31289134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Arginine acts as an epigenetic regulator that retains TEAD4 in the nucleus in a YAP1-independent but mTOR-dependent manner in prostate cancer cells. Nuclear TEAD4 is recruited to promoter/enhancer regions of nuclear-encoded OXPHOS genes and mediates their coordinated upregulation. Arginine also activates lysine acetyltransferases, increasing acetyl-CoA and histone acetylation to facilitate TEAD4 chromatin recruitment.\",\n      \"method\": \"ChIP-seq, amino acid deprivation experiments, mTOR pathway inhibition, siRNA knockdown, metabolic assays, xenograft model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with metabolic and signaling pathway validation using multiple orthogonal methods in single lab\",\n      \"pmids\": [\"33893278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Metformin inhibits BLCA cell proliferation via the AMPKα/YAP1/TEAD4/CCNE1/2 axis; YAP1 positively regulates CCNE1 and CCNE2 expression by forming a complex with TEAD4 (confirmed by Co-IP); TEAD4 is the only TEAD family member precipitated by YAP1 in bladder cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, dual-luciferase reporter, bioinformatics, siRNA, xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and luciferase reporter with functional follow-up, single lab\",\n      \"pmids\": [\"31455378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TEAD4 promotes cell adhesion, EMT, and vimentin expression in colorectal cancer cells through a YAP-independent mechanism; a YAP-binding-defective TEAD4 mutant (Y429H) retains full ability to reverse mesenchymal-to-epithelial transition and increase vimentin expression, confirming YAP-independent transcriptional activity of TEAD4.\",\n      \"method\": \"Knockdown/rescue with TEAD4 mutant defective in YAP binding, microarray analysis, in vivo metastasis model, YAP knockdown negative control\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis rescue experiment establishing YAP-independence, multiple methods, single lab\",\n      \"pmids\": [\"26387538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AP-1 (FOS/JUN) factors are required for de novo binding of TEAD4 to regulatory chromatin regions during vascular/hematopoietic development; AP-1 and TEAD4 co-occupy cis-regulatory hubs that regulate the balance between smooth muscle and hemogenic cell fates.\",\n      \"method\": \"Genome-wide ChIP-seq, dominant-negative FOS inhibition, ES cell differentiation assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with functional perturbation, single lab\",\n      \"pmids\": [\"27802171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TEAD4 ensures trophoblast progenitor self-renewal postimplantation; in both mouse and human, TEAD4 directly regulates cell cycle gene expression in trophoblast stem cells (TSCs). TEAD4 and its cofactor YAP1 are specifically expressed in cytotrophoblast progenitors of the first-trimester human placenta.\",\n      \"method\": \"Conditional trophoblast-specific Tead4 knockout in mouse, human TSC derivation from RPL patients, RNA-seq, ChIP-seq, functional rescue of TEAD4 expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined phenotype, human patient-derived TSC model, and multiple genomics methods in a single rigorous study\",\n      \"pmids\": [\"32669432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TEAD4 functions as a master regulator in a positive feedback loop with MYCN in high-risk neuroblastoma; silencing either gene collapses MYCN-amplified neuroblastoma transcriptional hallmarks and abrogates viability in vitro and in vivo. TEAD4 activity in this context is independent of the canonical Hippo coactivators YAP and TAZ.\",\n      \"method\": \"Transcriptional regulatory network analysis, gene silencing, in vitro and in vivo viability assays, multi-cohort analysis\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gene silencing with in vivo validation and network analysis; mechanistic independence of YAP/TAZ demonstrated functionally\",\n      \"pmids\": [\"29510988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CK2 (casein kinase 2) phosphorylates HHEX and enhances its interaction with TEAD4; HHEX associates with and stabilizes the YAP-TEAD4 complex at regulatory genomic loci to co-regulate YAP/TEAD target genes. A CK2 inhibitor (CX-4945) diminishes the HHEX-TEAD4 interaction, reducing target gene expression.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, kinase assay, CK2 inhibitor treatment, serum stimulation experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, and kinase assay with pharmacological validation, single lab\",\n      \"pmids\": [\"36008411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NF2 directly interacts with TEAD4 through its FERM domain and C-terminal tail, decreasing TEAD4 protein stability independently of LATS1/2 and YAP. NF2 inhibits TEAD4 palmitoylation and induces cytoplasmic translocation of TEAD4, leading to its ubiquitination and functional inactivation. NF2-TEAD4 interaction is required for NF2's cell proliferation-suppressing activity.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping experiments, palmitoylation assay, subcellular fractionation, ubiquitination assay, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (Co-IP, palmitoylation, ubiquitination, localization) establishing a direct physical interaction with functional consequence, single lab\",\n      \"pmids\": [\"38522513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD4 and TFAP2C promote embryo polarization and accelerate loss of totipotency in mouse embryos; they paradoxically promote and inhibit Hippo signaling before lineage diversification, driving expression of multiple Hippo regulators while also promoting apical domain formation that inactivates Hippo. Asymmetric apical domain segregation resolves these opposing activities into TE (Hippo OFF) versus ICM (Hippo ON) fates.\",\n      \"method\": \"Genetic manipulation of TFAP2C and TEAD4, embryo polarization assays, Hippo pathway component expression analysis, live imaging\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation with multiple functional readouts, single lab\",\n      \"pmids\": [\"38789684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TEAD4 directly binds the TEAD4 promoter to activate its own transcription, forming a positive feedback loop with NT5DC2 in leiomyosarcoma; NT5DC2 interacts with unpalmitoylated TEAD4 and reduces its degradation via the ubiquitin-proteasome pathway. The E3 ubiquitin ligase TRIM27 induces K27/K48-linked ubiquitination of unpalmitoylated TEAD4 at Lys278.\",\n      \"method\": \"Dual-luciferase assay, co-immunoprecipitation, ubiquitination assay, cell proliferation and in vivo xenograft assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays identifying specific ubiquitination site and binding partner, single lab\",\n      \"pmids\": [\"33993634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TEAD4 binds KLF5 and together they repress the CDK inhibitor p27 (CDKN1B) gene promoter, promoting triple-negative breast cancer cell proliferation; depletion of either TEAD4 or KLF5 activates p27 promoter and increases p27 mRNA levels.\",\n      \"method\": \"Co-immunoprecipitation, promoter reporter assay, siRNA knockdown, xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and promoter assay with functional rescue experiments, single lab\",\n      \"pmids\": [\"25970772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RTEF-1 (TEAD4) transactivates both the beta-myosin heavy chain and skeletal alpha-actin promoters through MCAT elements in cardiac myocytes and potentiates alpha1-adrenergic signaling responses, unlike TEF-1 which only activates betaMyHC. RTEF-1 can activate the SKA promoter through a mechanism independent of its MCAT element, suggesting promoter-specific cofactors.\",\n      \"method\": \"Cotransfection with promoter/reporter constructs in neonatal rat cardiac myocytes, MCAT mutation analysis, gel shift competition assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assays with mutagenesis in primary cells, single lab, multiple target genes tested\",\n      \"pmids\": [\"9670917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The C-terminal domain of RTEF-1 (TEAD4) mediates the alpha1-adrenergic response in cardiac myocytes; a single serine residue (Ser-322), not present in TEF-1, accounts for ~70% of the alpha1-adrenergic activation as demonstrated by site-directed mutagenesis, suggesting direct phosphorylation at Ser-322 by alpha1-adrenergic-dependent kinases.\",\n      \"method\": \"Chimeric protein analysis, site-directed mutagenesis of serine residues, cotransfection reporter assays in cardiac myocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional validation identifying specific phosphorylation site, single lab\",\n      \"pmids\": [\"10764782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RTEF-1 (TEAD4) transcriptionally activates VEGF by binding to the first Sp1 element (-97 to -87) in the VEGF promoter GC-rich region, confirmed by EMSA and ChIP. This is distinct from HIF-1alpha binding and does not require MCAT elements. RTEF-1-driven VEGF activation promotes endothelial cell proliferation and vascular structure formation.\",\n      \"method\": \"Sequential deletion analysis, site-directed mutagenesis of VEGF promoter, EMSA, ChIP, endothelial cell functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and EMSA with mutagenesis establishing direct DNA binding, single lab\",\n      \"pmids\": [\"15073166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RTEF-1 (TEAD4) transcriptionally regulates the HIF-1alpha gene by binding an MCAT-like element in the HIF-1alpha promoter (confirmed by ChIP). In VE-cadherin/RTEF-1 transgenic mice subjected to hindlimb ischemia, RTEF-1-driven HIF-1alpha upregulation accelerates blood flow recovery and increases capillary density.\",\n      \"method\": \"Sequential deletion of HIF-1alpha promoter, ChIP, siRNA knockdown, transgenic mouse hindlimb ischemia model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-validated direct promoter binding plus in vivo transgenic model with functional outcome, single lab\",\n      \"pmids\": [\"21540178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, impairing the binding of Smad2/3 to the histone acetyltransferase p300, thereby suppressing TGF-β/Smad target gene transcription and HCC cell proliferation/migration. This function is independent of YAP (shown by point mutagenesis disrupting TEAD4-YAP interaction and by YAP/TAZ depletion).\",\n      \"method\": \"Co-immunoprecipitation, YAP-binding-defective mutagenesis, siRNA knockdown, xenograft model, luciferase reporter\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis establishing YAP-independence, multiple functional assays, single lab\",\n      \"pmids\": [\"36806855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TEAD4 m6A methylation (mediated by WTAP) is recognized by YTHDF2, which stabilizes TEAD4 protein and leads to its aberrant upregulation in nasopharyngeal carcinoma. Upregulated TEAD4 drives NPC progression by transcriptionally activating BZW2, which induces the AKT oncogenic pathway; this activity is independent of YAP/TAZ.\",\n      \"method\": \"m6A methylation assay, YTHDF2/WTAP Co-IP and functional knockdown, ChIP and luciferase reporter for BZW2 transcription, AKT pathway analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods establishing m6A modification and downstream transcriptional target, single lab\",\n      \"pmids\": [\"36608137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VGLL1 partners with TEAD4 to regulate chromatin accessibility at target gene loci through histone acetylation during human trophectoderm specification and trophoblast stem cell self-renewal; VGLL1 cooperates with GATA3 and TFAP2C in this process.\",\n      \"method\": \"ChIP-seq/ATAC-seq for chromatin accessibility, histone acetylation assays, loss-of-function in human TELCs/TSCs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide chromatin and acetylation assays with functional validation, single lab\",\n      \"pmids\": [\"38233381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A trophoblast-specific inter-chromosomal enhancer on chromosome 19 physically interacts with the Tead4 promoter on chromosome 6 and is required for appropriate Tead4 expression level in mouse blastocysts, as shown by chromatin conformation capture and deletion of a 1.5 kb genomic interval causing a 42% decrease in Tead4 expression.\",\n      \"method\": \"Chromatin conformation capture (3C), luciferase reporter assay, CRISPR/Cas9 enhancer deletion mouse lines, quantitative RT-PCR and RNA-seq\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional deletion of enhancer with quantitative expression readout in vivo, single lab\",\n      \"pmids\": [\"31777916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TEAD4 in TEAD4 in Tead4 knockout mouse embryos shows a dramatic decrease in nuclear YAP in outside cells of the morula, suggesting that TEAD4 directly regulates Hippo signaling (nuclear YAP localization) and trophectoderm epithelium integrity through Krt8 regulation. Bovine TEAD4 depletion does not affect CDX2, GATA3, or SOX2 expression, confirming species-specific role.\",\n      \"method\": \"Base editing for Tead4 knockout in mouse, RNA-seq, immunofluorescence for nuclear YAP and KRT8\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — base editing with RNA-seq and immunofluorescence, multiple readouts, single lab\",\n      \"pmids\": [\"38206180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TEAD4 promotes colorectal tumorigenesis by directly binding the YAP1 gene promoter and transcriptionally activating YAP1 expression, establishing a TEAD4→YAP1 positive regulatory axis in CRC.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, RNA-seq/GSEA, siRNA knockdown with in vivo tumor growth\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and luciferase reporter validating direct transcriptional activation, single lab\",\n      \"pmids\": [\"29157094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RTEF-1 (TEAD4) upregulates IGFBP-1 transcription by binding the insulin response element in the IGFBP-1 promoter; endothelium-specific RTEF-1 knockout mice show increased blood glucose and insulin resistance with decreased serum IGFBP-1, while RTEF-1 transgenic mice show improved glucose clearance.\",\n      \"method\": \"Transgenic/knockout mice, ChIP, promoter reporter assay with insulin response element, metabolic phenotyping\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-validated direct binding plus bidirectional transgenic/knockout mouse models with metabolic phenotype, single lab\",\n      \"pmids\": [\"22843786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKCζ phosphorylates SP1 and enhances its interaction with TEAD4; SP1 physically interacts with and stabilizes the YAP/TEAD4 complex at regulatory genomic loci to co-regulate YAP/TEAD target genes including VISTA (an immune checkpoint gene); TEAD4-SP1-YAP co-occupancy of the VISTA enhancer drives VISTA expression and CD8+ T cell suppression.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, kinase assay (PKCζ), luciferase reporter, T cell functional assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, kinase assay with functional immune validation, single lab\",\n      \"pmids\": [\"39875519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TEAD4 promotes YAP/TAZ-TEAD4-BRD4 complex-dependent transcriptional upregulation of CCBE1 by directly binding the CCBE1 enhancer region in CRC cells and cancer-associated fibroblasts, promoting VEGFC proteolysis and tumor lymphangiogenesis.\",\n      \"method\": \"ChIP, luciferase reporter, Co-IP, in vitro and in vivo lymphangiogenesis assays, BET inhibitor (JQ1) treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter validating direct enhancer binding with in vivo functional validation, single lab\",\n      \"pmids\": [\"36781122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEAD4 (RTEF-1) inhibits beta-glycerophosphate-induced vascular smooth muscle cell calcification by suppressing the Wnt/β-catenin signaling pathway; RTEF-1 overexpression reduces Wnt3a and p-β-catenin (Ser675) levels while increasing phospho-β-catenin (Ser33/37), and a Wnt agonist (LiCl) reverses RTEF-1's protective effects.\",\n      \"method\": \"Overexpression/siRNA knockdown, alizarin red staining, calcium content assay, western blot pathway analysis, pharmacological rescue\",\n      \"journal\": \"Calcified tissue international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional overexpression/knockdown with pharmacological rescue, multiple labs corroborate RTEF-1/TEAD4 cardiovascular role, single lab for this specific mechanism\",\n      \"pmids\": [\"33713163\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEAD4 is a TEA-domain transcription factor that functions as the DNA-binding effector of the Hippo pathway, forming complexes with the co-activators YAP/TAZ (whose nuclear localization is controlled by LATS kinases) and alternative co-factors (VGLL1, VGLL3, VGLL4, KLF5, RUNX3, GR, HHEX, SP1, TCF4, CtBP2, Smad2/3/4) to regulate diverse transcriptional programs; its activity is controlled at multiple levels including palmitoylation-dependent stability and conformation, subcellular localization (nuclear vs. cytoplasmic vs. mitochondrial), NF2-mediated ubiquitination, m6A methylation-YTHDF2 stability, and alpha1-adrenergic/mTOR/PKC signaling, enabling context-specific outputs ranging from trophectoderm specification, mitochondrial transcription, OXPHOS regulation, and angiogenesis to cancer-promoting EMT, metabolic reprogramming, and immune evasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TEAD4 is a TEA-domain sequence-specific transcription factor that serves as the DNA-binding effector of the Hippo pathway, partnering with the co-activators YAP/TAZ to drive transcriptional programs governing cell fate, proliferation, and metabolism [#1, #2]. Its TEA domain recognizes MCAT DNA elements through an \\u03b13 recognition helix that contacts both major and minor grooves [#10], while a separate immunoglobulin-like C-terminal domain binds YAP/TAZ through a shared hydrophobic interface, with point mutations at this surface abolishing co-activator binding and transforming activity [#2, #6]. This same C-terminal cavity harbors an autopalmitoylation activity; acylation is dispensable for YAP/TAZ binding but stabilizes the active conformation of the protein [#13]. The earliest defined biological role is in preimplantation development, where TEAD4 acts upstream of Cdx2/Gata3 to specify the trophectoderm lineage, with outer-versus-inner cell fate decided by nuclear-versus-cytoplasmic TEAD4 localization and by Lats-controlled nuclear YAP availability [#0, #2, #3, #4]; postimplantation, TEAD4 sustains trophoblast progenitor self-renewal in mouse and human placenta by directly regulating cell-cycle genes [#23]. Beyond canonical nuclear transcription, TEAD4 uniquely localizes to mitochondria where it binds mtDNA and recruits POLRMT to drive mitochondrial transcription and oxidative phosphorylation, and it suppresses reactive oxygen species during blastocoel formation [#5, #12]. TEAD4 activity is tuned by combinatorial cofactor exchange — VGLL1/3/4, KLF5, RUNX3, glucocorticoid receptor, HHEX, SP1, TCF4, CtBP2, and Smad2/3/4 — many engagements occurring through the same co-activator pocket and producing context-specific activation or repression, frequently independent of YAP/TAZ [#7, #9, #15, #17, #18, #25, #29, #34, #41]. Stability and localization are further controlled negatively by NF2, which inhibits palmitoylation and drives cytoplasmic translocation and ubiquitination of TEAD4 independently of LATS/YAP [#26], and positively by m6A-YTHDF2-mediated protein stabilization [#35]. In its first-described context as cardiac/endothelial RTEF-1, TEAD4 transactivates MCAT- and Sp1-element targets including \\u03b2-MyHC, VEGF, and HIF-1\\u03b1, mediating \\u03b11-adrenergic responses through phosphorylation at Ser-322 and promoting angiogenesis and metabolic control [#30, #31, #32, #33]. Across cancers TEAD4 promotes EMT, proliferation, lymphangiogenesis, metabolic reprogramming, and immune evasion, often via YAP-independent transcriptional outputs and feed-forward autoregulation of its own and YAP1 expression [#19, #21, #24, #39, #41, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established TEAD4 as a required upstream determinant of the trophectoderm lineage, defining its first concrete developmental function.\",\n      \"evidence\": \"Tead4-/- mouse knockout with lineage-marker expression analysis\",\n      \"pmids\": [\"17913785\", \"18083014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the cofactor driving TE-specific transcription\", \"Did not address how the same factor is restricted to outer cells\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed TEAD4 downstream of Hippo signaling, showing Lats/YAP control of TEAD4 transcriptional output distinguishes TE from ICM.\",\n      \"evidence\": \"Genetic epistasis and YAP localization in embryos and ES cells\",\n      \"pmids\": [\"19289085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism positioning TEAD4 itself differently in inner vs outer cells not resolved\", \"Direct target gene set not yet mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the structural basis of TEAD4-YAP coactivation and parallel downstream effectors, explaining how the complex drives transforming and trophoblast programs.\",\n      \"evidence\": \"X-ray crystallography with interface mutagenesis; genetic epistasis identifying Gata3 parallel to Cdx2\",\n      \"pmids\": [\"20123908\", \"20081188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNA-binding specificity not yet structurally defined\", \"Other coactivators using the same interface not characterized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed that subcellular localization of TEAD4 itself, not just YAP, dictates the first cell-fate decision.\",\n      \"evidence\": \"ChIP-seq and forced nuclear restoration in preimplantation embryos\",\n      \"pmids\": [\"22529382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signal controlling TEAD4 nuclear import not identified\", \"Relationship to YAP localization not fully separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a non-canonical mitochondrial/ROS-suppressing role and reframed TEAD4 as essential for redox protection rather than strictly TE specification.\",\n      \"evidence\": \"Knockout under low-oxidative-stress conditions, ROS and mitochondrial membrane potential assays, subcellular localization; parallel biochemical mapping of the palmitoylation cavity\",\n      \"pmids\": [\"23903192\", \"23780915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mitochondrial import mechanism unknown\", \"How nuclear and mitochondrial pools are partitioned not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that diverse cofactors (VGLL1) engage the same TEAD4 surface as YAP/TAZ but with distinct structural requirements, foreshadowing combinatorial regulation.\",\n      \"evidence\": \"Biochemical peptide-binding and structural analysis\",\n      \"pmids\": [\"24504694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In-cell functional consequences of VGLL1 binding not shown here\", \"Selectivity determinants among cofactors not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the DNA-recognition mechanism and established functional consequences of disrupting promoter occupancy, and connected TEAD4 to Wnt signaling via TCF4.\",\n      \"evidence\": \"Crystal structure of TEA domain on MCAT DNA with mutagenesis; Co-IP/ChIP showing TEAD4-TCF4 complex disrupted by VGLL4\",\n      \"pmids\": [\"28368398\", \"28051067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide cofactor switching not quantified\", \"How DNA binding integrates with cofactor pocket occupancy not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined TEAD4 as a direct mitochondrial transcription factor and clarified that palmitoylation governs stability/conformation rather than coactivator binding.\",\n      \"evidence\": \"mtDNA ChIP and POLRMT Co-IP in trophoblast stem cells; NMR autopalmitoylation and C360S mutagenesis; VGLL4-CtBP2 repressor complex by Co-IP/ChIP\",\n      \"pmids\": [\"30201685\", \"29760238\", \"30209132\", \"28960584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mitochondrial TEAD4 requires palmitoylation not tested\", \"Acyltransferase regulating TEAD4 in vivo not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded the cofactor repertoire and signaling inputs, showing GR, VGLL3, and AMPK/YAP axes route TEAD4 into distinct transcriptional and proliferative programs.\",\n      \"evidence\": \"Co-IP/ChIP for GR autoregulatory loop; interaction proteomics for VGLL3; Co-IP and reporter for YAP1/TEAD4/CCNE axis\",\n      \"pmids\": [\"31289134\", \"31138678\", \"31455378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-method interaction evidence for several partners\", \"Hierarchy among competing cofactors at shared sites unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a metabolite-driven, YAP-independent mode in which arginine/mTOR retains TEAD4 in the nucleus to coordinately upregulate OXPHOS genes.\",\n      \"evidence\": \"ChIP-seq, amino acid deprivation, mTOR inhibition and metabolic assays in prostate cancer cells\",\n      \"pmids\": [\"33893278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct sensor linking arginine to TEAD4 retention not identified\", \"Generalizability beyond prostate cancer not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified NF2 as a direct LATS/YAP-independent negative regulator controlling TEAD4 palmitoylation, localization, and ubiquitin-mediated turnover.\",\n      \"evidence\": \"Co-IP, domain mapping, palmitoylation/ubiquitination assays and localization in proliferation assays; VGLL1-chromatin accessibility and TEAD4/TFAP2C polarization studies\",\n      \"pmids\": [\"38522513\", \"38233381\", \"38789684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase acting in the NF2 axis not defined here\", \"Integration of NF2 control with mitochondrial pool unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked TEAD4 to immune evasion by showing PKC\\u03b6-phosphorylated SP1 stabilizes a TEAD4-SP1-YAP complex driving the VISTA immune checkpoint.\",\n      \"evidence\": \"Co-IP, ChIP-seq, PKC\\u03b6 kinase assay and CD8+ T cell functional assays\",\n      \"pmids\": [\"39875519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of the ternary complex limited to one system\", \"In vivo immune-checkpoint relevance not fully established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TEAD4 partitions between nuclear, cytoplasmic, and mitochondrial pools and how competing cofactors are selected at shared interfaces to specify opposing transcriptional outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of localization control across compartments\", \"Determinants of YAP-dependent vs YAP-independent activity not predictable\", \"Quantitative cofactor competition at the C-terminal pocket not measured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 8, 10, 24, 39]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10, 12, 32, 33]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 18, 19, 34]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 11, 26]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 10, 12, 39]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3, 4, 23]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 19, 40]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21, 24, 35, 39, 42]}\n    ],\n    \"complexes\": [\n      \"TEAD4-YAP/TAZ\",\n      \"TEAD4-VGLL4-CtBP2\",\n      \"YAP-TEAD4-RUNX3\",\n      \"YAP/TAZ-TEAD4-BRD4\"\n    ],\n    \"partners\": [\n      \"YAP1\",\n      \"TAZ\",\n      \"VGLL4\",\n      \"VGLL1\",\n      \"TCF4\",\n      \"NF2\",\n      \"RUNX3\",\n      \"SP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}