{"gene":"ZEB1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1997,"finding":"ZEB (vertebrate homolog of Drosophila Zfh-1) binds to a subset of E-box sequences in muscle gene promoters and actively represses transcription, inhibiting muscle differentiation by repressing MEF-2 family members; as myogenic bHLH proteins accumulate during differentiation, they displace ZEB from E-boxes, releasing repression.","method":"DNA binding assays, transcriptional reporter assays, overexpression in mammalian cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (DNA binding, reporter assays, functional differentiation assays) in a focused mechanistic study replicated across muscle gene targets","pmids":["9233803"],"is_preprint":false},{"year":1994,"finding":"BZP (ZEB1) binds the 9-bp sequence AAAGGTGCA through two zinc finger clusters and functions as a transcriptional repressor of linked promoters; its subcellular localization shifts between nuclear (proliferating cells) and cytoplasmic (serum-deprived cells), correlating with its transcriptional inhibitory activity.","method":"DNA binding assays (Kd measurement), transcriptional reporter assays, immunocytochemistry, serum-deprivation experiments","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DNA binding and reporter assays with localization, single lab, multiple methods","pmids":["7935395"],"is_preprint":false},{"year":1995,"finding":"AREB6 (ZEB1) has two zinc finger clusters with distinct optimal DNA binding sequences (N-terminal: GTCACCTGT/TGCACCTGT; C-terminal: C/TACCTG/TT); the homeodomain lacks specific DNA binding but interacts with the N-terminal zinc finger cluster. Depending on the presence of an additional GTTTC/G consensus sequence, AREB6 can either repress or activate transcription from the same CACCTGT-containing promoter.","method":"CASTing (cyclic amplification and selection of targets), zinc-finger mutagenesis, transient transfection reporter assays","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro DNA binding with mutagenesis and functional reporter assays defining dual activator/repressor mechanism","pmids":["7588776"],"is_preprint":false},{"year":1998,"finding":"AREB6 (ZEB1) contains a hydrophobic repression domain (aa 754–901) and an acidic activation domain (aa 1011–1124). The repression domain requires the general transcriptional cofactor NC2 (NC2α/DRAP1 and NC2β/Dr1): it represses transcription in HeLa nuclear extract but not in a reconstituted system lacking NC2; addition of recombinant NC2 restores repressor activity. Direct interaction between the AREB6 repression domain and NC2α was demonstrated by yeast two-hybrid.","method":"In vitro transcription reconstitution assay, recombinant protein addition, yeast two-hybrid, transient transfection domain-mapping","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined components plus yeast two-hybrid interaction, multiple orthogonal methods","pmids":["9418848"],"is_preprint":false},{"year":1999,"finding":"ZEB and its Drosophila ortholog zfh-1 interact with corepressor CtBP through PLDLS motifs; ZEB contains three CtBP-binding sites whose mutation abolishes both CtBP binding and repressor activity, demonstrating that CtBP recruitment to the promoter is necessary for ZEB-mediated transcriptional repression.","method":"Co-immunoprecipitation, mutagenesis of PLDLS motifs, transcriptional reporter assays, promoter recruitment assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — binding-site mutagenesis abolishing both interaction and function, replicated across ZEB and zfh-1 orthologs with multiple assays","pmids":["10359772"],"is_preprint":false},{"year":1999,"finding":"ZEB contains two independent repressor domains with distinct tissue specificities: the C-terminal domain inhibits muscle differentiation by specifically blocking MEF2C transcriptional activity, while the N-terminal domain represses hematopoietic transcription factors (c-myb, ets family members, TFE-III) in T lymphocytes.","method":"Domain-swap constructs, transcriptional reporter assays, co-expression with specific transcription factors in mammalian cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain-specific mutagenesis and functional dissection across two distinct cell lineages with defined transcription factor targets","pmids":["10567522"],"is_preprint":false},{"year":2001,"finding":"ZEB binds six consensus E-box sites in the first intron of p73 both in vitro and in vivo (chromatin immunoprecipitation), repressing p73 transcription during cell proliferation; expression of dominant-negative ZEB (ZEB-DB) derepresses p73 in proliferating C2C12 and P19 cells.","method":"ChIP, EMSA, dominant-negative ZEB expression, RT-PCR","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo ChIP plus in vitro binding plus functional rescue with dominant-negative, multiple orthogonal methods","pmids":["11713281"],"is_preprint":false},{"year":2002,"finding":"Zfhep/ZEB1 is post-translationally modified by phosphorylation on Ser/Thr residues; PP2A dephosphorylates the slower-mobility (hyperphosphorylated) form. Phosphorylation is cell-type-specific, with different cell lines expressing predominantly phosphorylated or non-phosphorylated forms.","method":"Western blot (mobility shift), phosphatase treatment (PP2A), O-GlcNAcase treatment (negative)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphatase assay confirms phosphorylation, cell-type specificity established, single lab","pmids":["12163027"],"is_preprint":false},{"year":2003,"finding":"ZEB1/deltaEF1 synergizes with Smad-mediated transcriptional activation by binding to p300 and promoting formation of a p300-Smad transcriptional complex, whereas ZEB2/SIP1 represses Smad signaling by recruiting CtBP. These opposing effects on TGFβ/BMP target genes were demonstrated in vitro and in vivo in Xenopus development.","method":"Co-immunoprecipitation, transcriptional reporter assays, in vivo Xenopus developmental assays, dominant-negative constructs","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, functional reporter assays, and in vivo developmental epistasis across multiple systems","pmids":["12743039"],"is_preprint":false},{"year":2003,"finding":"ZEB directly binds the ZV element (CAGGTA sequence) within the BZLF1 promoter of Epstein-Barr virus, functioning as the cellular repressor ZVR; overexpression of ZEB in B-lymphocytic and mammary epithelial cells represses Zta-induced BZLF1 promoter activity four- to fivefold via this ZV site.","method":"Immunoshift assay with anti-deltaEF1 antibody, competition EMSA, reporter assay with ZV site mutations","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — antibody supershift confirms identity, competition EMSA confirms binding specificity, site-specific reporter assays confirm functional repression","pmids":["12477825"],"is_preprint":false},{"year":2006,"finding":"NF-κB (p65) transcriptionally activates the ZEB1 promoter; overexpression of ZEB1 reduces E-cadherin and p63 expression and induces EMT in MCF10A cells; siRNA knockdown of ZEB1 reduces viability of NF-κB-activated but not parental cells.","method":"Promoter-luciferase reporter assay, ZEB1 overexpression, siRNA knockdown, E-cadherin protein measurement","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter activation by p65 shown by reporter assay, functional EMT phenotype confirmed by ZEB1 overexpression and siRNA, single lab","pmids":["16862183"],"is_preprint":false},{"year":2009,"finding":"Zeb1 binds the Mitf-A promoter in vivo (by chromatin immunoprecipitation) and represses Mitf transcription; heterozygous mutation or shRNA knockdown of Zeb1 prevents RPE dedifferentiation (loss of pigment, proliferation, and epithelial morphology) through derepression of Mitf.","method":"ChIP, shRNA knockdown, heterozygous mouse mutant, RT-PCR","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo ChIP identifies direct binding, genetic knockdown produces specific phenotype, corroborated by heterozygous mutation","pmids":["19515996"],"is_preprint":false},{"year":2009,"finding":"ZEB-1 directly binds to two conserved E-box sites in the SEMA3F gene (confirmed by ChIP) and represses its transcription in lung cancer cells; ZEB-1 levels specifically correlate with SEMA3F repression, and HDAC inhibitor treatment reduces ZEB-1 binding and restores SEMA3F expression.","method":"ChIP, ZEB-1 overexpression and siRNA knockdown, RT-PCR, HDAC inhibitor treatment","journal":"Neoplasia (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo ChIP confirms direct binding, bidirectional gain/loss of function, pharmacological validation","pmids":["19177200"],"is_preprint":false},{"year":2011,"finding":"ZEB1 drives EMT in lung cancer by directly repressing ESRP1, leading to increased expression of a mesenchymal splice variant of CD44 and a more invasive phenotype.","method":"ZEB1 overexpression and knockdown, splice variant analysis, invasion assays","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional loss/gain of function with defined molecular mechanism (ESRP1 repression → CD44 splicing), single lab","pmids":["27500490"],"is_preprint":false},{"year":2014,"finding":"ATM phosphorylates and stabilizes ZEB1 in response to DNA damage; ZEB1 in turn directly interacts with USP7 and enhances USP7-mediated deubiquitylation and stabilization of CHK1, promoting homologous recombination-dependent DNA repair and radioresistance.","method":"Co-immunoprecipitation, phosphorylation assays, ATM kinase assay, USP7-ZEB1 binding, CHK1 ubiquitination assay, in vitro and in vivo radioresistance","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — kinase assay identifies ATM as ZEB1 writer, Co-IP establishes ZEB1-USP7 complex, ubiquitination assay demonstrates CHK1 deubiquitylation, validated in vivo","pmids":["25086746"],"is_preprint":false},{"year":2015,"finding":"Zeb1 promotes expression of a-series glycosphingolipids by binding to the St3gal5 (GM3 synthase) promoter and suppressing microRNA-mediated repression of St3gal5, thereby modulating epithelial cell adhesion.","method":"Promoter binding assay (ChIP), miRNA suppression analysis, St3gal5 knockdown/overexpression, cell adhesion assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional rescue experiments demonstrate pathway, single lab","pmids":["25643708"],"is_preprint":false},{"year":2016,"finding":"ZEB1 transcriptionally activates VEGFA by increasing SP1 recruitment to the VEGFA promoter via PI3K and p38 pathway activation, promoting tumor angiogenesis in breast cancer.","method":"ChIP (SP1 recruitment), ZEB1 overexpression/knockdown, pathway inhibitors (PI3K, p38), VEGFA reporter assay, HUVEC tube formation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates SP1 recruitment, pathway inhibitors identify mediating signals, functional angiogenesis assay, single lab","pmids":["26882471"],"is_preprint":false},{"year":2016,"finding":"In EGFR-mutated lung cancer cells, ZEB1 suppresses tumor cell growth by increasing miR-200 targets to antagonize ERBB3; NOTCH1, a miR-200 target, represses ERBB3 promoter activity, placing ZEB1 upstream of a NOTCH1-ERBB3 growth-suppressive axis.","method":"ZEB1 knockdown/overexpression, ERBB3 promoter reporter assay, miR-200 target analysis, genetic epistasis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay and genetic epistasis define pathway, single lab with multiple functional assays","pmids":["27456471"],"is_preprint":false},{"year":2017,"finding":"USP51 binds, deubiquitinates, and stabilizes ZEB1 protein; depletion of USP51 leads to ZEB1 protein downregulation, mesenchymal-to-epithelial shift, and inhibition of cell invasion in breast cancer cells.","method":"Deubiquitinase library screen, Co-immunoprecipitation, ubiquitination assay, USP51 knockdown/overexpression, invasion assays","journal":"American journal of cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic screen identifies USP51, co-IP confirms binding, in vitro deubiquitination assay, bidirectional functional validation","pmids":["29119051"],"is_preprint":false},{"year":2017,"finding":"ZEB1 directly represses transcription of T cell-attracting chemokines including CXCL10 in melanoma cells (confirmed by ChIP), thereby impairing CD8+ T cell recruitment and promoting immune evasion.","method":"ChIP, ZEB1 gain/loss-of-function in syngeneic mouse models, flow cytometry, multiplex cytokine analysis","journal":"Journal for immunotherapy of cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP confirms direct promoter binding, syngeneic in vivo model validates immune evasion, multiple orthogonal methods","pmids":["35288462"],"is_preprint":false},{"year":2017,"finding":"CSN5 directly binds ZEB1 and decreases its ubiquitination, enhancing ZEB1 protein stability and promoting EMT and metastasis in renal cell carcinoma.","method":"Co-immunoprecipitation, ubiquitination assay, CSN5 knockdown, invasion/migration assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and ubiquitination assay demonstrate direct binding and deubiquitination mechanism, single lab","pmids":["28479251"],"is_preprint":false},{"year":2017,"finding":"ZEB1 controls production of inflammatory cytokines IL-6 and IL-8 in breast cancer cells, as identified by ChIP-seq showing ZEB1 binding to genomic regions near these cytokine genes, with ZEB1 knockdown reducing their expression.","method":"ChIP-seq, RNA-seq, GSEA, antibody array, ELISA, ZEB1 knockdown","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq provides genome-wide binding data, functional knockdown confirms regulation, single lab","pmids":["28618162"],"is_preprint":false},{"year":2017,"finding":"ZEB1 in stromal fibroblasts increases acetylation and expression of p53, which is then recruited to FGF2/7, VEGF, and IL6 promoters; ZEB1 deletion in fibroblasts reduces their secretion into the tumor stroma, and p53 ablation rescues impaired tumor growth in ZEB1-deleted stroma—establishing a ZEB1/p53 axis in cancer-associated fibroblasts.","method":"Conditional ZEB1 knockout in fibroblasts (mouse model), p53 acetylation assay, ChIP, cytokine measurement, genetic rescue (p53 knockout)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO mouse model, ChIP, genetic epistasis (double KO rescue), multiple orthogonal methods","pmids":["31324807"],"is_preprint":false},{"year":2017,"finding":"ZEB1 directly represses the miR-375 gene in prostate cancer; miR-375 in turn targets YAP1, establishing a ZEB1-miR-375-YAP1 regulatory circuit controlling epithelial plasticity and invasion.","method":"ZEB1 ChIP on miR-375 promoter, miR-375 overexpression and knockdown, YAP1 reporter assay, invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct ZEB1 binding, functional epistasis establishes pathway, single lab","pmids":["27270433"],"is_preprint":false},{"year":2018,"finding":"In glioblastoma stem-like cells, Zeb1 binds chromatin at both active and repressed gene loci genome-wide; transcriptional repression requires direct DNA binding of Zeb1, while gene activation occurs through indirect recruitment to regulatory regions by Lef1 (Wnt pathway effector), independently of Wnt signaling. ZEB1/Lef1 complex activates the GEF Prex1, which promotes glioblastoma cell invasion in vivo.","method":"ChIP-seq, RNA-seq, ZEB1 DNA-binding mutants, Lef1 Co-IP and co-binding analysis, in vivo invasion assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide ChIP-seq, DNA-binding mutants dissect direct vs. indirect mechanisms, Lef1-ZEB1 co-IP, in vivo validation","pmids":["29903919"],"is_preprint":false},{"year":2018,"finding":"Simultaneous deletion of Zeb1 restores directional migration to Ovol2-deficient hair follicle bulge stem cells, establishing Zeb1 as a downstream effector of the Ovol2-Zeb1 EMT circuit that controls directional migration in skin epithelial regeneration.","method":"Conditional double knockout (Ovol2 and Zeb1), live imaging of wound explants and hair follicle stem cells, cell cycle analysis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic epistasis via double knockout with live imaging functional readout demonstrates Zeb1's causal role downstream of Ovol2","pmids":["30413481"],"is_preprint":false},{"year":2019,"finding":"Thyroid hormone (T3) transcriptionally upregulates ZEB1 expression in squamous cell carcinoma cells, and elevated ZEB1 promotes EMT and metastatic transformation, establishing TH/D2 as an upstream regulator of the ZEB1-E-cadherin switch.","method":"ZEB1 reporter assay, ZEB1 overexpression/knockdown, in vivo tumor models, T3-treatment experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay shows T3-dependent ZEB1 transcription, in vivo tumor model validates phenotype, single lab","pmids":["31776338"],"is_preprint":false},{"year":2019,"finding":"FOXE1 directly interacts with the ZEB1 promoter and activates its transcription in thyroid cancer cells; ZEB1 silencing decreases migration and invasion, placing ZEB1 downstream of FOXE1 in thyroid cancer EMT.","method":"Promoter ChIP, ZEB1 knockdown/overexpression, FOXE1 gain/loss-of-function, migration and invasion assays","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct FOXE1 binding to ZEB1 promoter, functional epistasis with ZEB1 knockdown, single lab","pmids":["31846430"],"is_preprint":false},{"year":2020,"finding":"Endothelial ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, epigenetically suppressing Notch signaling in bone vasculature, thereby impairing CD31hi/endomucinhi vessel formation and osteogenesis; delivery of Zeb1-packaged liposomes to osteoporotic mice restores Notch activity.","method":"Endothelial-specific ZEB1 conditional knockout mice, ChIP (histone acetylation), Notch signaling reporters, bone phenotype analysis, liposome delivery rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO mouse, ChIP demonstrates epigenetic mechanism, in vivo rescue with liposome delivery, multiple orthogonal methods","pmids":["31974363"],"is_preprint":false},{"year":2020,"finding":"Endothelial ZEB1 deletion elicits persistent tumor vascular normalization by epigenetically repressing TGF-β signaling, improving blood/oxygen perfusion and immune cell infiltration, and reducing tumor growth and metastasis.","method":"Endothelial-specific ZEB1 conditional knockout in tumor-bearing mice, ChIP (epigenetic repression of TGF-β pathway), tumor perfusion measurements, immune cell profiling","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO mouse model, ChIP-based epigenetic mechanism, multiple functional readouts in vivo","pmids":["32039918"],"is_preprint":false},{"year":2020,"finding":"ZEB1 promotes CD4+ T cell pathogenic Th1 and Th17 differentiation by inhibiting miR-101-3p, which would otherwise repress JAK2 expression; this disinhibits JAK2 and downstream STAT3/STAT4 phosphorylation, enabling IL-17 and IFN-γ expression. ZEB1 deletion protects against EAE (mouse MS model).","method":"Conditional ZEB1 knockout in T cells, miR-101-3p overexpression/inhibition, JAK2 and STAT3/4 phosphorylation assays, cytokine measurement, EAE model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO establishes causal role, pathway mechanism through miR-101-3p/JAK2/STAT signaling defined by multiple orthogonal methods, validated in vivo","pmids":["34433042"],"is_preprint":false},{"year":2021,"finding":"ZEB1 transcriptionally activates PFKM (phosphofructokinase-1 muscle isoform) by binding a non-canonical binding sequence in its promoter (confirmed by ChIP and luciferase assay), enhancing glycolysis and Warburg effect; ZEB1 knockdown impairs PFKM expression and glycolysis, rescued by exogenous PFKM.","method":"ChIP, luciferase reporter assay, ZEB1 shRNA knockdown, metabolic assays (glucose uptake, ECAR, OCR), rescue with PFKM re-expression, orthotopic xenograft","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP and luciferase confirm direct binding and activation, functional rescue experiments, in vivo xenograft validation","pmids":["33897890"],"is_preprint":false},{"year":2021,"finding":"ZEB1 directly represses LIF in glioma stem cells; ZEB1 knockdown induces LIF, promoting GCSC self-renewal; IFN-γ treatment induces ZEB1 expression and attenuates LIF-driven stemness. ZEB1 binding sites were identified within the LIF promoter.","method":"ZEB1 promoter binding site analysis, ZEB1 knockdown, LIF induction assay, self-renewal assay, IFN-γ treatment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter binding sites identified, functional knockdown with LIF induction and stemness readout, single lab","pmids":["28246407"],"is_preprint":false},{"year":2021,"finding":"Conditional acute deletion of Zeb1 in hematopoietic stem cells causes self-renewal defect, multilineage differentiation block, apoptosis-driven thymocyte loss, and upregulation of EpCAM; Zeb1 KO in leukemic stem cells accelerates AML progression, establishing Zeb1 as a tumor suppressor in LSCs.","method":"Mx1-Cre conditional knockout, transcriptomic analysis, bone marrow transplantation, AML model (MLL-AF9, Meis1a/Hoxa9)","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO with cell-autonomous phenotypes, multiple leukemia models, transcriptomics, in vivo validation","pmids":["33108352"],"is_preprint":false},{"year":2022,"finding":"O-GlcNAcylation of ZEB1 at Ser555 enhances its stabilization and nuclear translocation; this promotes transcription of lipogenesis genes FASN and FADS2, resulting in lipid peroxidation-dependent ferroptosis in mesenchymal pancreatic cancer cells under high-glucose conditions.","method":"Site-specific mutagenesis (Ser555), O-GlcNAcylation assay, subcellular fractionation, ChIP/reporter for FASN/FADS2, ferroptosis cell death assay","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific mutagenesis identifies modification site, nuclear translocation confirmed by fractionation, transcriptional targets validated by ChIP, in vivo xenograft corroboration","pmids":["35844792"],"is_preprint":false},{"year":2022,"finding":"ZEB directly binds the LPCAT3 promoter (-1600 to -1401 nt region) to stimulate its transcription in a YAP-dependent manner; ZEB and YAP physically interact through ZEB's zinc-finger cluster domain and YAP's WW domain; EP300 simultaneously binds YAP (via Bromo domain) and ZEB (via CBP/p300-HAT domain) and induces H3K27Ac at the LPCAT3 locus.","method":"ChIP, reporter assay, domain-specific binding assays (Co-IP with domain mutants), H3K27Ac ChIP","journal":"Antioxidants & redox signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP confirms direct promoter binding, domain-specific Co-IP maps interaction surfaces, histone modification assay, validated in xenograft","pmids":["37166352"],"is_preprint":false},{"year":2023,"finding":"USP10 binds ZEB1 and promotes its proteasomal degradation by modifying ZEB1 ubiquitination; MEK-ERK signaling phosphorylates USP10 at Ser236, impairing the USP10-ZEB1 interaction and enabling ZEB1 protein stabilization, which promotes colorectal cancer metastatic colonization.","method":"Co-immunoprecipitation, ubiquitination assay, MEK-ERK inhibitor treatment, USP10 phospho-site mutagenesis, tail vein metastasis mouse model","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, ubiquitination assay, phospho-site mutagenesis, signaling pathway manipulation, in vivo metastasis model","pmids":["36940483"],"is_preprint":false},{"year":2023,"finding":"USP43 physically interacts with ZEB1 (Co-IP), deubiquitinates it, and stabilizes the ZEB1 protein, promoting proliferation, migration, and invasion of colorectal cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, USP43 overexpression/knockdown, invasion/migration assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and ubiquitination assay, bidirectional functional validation, single lab","pmids":["33391437"],"is_preprint":false},{"year":2023,"finding":"ZEB1 transcriptionally activates PHGDH by binding a non-classical binding site in its promoter (confirmed by ChIP and luciferase assay), driving serine synthesis pathway flux; conditional liver-specific Zeb1 knockout impairs PHGDH expression and HCC carcinogenesis, rescued by exogenous PHGDH expression.","method":"ChIP, luciferase reporter assay, [13C]-glucose metabolic tracing, liver-specific conditional Zeb1 KO mouse, PHGDH rescue experiments, orthotopic xenograft","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP and reporter confirm direct promoter binding, isotope tracing validates pathway flux, conditional KO mouse with genetic rescue, multiple orthogonal methods","pmids":["37331567"],"is_preprint":false},{"year":2023,"finding":"In osteoclasts, Zeb1 transcriptionally represses MtCK1 (mitochondrial creatine kinase 1), thereby controlling the phosphocreatine energy shuttle and mitochondrial respiration; Zeb1-null osteoclasts are hyperactivated and cause excessive bone resorption in vivo, identifying a Zeb1/MtCK1 metabolic axis controlling osteoclast activity.","method":"Conditional Zeb1 knockout in osteoclasts, ChIP (Zeb1 binding to MtCK1 locus), metabolic flux assays (phosphocreatine shuttle, mitochondrial respiration), in vivo bone density measurement","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO, ChIP confirms direct target, metabolic assays validate mechanism, in vivo skeletal phenotype","pmids":["36843552"],"is_preprint":false},{"year":2023,"finding":"USP22 acts as a co-activator of ZEB1-mediated VEGFA transcription by maintaining ZEB1 stability via deubiquitinase activity and being recruited to ZEB1-binding elements on the VEGFA promoter, where it alters histone H2Bub levels to enhance transcription.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP (USP22 and ZEB1 at VEGFA promoter), H2Bub ChIP, USP22 knockdown/overexpression, tumor xenograft","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, ubiquitination assay, co-ChIP at promoter, histone modification assay, in vivo xenograft","pmids":["36906615"],"is_preprint":false},{"year":2023,"finding":"BMPR1A activation induces ID2 to physically interact with and sequester ZEB1, attenuating ZEB1-driven transcription of Tgfbr2 and preventing excessive endothelial-to-mesenchymal transition; endothelial-specific Bmpr1a deletion causes PAH in mice, rescued by siRNA against Tgfbr2.","method":"Co-immunoprecipitation (ID2-ZEB1 interaction), endothelial-specific Bmpr1a conditional KO mouse, lineage tracing, siRNA-lipid nanoparticle rescue, TGFBR2 expression analysis","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP identifies ID2-ZEB1 complex, conditional KO with lineage tracing, in vivo rescue experiment, multiple orthogonal methods","pmids":["36166408"],"is_preprint":false},{"year":2016,"finding":"Dephosphorylation of the Retinoblastoma protein (Rb) is associated with ZEB1 physical interaction (co-immunoprecipitation), and leads to inhibition of ZEB1 transcriptional activity, reducing EMT in mesenchymal cancer cells in 3D Matrigel culture.","method":"Co-immunoprecipitation (Rb-ZEB1), PNUTS shRNA-mediated Rb dephosphorylation, transcriptional activity assay, 3D Matrigel invasion assay","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifies interaction, functional transcriptional assay, single lab, one indirect dephosphorylation approach","pmids":["27645778"],"is_preprint":false},{"year":2013,"finding":"In glioblastoma, ZEB1 is a central regulator interconnecting invasion, chemoresistance, and tumorigenesis through the ZEB1-miR-200 feedback loop, with downstream effectors ROBO1, c-MYB, and MGMT identified as novel ZEB1 pathway targets.","method":"ZEB1 knockdown and overexpression, miR-200 manipulation, invasion and chemoresistance assays, target gene expression analysis","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown/overexpression with multiple defined downstream targets, single lab","pmids":["23818228"],"is_preprint":false},{"year":2019,"finding":"ZEB1 directly activates transcription of the CD47 gene in hypoxic cervical cancer cells (confirmed by transcriptional activation assay); exosomal ZEB1 retains transcriptional activity and reprograms macrophages toward SIRPα+ TAM polarization via STAT3 signaling, promoting immune evasion.","method":"Reporter/transcriptional assay for CD47, exosome isolation and transfer experiments, STAT3 signaling inhibition, in vivo xenograft phagocytosis assays","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct CD47 transcriptional activation assay, exosome transfer functional experiments, STAT3 pathway inhibition, single lab","pmids":["38183060"],"is_preprint":false}],"current_model":"ZEB1 is a dual-function zinc finger/homeodomain transcription factor that represses epithelial genes (E-cadherin, ESRP1, SEMA3F, p73, miR-200 family, CXCL10) and activates mesenchymal/metabolic targets (PFKM, PHGDH, VEGFA, vimentin, CD47) by binding E-box sequences directly or through cofactor complexes (CtBP, p300, YAP/EP300, Lef1); its activity is regulated by multiple post-translational modifications including ATM-mediated phosphorylation-stabilization, deubiquitination by USP7/USP51/USP22/USP43/CSN5, O-GlcNAcylation at Ser555, and Rb-dephosphorylation-dependent inhibition, placing ZEB1 at the intersection of EMT, DNA damage response, metabolic reprogramming, immune evasion, and stem cell maintenance."},"narrative":{"mechanistic_narrative":"ZEB1 is a dual zinc-finger/homeodomain transcription factor that binds E-box-like sequences (consensus CACCTG/AAAGGTGCA) through two distinct N- and C-terminal zinc-finger clusters and acts as both a context-dependent repressor and activator of target promoters [PMID:7935395, PMID:7588776]. Its repressive output is executed by recruitment of corepressors: the general cofactor NC2 to a defined hydrophobic repression domain [PMID:9418848] and CtBP through PLDLS motifs whose mutation abolishes repression [PMID:10359772], with separable N- and C-terminal repressor domains targeting distinct lineage factors [PMID:10567522]. Through this machinery ZEB1 directly represses a broad epithelial/differentiation program—p73, SEMA3F, ESRP1, MITF, miR-375, the T-cell chemokine CXCL10, and LIF—to drive EMT, invasion, dedifferentiation, and immune evasion [PMID:11713281, PMID:19177200, PMID:27500490, PMID:19515996, PMID:27270433, PMID:35288462]. ZEB1 also functions as a direct or cofactor-assisted activator, partnering with p300 to potentiate Smad signaling [PMID:12743039], with Lef1 to activate invasion genes such as Prex1 [PMID:29903919], and with YAP/EP300 to drive H3K27Ac-dependent LPCAT3 transcription [PMID:37166352], and it directly activates metabolic genes including PFKM and PHGDH to reprogram glycolysis and serine synthesis [PMID:33897890, PMID:37331567]. ZEB1 stability and activity are heavily post-translationally controlled: ATM phosphorylates and stabilizes ZEB1 to enable USP7-dependent CHK1 deubiquitylation and homologous-recombination DNA repair [PMID:25086746], multiple deubiquitinases (USP51, USP22, USP43, CSN5) and the antagonistic USP10/MEK-ERK axis set ZEB1 levels [PMID:29119051, PMID:36906615, PMID:36940483], and O-GlcNAcylation at Ser555 promotes its nuclear translocation and lipogenic-gene activation [PMID:35844792]. In vivo conditional-knockout studies establish ZEB1 as a regulator of hematopoietic and leukemic stem cells, endothelial Notch/TGF-β signaling, osteoclast metabolism, and T-cell pathogenic differentiation, placing it at the intersection of EMT, the DNA-damage response, metabolic reprogramming, immunity, and stem-cell maintenance [PMID:33108352, PMID:31974363, PMID:36843552, PMID:34433042].","teleology":[{"year":1994,"claim":"Established ZEB1 as a sequence-specific DNA-binding transcriptional repressor and defined its bipartite zinc-finger recognition architecture, answering what kind of regulator it is.","evidence":"DNA binding/Kd measurement, reporter assays, and immunocytochemistry defining the AAAGGTGCA site and nuclear/cytoplasmic shifts","pmids":["7935395"],"confidence":"Medium","gaps":["Functional significance of the nuclear/cytoplasmic shift not mechanistically defined","Endogenous target genes not identified"]},{"year":1995,"claim":"Resolved that ZEB1's two zinc-finger clusters have distinct optimal binding sequences and that promoter context (presence of a GTTTC/G element) switches it between repressor and activator, explaining its dual transcriptional behavior.","evidence":"CASTing site selection, zinc-finger mutagenesis, and transient reporter assays","pmids":["7588776"],"confidence":"High","gaps":["Cofactors mediating the activator vs repressor switch not yet identified","Homeodomain function beyond zinc-finger interaction unclear"]},{"year":1997,"claim":"Showed ZEB1 represses muscle differentiation by occupying E-boxes and is displaced by accumulating myogenic bHLH factors, providing a developmental logic for its repressive role.","evidence":"DNA binding, reporter assays, and overexpression differentiation assays targeting MEF-2","pmids":["9233803"],"confidence":"High","gaps":["Corepressor identity not yet defined","Direct vs competitive displacement mechanism not fully resolved"]},{"year":1999,"claim":"Identified the corepressor machinery—NC2 and CtBP via PLDLS motifs—and separable lineage-specific repressor domains, defining how ZEB1 silences transcription mechanistically.","evidence":"In vitro transcription reconstitution, yeast two-hybrid, PLDLS-motif mutagenesis, and domain-swap reporter assays","pmids":["9418848","10359772","10567522"],"confidence":"High","gaps":["Whether NC2 and CtBP act on the same or distinct target sets unresolved","Chromatin-level consequences not characterized in this era"]},{"year":2003,"claim":"Distinguished ZEB1 from ZEB2 functionally, showing ZEB1 recruits p300 to promote Smad-dependent activation whereas ZEB2 recruits CtBP to repress, establishing cofactor choice as the determinant of opposing signaling outputs.","evidence":"Reciprocal Co-IP, reporter assays, and in vivo Xenopus developmental epistasis","pmids":["12743039"],"confidence":"High","gaps":["Signal determining p300 vs CtBP recruitment unknown","Structural basis of p300 interaction not defined"]},{"year":2009,"claim":"Demonstrated through in vivo ChIP that ZEB1 directly represses tissue-specific targets (p73, SEMA3F, MITF) to control proliferation, dedifferentiation, and tumor invasion, generalizing its repressive program.","evidence":"ChIP, shRNA/dominant-negative knockdown, and heterozygous mouse mutants","pmids":["11713281","19177200","19515996"],"confidence":"High","gaps":["Genome-wide target catalog still incomplete","Cofactor requirements at these loci not mapped"]},{"year":2014,"claim":"Connected ZEB1 to the DNA-damage response, showing ATM phosphorylates and stabilizes ZEB1, which then promotes USP7-mediated CHK1 deubiquitylation and radioresistance—a non-transcriptional protein-stabilizing role.","evidence":"ATM kinase assay, Co-IP, CHK1 ubiquitination assay, and in vivo radioresistance models","pmids":["25086746"],"confidence":"High","gaps":["ATM phosphosite(s) on ZEB1 not mapped here","Relationship between this function and ZEB1's transcriptional output unclear"]},{"year":2018,"claim":"Used genome-wide ChIP-seq and DNA-binding mutants to separate ZEB1's direct repression from Lef1-dependent indirect activation, mechanistically resolving its dual activator/repressor function at the chromatin level.","evidence":"ChIP-seq, RNA-seq, ZEB1 DNA-binding mutants, Lef1 Co-IP, and in vivo invasion assays","pmids":["29903919"],"confidence":"High","gaps":["How ZEB1 is recruited by Lef1 without direct DNA binding not fully defined","Generalizability across tissues untested"]},{"year":2021,"claim":"Established ZEB1 as a direct transcriptional activator of metabolic genes (PFKM, PHGDH) via non-canonical promoter sites, revealing its role in glycolytic and serine-synthesis reprogramming with in vivo rescue validation.","evidence":"ChIP, luciferase assays, metabolic flux/isotope tracing, conditional KO mice, and PFKM/PHGDH rescue experiments","pmids":["33897890","37331567"],"confidence":"High","gaps":["Cofactors enabling activation at non-canonical sites not identified","Whether these activation events require the acidic activation domain untested"]},{"year":2022,"claim":"Defined O-GlcNAcylation at Ser555 as a modification controlling ZEB1 nuclear translocation and lipogenic-gene activation, adding a metabolic-sensing PTM layer to ZEB1 regulation.","evidence":"Site-specific Ser555 mutagenesis, O-GlcNAcylation assay, subcellular fractionation, and ChIP for FASN/FADS2","pmids":["35844792"],"confidence":"High","gaps":["Enzyme(s) adding/removing the O-GlcNAc mark not identified","Interplay with phosphorylation not resolved"]},{"year":2023,"claim":"Mapped the deubiquitinase/E3 network (USP22, USP43, USP10/MEK-ERK) and YAP/EP300 cofactor complexes controlling ZEB1 stability and chromatin activity, showing protein turnover is a major control node for ZEB1 output.","evidence":"Co-IP, ubiquitination assays, domain-mapping Co-IP, H3K27Ac/H2Bub ChIP, phosphosite mutagenesis, and in vivo metastasis models","pmids":["36906615","33391437","36940483","37166352"],"confidence":"High","gaps":["Cognate E3 ligase(s) for ZEB1 not fully identified","Hierarchy among competing DUBs in a given cell type unclear"]},{"year":2023,"claim":"Conditional in vivo deletions across hematopoietic/leukemic stem cells, endothelium, osteoclasts, and T cells established ZEB1's physiological and tumor-suppressive/context-dependent roles beyond cancer-cell EMT.","evidence":"Tissue-specific conditional KO mice with transcriptomics, ChIP, metabolic flux, lineage tracing, and disease-model rescues (AML, osteoporosis, EAE, PAH)","pmids":["33108352","31974363","36843552","34433042","36166408"],"confidence":"High","gaps":["Direct vs indirect targets in each tissue not exhaustively mapped","Reconciling tumor-suppressive (LSC) and oncogenic (EMT) roles mechanistically unresolved"]},{"year":null,"claim":"How ZEB1 integrates competing post-translational modifications, cofactor choice, and DNA-binding context into a single cell-type-specific transcriptional decision remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM state to activator vs repressor switching","Cognate E3 ligases and the full cofactor selection logic not defined","Structural basis of zinc-finger/homeodomain cooperation not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,4,6,24,31]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,2,6,24]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,24,35]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,34]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,4,6,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,25,28,41]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[31,38,34,39]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,30,44]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,20,36,43]}],"complexes":[],"partners":["CTBP","P300","USP7","LEF1","YAP1","EP300","USP22","ID2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P37275","full_name":"Zinc 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Inhibits interleukin-2 (IL-2) gene expression. Enhances or represses the promoter activity of the ATP1A1 gene depending on the quantity of cDNA and on the cell type. Represses E-cadherin promoter and induces an epithelial-mesenchymal transition (EMT) by recruiting SMARCA4/BRG1. Represses BCL6 transcription in the presence of the corepressor CTBP1. Positively regulates neuronal differentiation. Represses RCOR1 transcription activation during neurogenesis. Represses transcription by binding to the E box (5'-CANNTG-3'). In the absence of TGFB1, acts as a repressor of COL1A2 transcription via binding to the E-box in the upstream enhancer region (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P37275/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZEB1","classification":"Not Classified","n_dependent_lines":100,"n_total_lines":1208,"dependency_fraction":0.08278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTBP1","stoichiometry":0.2},{"gene":"CTBP2","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZEB1","total_profiled":1310},"omim":[{"mim_id":"620431","title":"FLYWCH-TYPE ZINC FINGER PROTEIN 1; FLYWCH1","url":"https://www.omim.org/entry/620431"},{"mim_id":"619628","title":"AFTIPHILIN; AFTPH","url":"https://www.omim.org/entry/619628"},{"mim_id":"619152","title":"TBC1 DOMAIN FAMILY, MEMBER 2B; TBC1D2B","url":"https://www.omim.org/entry/619152"},{"mim_id":"618887","title":"NUCLEAR FACTOR KAPPA-B INHIBITOR, DELTA; NFKBID","url":"https://www.omim.org/entry/618887"},{"mim_id":"616514","title":"FAMILY WITH SEQUENCE SIMILARITY 195, MEMBER B; FAM195B","url":"https://www.omim.org/entry/616514"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZEB1"},"hgnc":{"alias_symbol":["BZP","ZEB","AREB6","NIL-2-A","Zfhep","Zfhx1a","FECD6"],"prev_symbol":["TCF8","PPCD3"]},"alphafold":{"accession":"P37275","domains":[{"cath_id":"3.30.160","chopping":"169-221","consensus_level":"medium","plddt":81.7098,"start":169,"end":221},{"cath_id":"3.30.160.60","chopping":"240-293","consensus_level":"medium","plddt":85.5341,"start":240,"end":293},{"cath_id":"1.10.10.60","chopping":"604-632","consensus_level":"medium","plddt":89.9455,"start":604,"end":632},{"cath_id":"3.30.160.60","chopping":"931-993","consensus_level":"medium","plddt":75.7573,"start":931,"end":993},{"cath_id":"3.30.160","chopping":"899-925","consensus_level":"medium","plddt":82.3789,"start":899,"end":925}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P37275","model_url":"https://alphafold.ebi.ac.uk/files/AF-P37275-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P37275-F1-predicted_aligned_error_v6.png","plddt_mean":47.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZEB1","jax_strain_url":"https://www.jax.org/strain/search?query=ZEB1"},"sequence":{"accession":"P37275","fasta_url":"https://rest.uniprot.org/uniprotkb/P37275.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P37275/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P37275"}},"corpus_meta":[{"pmid":"17508028","id":"PMC_17508028","title":"Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?","date":"2007","source":"Nature reviews. 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promoters and actively represses transcription, inhibiting muscle differentiation by repressing MEF-2 family members; as myogenic bHLH proteins accumulate during differentiation, they displace ZEB from E-boxes, releasing repression.\",\n      \"method\": \"DNA binding assays, transcriptional reporter assays, overexpression in mammalian cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (DNA binding, reporter assays, functional differentiation assays) in a focused mechanistic study replicated across muscle gene targets\",\n      \"pmids\": [\"9233803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"BZP (ZEB1) binds the 9-bp sequence AAAGGTGCA through two zinc finger clusters and functions as a transcriptional repressor of linked promoters; its subcellular localization shifts between nuclear (proliferating cells) and cytoplasmic (serum-deprived cells), correlating with its transcriptional inhibitory activity.\",\n      \"method\": \"DNA binding assays (Kd measurement), transcriptional reporter assays, immunocytochemistry, serum-deprivation experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DNA binding and reporter assays with localization, single lab, multiple methods\",\n      \"pmids\": [\"7935395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"AREB6 (ZEB1) has two zinc finger clusters with distinct optimal DNA binding sequences (N-terminal: GTCACCTGT/TGCACCTGT; C-terminal: C/TACCTG/TT); the homeodomain lacks specific DNA binding but interacts with the N-terminal zinc finger cluster. Depending on the presence of an additional GTTTC/G consensus sequence, AREB6 can either repress or activate transcription from the same CACCTGT-containing promoter.\",\n      \"method\": \"CASTing (cyclic amplification and selection of targets), zinc-finger mutagenesis, transient transfection reporter assays\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro DNA binding with mutagenesis and functional reporter assays defining dual activator/repressor mechanism\",\n      \"pmids\": [\"7588776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"AREB6 (ZEB1) contains a hydrophobic repression domain (aa 754–901) and an acidic activation domain (aa 1011–1124). The repression domain requires the general transcriptional cofactor NC2 (NC2α/DRAP1 and NC2β/Dr1): it represses transcription in HeLa nuclear extract but not in a reconstituted system lacking NC2; addition of recombinant NC2 restores repressor activity. Direct interaction between the AREB6 repression domain and NC2α was demonstrated by yeast two-hybrid.\",\n      \"method\": \"In vitro transcription reconstitution assay, recombinant protein addition, yeast two-hybrid, transient transfection domain-mapping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined components plus yeast two-hybrid interaction, multiple orthogonal methods\",\n      \"pmids\": [\"9418848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ZEB and its Drosophila ortholog zfh-1 interact with corepressor CtBP through PLDLS motifs; ZEB contains three CtBP-binding sites whose mutation abolishes both CtBP binding and repressor activity, demonstrating that CtBP recruitment to the promoter is necessary for ZEB-mediated transcriptional repression.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of PLDLS motifs, transcriptional reporter assays, promoter recruitment assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — binding-site mutagenesis abolishing both interaction and function, replicated across ZEB and zfh-1 orthologs with multiple assays\",\n      \"pmids\": [\"10359772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ZEB contains two independent repressor domains with distinct tissue specificities: the C-terminal domain inhibits muscle differentiation by specifically blocking MEF2C transcriptional activity, while the N-terminal domain represses hematopoietic transcription factors (c-myb, ets family members, TFE-III) in T lymphocytes.\",\n      \"method\": \"Domain-swap constructs, transcriptional reporter assays, co-expression with specific transcription factors in mammalian cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain-specific mutagenesis and functional dissection across two distinct cell lineages with defined transcription factor targets\",\n      \"pmids\": [\"10567522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ZEB binds six consensus E-box sites in the first intron of p73 both in vitro and in vivo (chromatin immunoprecipitation), repressing p73 transcription during cell proliferation; expression of dominant-negative ZEB (ZEB-DB) derepresses p73 in proliferating C2C12 and P19 cells.\",\n      \"method\": \"ChIP, EMSA, dominant-negative ZEB expression, RT-PCR\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo ChIP plus in vitro binding plus functional rescue with dominant-negative, multiple orthogonal methods\",\n      \"pmids\": [\"11713281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Zfhep/ZEB1 is post-translationally modified by phosphorylation on Ser/Thr residues; PP2A dephosphorylates the slower-mobility (hyperphosphorylated) form. Phosphorylation is cell-type-specific, with different cell lines expressing predominantly phosphorylated or non-phosphorylated forms.\",\n      \"method\": \"Western blot (mobility shift), phosphatase treatment (PP2A), O-GlcNAcase treatment (negative)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphatase assay confirms phosphorylation, cell-type specificity established, single lab\",\n      \"pmids\": [\"12163027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ZEB1/deltaEF1 synergizes with Smad-mediated transcriptional activation by binding to p300 and promoting formation of a p300-Smad transcriptional complex, whereas ZEB2/SIP1 represses Smad signaling by recruiting CtBP. These opposing effects on TGFβ/BMP target genes were demonstrated in vitro and in vivo in Xenopus development.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, in vivo Xenopus developmental assays, dominant-negative constructs\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, functional reporter assays, and in vivo developmental epistasis across multiple systems\",\n      \"pmids\": [\"12743039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ZEB directly binds the ZV element (CAGGTA sequence) within the BZLF1 promoter of Epstein-Barr virus, functioning as the cellular repressor ZVR; overexpression of ZEB in B-lymphocytic and mammary epithelial cells represses Zta-induced BZLF1 promoter activity four- to fivefold via this ZV site.\",\n      \"method\": \"Immunoshift assay with anti-deltaEF1 antibody, competition EMSA, reporter assay with ZV site mutations\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — antibody supershift confirms identity, competition EMSA confirms binding specificity, site-specific reporter assays confirm functional repression\",\n      \"pmids\": [\"12477825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NF-κB (p65) transcriptionally activates the ZEB1 promoter; overexpression of ZEB1 reduces E-cadherin and p63 expression and induces EMT in MCF10A cells; siRNA knockdown of ZEB1 reduces viability of NF-κB-activated but not parental cells.\",\n      \"method\": \"Promoter-luciferase reporter assay, ZEB1 overexpression, siRNA knockdown, E-cadherin protein measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter activation by p65 shown by reporter assay, functional EMT phenotype confirmed by ZEB1 overexpression and siRNA, single lab\",\n      \"pmids\": [\"16862183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Zeb1 binds the Mitf-A promoter in vivo (by chromatin immunoprecipitation) and represses Mitf transcription; heterozygous mutation or shRNA knockdown of Zeb1 prevents RPE dedifferentiation (loss of pigment, proliferation, and epithelial morphology) through derepression of Mitf.\",\n      \"method\": \"ChIP, shRNA knockdown, heterozygous mouse mutant, RT-PCR\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo ChIP identifies direct binding, genetic knockdown produces specific phenotype, corroborated by heterozygous mutation\",\n      \"pmids\": [\"19515996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ZEB-1 directly binds to two conserved E-box sites in the SEMA3F gene (confirmed by ChIP) and represses its transcription in lung cancer cells; ZEB-1 levels specifically correlate with SEMA3F repression, and HDAC inhibitor treatment reduces ZEB-1 binding and restores SEMA3F expression.\",\n      \"method\": \"ChIP, ZEB-1 overexpression and siRNA knockdown, RT-PCR, HDAC inhibitor treatment\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo ChIP confirms direct binding, bidirectional gain/loss of function, pharmacological validation\",\n      \"pmids\": [\"19177200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZEB1 drives EMT in lung cancer by directly repressing ESRP1, leading to increased expression of a mesenchymal splice variant of CD44 and a more invasive phenotype.\",\n      \"method\": \"ZEB1 overexpression and knockdown, splice variant analysis, invasion assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional loss/gain of function with defined molecular mechanism (ESRP1 repression → CD44 splicing), single lab\",\n      \"pmids\": [\"27500490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ATM phosphorylates and stabilizes ZEB1 in response to DNA damage; ZEB1 in turn directly interacts with USP7 and enhances USP7-mediated deubiquitylation and stabilization of CHK1, promoting homologous recombination-dependent DNA repair and radioresistance.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, ATM kinase assay, USP7-ZEB1 binding, CHK1 ubiquitination assay, in vitro and in vivo radioresistance\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — kinase assay identifies ATM as ZEB1 writer, Co-IP establishes ZEB1-USP7 complex, ubiquitination assay demonstrates CHK1 deubiquitylation, validated in vivo\",\n      \"pmids\": [\"25086746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Zeb1 promotes expression of a-series glycosphingolipids by binding to the St3gal5 (GM3 synthase) promoter and suppressing microRNA-mediated repression of St3gal5, thereby modulating epithelial cell adhesion.\",\n      \"method\": \"Promoter binding assay (ChIP), miRNA suppression analysis, St3gal5 knockdown/overexpression, cell adhesion assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional rescue experiments demonstrate pathway, single lab\",\n      \"pmids\": [\"25643708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZEB1 transcriptionally activates VEGFA by increasing SP1 recruitment to the VEGFA promoter via PI3K and p38 pathway activation, promoting tumor angiogenesis in breast cancer.\",\n      \"method\": \"ChIP (SP1 recruitment), ZEB1 overexpression/knockdown, pathway inhibitors (PI3K, p38), VEGFA reporter assay, HUVEC tube formation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates SP1 recruitment, pathway inhibitors identify mediating signals, functional angiogenesis assay, single lab\",\n      \"pmids\": [\"26882471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In EGFR-mutated lung cancer cells, ZEB1 suppresses tumor cell growth by increasing miR-200 targets to antagonize ERBB3; NOTCH1, a miR-200 target, represses ERBB3 promoter activity, placing ZEB1 upstream of a NOTCH1-ERBB3 growth-suppressive axis.\",\n      \"method\": \"ZEB1 knockdown/overexpression, ERBB3 promoter reporter assay, miR-200 target analysis, genetic epistasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay and genetic epistasis define pathway, single lab with multiple functional assays\",\n      \"pmids\": [\"27456471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP51 binds, deubiquitinates, and stabilizes ZEB1 protein; depletion of USP51 leads to ZEB1 protein downregulation, mesenchymal-to-epithelial shift, and inhibition of cell invasion in breast cancer cells.\",\n      \"method\": \"Deubiquitinase library screen, Co-immunoprecipitation, ubiquitination assay, USP51 knockdown/overexpression, invasion assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic screen identifies USP51, co-IP confirms binding, in vitro deubiquitination assay, bidirectional functional validation\",\n      \"pmids\": [\"29119051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZEB1 directly represses transcription of T cell-attracting chemokines including CXCL10 in melanoma cells (confirmed by ChIP), thereby impairing CD8+ T cell recruitment and promoting immune evasion.\",\n      \"method\": \"ChIP, ZEB1 gain/loss-of-function in syngeneic mouse models, flow cytometry, multiplex cytokine analysis\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP confirms direct promoter binding, syngeneic in vivo model validates immune evasion, multiple orthogonal methods\",\n      \"pmids\": [\"35288462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CSN5 directly binds ZEB1 and decreases its ubiquitination, enhancing ZEB1 protein stability and promoting EMT and metastasis in renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, CSN5 knockdown, invasion/migration assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and ubiquitination assay demonstrate direct binding and deubiquitination mechanism, single lab\",\n      \"pmids\": [\"28479251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZEB1 controls production of inflammatory cytokines IL-6 and IL-8 in breast cancer cells, as identified by ChIP-seq showing ZEB1 binding to genomic regions near these cytokine genes, with ZEB1 knockdown reducing their expression.\",\n      \"method\": \"ChIP-seq, RNA-seq, GSEA, antibody array, ELISA, ZEB1 knockdown\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq provides genome-wide binding data, functional knockdown confirms regulation, single lab\",\n      \"pmids\": [\"28618162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZEB1 in stromal fibroblasts increases acetylation and expression of p53, which is then recruited to FGF2/7, VEGF, and IL6 promoters; ZEB1 deletion in fibroblasts reduces their secretion into the tumor stroma, and p53 ablation rescues impaired tumor growth in ZEB1-deleted stroma—establishing a ZEB1/p53 axis in cancer-associated fibroblasts.\",\n      \"method\": \"Conditional ZEB1 knockout in fibroblasts (mouse model), p53 acetylation assay, ChIP, cytokine measurement, genetic rescue (p53 knockout)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO mouse model, ChIP, genetic epistasis (double KO rescue), multiple orthogonal methods\",\n      \"pmids\": [\"31324807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZEB1 directly represses the miR-375 gene in prostate cancer; miR-375 in turn targets YAP1, establishing a ZEB1-miR-375-YAP1 regulatory circuit controlling epithelial plasticity and invasion.\",\n      \"method\": \"ZEB1 ChIP on miR-375 promoter, miR-375 overexpression and knockdown, YAP1 reporter assay, invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct ZEB1 binding, functional epistasis establishes pathway, single lab\",\n      \"pmids\": [\"27270433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In glioblastoma stem-like cells, Zeb1 binds chromatin at both active and repressed gene loci genome-wide; transcriptional repression requires direct DNA binding of Zeb1, while gene activation occurs through indirect recruitment to regulatory regions by Lef1 (Wnt pathway effector), independently of Wnt signaling. ZEB1/Lef1 complex activates the GEF Prex1, which promotes glioblastoma cell invasion in vivo.\",\n      \"method\": \"ChIP-seq, RNA-seq, ZEB1 DNA-binding mutants, Lef1 Co-IP and co-binding analysis, in vivo invasion assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide ChIP-seq, DNA-binding mutants dissect direct vs. indirect mechanisms, Lef1-ZEB1 co-IP, in vivo validation\",\n      \"pmids\": [\"29903919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Simultaneous deletion of Zeb1 restores directional migration to Ovol2-deficient hair follicle bulge stem cells, establishing Zeb1 as a downstream effector of the Ovol2-Zeb1 EMT circuit that controls directional migration in skin epithelial regeneration.\",\n      \"method\": \"Conditional double knockout (Ovol2 and Zeb1), live imaging of wound explants and hair follicle stem cells, cell cycle analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic epistasis via double knockout with live imaging functional readout demonstrates Zeb1's causal role downstream of Ovol2\",\n      \"pmids\": [\"30413481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Thyroid hormone (T3) transcriptionally upregulates ZEB1 expression in squamous cell carcinoma cells, and elevated ZEB1 promotes EMT and metastatic transformation, establishing TH/D2 as an upstream regulator of the ZEB1-E-cadherin switch.\",\n      \"method\": \"ZEB1 reporter assay, ZEB1 overexpression/knockdown, in vivo tumor models, T3-treatment experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay shows T3-dependent ZEB1 transcription, in vivo tumor model validates phenotype, single lab\",\n      \"pmids\": [\"31776338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXE1 directly interacts with the ZEB1 promoter and activates its transcription in thyroid cancer cells; ZEB1 silencing decreases migration and invasion, placing ZEB1 downstream of FOXE1 in thyroid cancer EMT.\",\n      \"method\": \"Promoter ChIP, ZEB1 knockdown/overexpression, FOXE1 gain/loss-of-function, migration and invasion assays\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct FOXE1 binding to ZEB1 promoter, functional epistasis with ZEB1 knockdown, single lab\",\n      \"pmids\": [\"31846430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endothelial ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, epigenetically suppressing Notch signaling in bone vasculature, thereby impairing CD31hi/endomucinhi vessel formation and osteogenesis; delivery of Zeb1-packaged liposomes to osteoporotic mice restores Notch activity.\",\n      \"method\": \"Endothelial-specific ZEB1 conditional knockout mice, ChIP (histone acetylation), Notch signaling reporters, bone phenotype analysis, liposome delivery rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO mouse, ChIP demonstrates epigenetic mechanism, in vivo rescue with liposome delivery, multiple orthogonal methods\",\n      \"pmids\": [\"31974363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endothelial ZEB1 deletion elicits persistent tumor vascular normalization by epigenetically repressing TGF-β signaling, improving blood/oxygen perfusion and immune cell infiltration, and reducing tumor growth and metastasis.\",\n      \"method\": \"Endothelial-specific ZEB1 conditional knockout in tumor-bearing mice, ChIP (epigenetic repression of TGF-β pathway), tumor perfusion measurements, immune cell profiling\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO mouse model, ChIP-based epigenetic mechanism, multiple functional readouts in vivo\",\n      \"pmids\": [\"32039918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZEB1 promotes CD4+ T cell pathogenic Th1 and Th17 differentiation by inhibiting miR-101-3p, which would otherwise repress JAK2 expression; this disinhibits JAK2 and downstream STAT3/STAT4 phosphorylation, enabling IL-17 and IFN-γ expression. ZEB1 deletion protects against EAE (mouse MS model).\",\n      \"method\": \"Conditional ZEB1 knockout in T cells, miR-101-3p overexpression/inhibition, JAK2 and STAT3/4 phosphorylation assays, cytokine measurement, EAE model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO establishes causal role, pathway mechanism through miR-101-3p/JAK2/STAT signaling defined by multiple orthogonal methods, validated in vivo\",\n      \"pmids\": [\"34433042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZEB1 transcriptionally activates PFKM (phosphofructokinase-1 muscle isoform) by binding a non-canonical binding sequence in its promoter (confirmed by ChIP and luciferase assay), enhancing glycolysis and Warburg effect; ZEB1 knockdown impairs PFKM expression and glycolysis, rescued by exogenous PFKM.\",\n      \"method\": \"ChIP, luciferase reporter assay, ZEB1 shRNA knockdown, metabolic assays (glucose uptake, ECAR, OCR), rescue with PFKM re-expression, orthotopic xenograft\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP and luciferase confirm direct binding and activation, functional rescue experiments, in vivo xenograft validation\",\n      \"pmids\": [\"33897890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZEB1 directly represses LIF in glioma stem cells; ZEB1 knockdown induces LIF, promoting GCSC self-renewal; IFN-γ treatment induces ZEB1 expression and attenuates LIF-driven stemness. ZEB1 binding sites were identified within the LIF promoter.\",\n      \"method\": \"ZEB1 promoter binding site analysis, ZEB1 knockdown, LIF induction assay, self-renewal assay, IFN-γ treatment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter binding sites identified, functional knockdown with LIF induction and stemness readout, single lab\",\n      \"pmids\": [\"28246407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional acute deletion of Zeb1 in hematopoietic stem cells causes self-renewal defect, multilineage differentiation block, apoptosis-driven thymocyte loss, and upregulation of EpCAM; Zeb1 KO in leukemic stem cells accelerates AML progression, establishing Zeb1 as a tumor suppressor in LSCs.\",\n      \"method\": \"Mx1-Cre conditional knockout, transcriptomic analysis, bone marrow transplantation, AML model (MLL-AF9, Meis1a/Hoxa9)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO with cell-autonomous phenotypes, multiple leukemia models, transcriptomics, in vivo validation\",\n      \"pmids\": [\"33108352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"O-GlcNAcylation of ZEB1 at Ser555 enhances its stabilization and nuclear translocation; this promotes transcription of lipogenesis genes FASN and FADS2, resulting in lipid peroxidation-dependent ferroptosis in mesenchymal pancreatic cancer cells under high-glucose conditions.\",\n      \"method\": \"Site-specific mutagenesis (Ser555), O-GlcNAcylation assay, subcellular fractionation, ChIP/reporter for FASN/FADS2, ferroptosis cell death assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific mutagenesis identifies modification site, nuclear translocation confirmed by fractionation, transcriptional targets validated by ChIP, in vivo xenograft corroboration\",\n      \"pmids\": [\"35844792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZEB directly binds the LPCAT3 promoter (-1600 to -1401 nt region) to stimulate its transcription in a YAP-dependent manner; ZEB and YAP physically interact through ZEB's zinc-finger cluster domain and YAP's WW domain; EP300 simultaneously binds YAP (via Bromo domain) and ZEB (via CBP/p300-HAT domain) and induces H3K27Ac at the LPCAT3 locus.\",\n      \"method\": \"ChIP, reporter assay, domain-specific binding assays (Co-IP with domain mutants), H3K27Ac ChIP\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP confirms direct promoter binding, domain-specific Co-IP maps interaction surfaces, histone modification assay, validated in xenograft\",\n      \"pmids\": [\"37166352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP10 binds ZEB1 and promotes its proteasomal degradation by modifying ZEB1 ubiquitination; MEK-ERK signaling phosphorylates USP10 at Ser236, impairing the USP10-ZEB1 interaction and enabling ZEB1 protein stabilization, which promotes colorectal cancer metastatic colonization.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, MEK-ERK inhibitor treatment, USP10 phospho-site mutagenesis, tail vein metastasis mouse model\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, ubiquitination assay, phospho-site mutagenesis, signaling pathway manipulation, in vivo metastasis model\",\n      \"pmids\": [\"36940483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP43 physically interacts with ZEB1 (Co-IP), deubiquitinates it, and stabilizes the ZEB1 protein, promoting proliferation, migration, and invasion of colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, USP43 overexpression/knockdown, invasion/migration assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and ubiquitination assay, bidirectional functional validation, single lab\",\n      \"pmids\": [\"33391437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZEB1 transcriptionally activates PHGDH by binding a non-classical binding site in its promoter (confirmed by ChIP and luciferase assay), driving serine synthesis pathway flux; conditional liver-specific Zeb1 knockout impairs PHGDH expression and HCC carcinogenesis, rescued by exogenous PHGDH expression.\",\n      \"method\": \"ChIP, luciferase reporter assay, [13C]-glucose metabolic tracing, liver-specific conditional Zeb1 KO mouse, PHGDH rescue experiments, orthotopic xenograft\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP and reporter confirm direct promoter binding, isotope tracing validates pathway flux, conditional KO mouse with genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"37331567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In osteoclasts, Zeb1 transcriptionally represses MtCK1 (mitochondrial creatine kinase 1), thereby controlling the phosphocreatine energy shuttle and mitochondrial respiration; Zeb1-null osteoclasts are hyperactivated and cause excessive bone resorption in vivo, identifying a Zeb1/MtCK1 metabolic axis controlling osteoclast activity.\",\n      \"method\": \"Conditional Zeb1 knockout in osteoclasts, ChIP (Zeb1 binding to MtCK1 locus), metabolic flux assays (phosphocreatine shuttle, mitochondrial respiration), in vivo bone density measurement\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO, ChIP confirms direct target, metabolic assays validate mechanism, in vivo skeletal phenotype\",\n      \"pmids\": [\"36843552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP22 acts as a co-activator of ZEB1-mediated VEGFA transcription by maintaining ZEB1 stability via deubiquitinase activity and being recruited to ZEB1-binding elements on the VEGFA promoter, where it alters histone H2Bub levels to enhance transcription.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP (USP22 and ZEB1 at VEGFA promoter), H2Bub ChIP, USP22 knockdown/overexpression, tumor xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, ubiquitination assay, co-ChIP at promoter, histone modification assay, in vivo xenograft\",\n      \"pmids\": [\"36906615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BMPR1A activation induces ID2 to physically interact with and sequester ZEB1, attenuating ZEB1-driven transcription of Tgfbr2 and preventing excessive endothelial-to-mesenchymal transition; endothelial-specific Bmpr1a deletion causes PAH in mice, rescued by siRNA against Tgfbr2.\",\n      \"method\": \"Co-immunoprecipitation (ID2-ZEB1 interaction), endothelial-specific Bmpr1a conditional KO mouse, lineage tracing, siRNA-lipid nanoparticle rescue, TGFBR2 expression analysis\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP identifies ID2-ZEB1 complex, conditional KO with lineage tracing, in vivo rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"36166408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dephosphorylation of the Retinoblastoma protein (Rb) is associated with ZEB1 physical interaction (co-immunoprecipitation), and leads to inhibition of ZEB1 transcriptional activity, reducing EMT in mesenchymal cancer cells in 3D Matrigel culture.\",\n      \"method\": \"Co-immunoprecipitation (Rb-ZEB1), PNUTS shRNA-mediated Rb dephosphorylation, transcriptional activity assay, 3D Matrigel invasion assay\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifies interaction, functional transcriptional assay, single lab, one indirect dephosphorylation approach\",\n      \"pmids\": [\"27645778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In glioblastoma, ZEB1 is a central regulator interconnecting invasion, chemoresistance, and tumorigenesis through the ZEB1-miR-200 feedback loop, with downstream effectors ROBO1, c-MYB, and MGMT identified as novel ZEB1 pathway targets.\",\n      \"method\": \"ZEB1 knockdown and overexpression, miR-200 manipulation, invasion and chemoresistance assays, target gene expression analysis\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown/overexpression with multiple defined downstream targets, single lab\",\n      \"pmids\": [\"23818228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZEB1 directly activates transcription of the CD47 gene in hypoxic cervical cancer cells (confirmed by transcriptional activation assay); exosomal ZEB1 retains transcriptional activity and reprograms macrophages toward SIRPα+ TAM polarization via STAT3 signaling, promoting immune evasion.\",\n      \"method\": \"Reporter/transcriptional assay for CD47, exosome isolation and transfer experiments, STAT3 signaling inhibition, in vivo xenograft phagocytosis assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct CD47 transcriptional activation assay, exosome transfer functional experiments, STAT3 pathway inhibition, single lab\",\n      \"pmids\": [\"38183060\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZEB1 is a dual-function zinc finger/homeodomain transcription factor that represses epithelial genes (E-cadherin, ESRP1, SEMA3F, p73, miR-200 family, CXCL10) and activates mesenchymal/metabolic targets (PFKM, PHGDH, VEGFA, vimentin, CD47) by binding E-box sequences directly or through cofactor complexes (CtBP, p300, YAP/EP300, Lef1); its activity is regulated by multiple post-translational modifications including ATM-mediated phosphorylation-stabilization, deubiquitination by USP7/USP51/USP22/USP43/CSN5, O-GlcNAcylation at Ser555, and Rb-dephosphorylation-dependent inhibition, placing ZEB1 at the intersection of EMT, DNA damage response, metabolic reprogramming, immune evasion, and stem cell maintenance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZEB1 is a dual zinc-finger/homeodomain transcription factor that binds E-box-like sequences (consensus CACCTG/AAAGGTGCA) through two distinct N- and C-terminal zinc-finger clusters and acts as both a context-dependent repressor and activator of target promoters [#1, #2]. Its repressive output is executed by recruitment of corepressors: the general cofactor NC2 to a defined hydrophobic repression domain [#3] and CtBP through PLDLS motifs whose mutation abolishes repression [#4], with separable N- and C-terminal repressor domains targeting distinct lineage factors [#5]. Through this machinery ZEB1 directly represses a broad epithelial/differentiation program—p73, SEMA3F, ESRP1, MITF, miR-375, the T-cell chemokine CXCL10, and LIF—to drive EMT, invasion, dedifferentiation, and immune evasion [#6, #12, #13, #11, #23, #19]. ZEB1 also functions as a direct or cofactor-assisted activator, partnering with p300 to potentiate Smad signaling [#8], with Lef1 to activate invasion genes such as Prex1 [#24], and with YAP/EP300 to drive H3K27Ac-dependent LPCAT3 transcription [#35], and it directly activates metabolic genes including PFKM and PHGDH to reprogram glycolysis and serine synthesis [#31, #38]. ZEB1 stability and activity are heavily post-translationally controlled: ATM phosphorylates and stabilizes ZEB1 to enable USP7-dependent CHK1 deubiquitylation and homologous-recombination DNA repair [#14], multiple deubiquitinases (USP51, USP22, USP43, CSN5) and the antagonistic USP10/MEK-ERK axis set ZEB1 levels [#18, #40, #36], and O-GlcNAcylation at Ser555 promotes its nuclear translocation and lipogenic-gene activation [#34]. In vivo conditional-knockout studies establish ZEB1 as a regulator of hematopoietic and leukemic stem cells, endothelial Notch/TGF-β signaling, osteoclast metabolism, and T-cell pathogenic differentiation, placing it at the intersection of EMT, the DNA-damage response, metabolic reprogramming, immunity, and stem-cell maintenance [#33, #28, #39, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established ZEB1 as a sequence-specific DNA-binding transcriptional repressor and defined its bipartite zinc-finger recognition architecture, answering what kind of regulator it is.\",\n      \"evidence\": \"DNA binding/Kd measurement, reporter assays, and immunocytochemistry defining the AAAGGTGCA site and nuclear/cytoplasmic shifts\",\n      \"pmids\": [\"7935395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of the nuclear/cytoplasmic shift not mechanistically defined\", \"Endogenous target genes not identified\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Resolved that ZEB1's two zinc-finger clusters have distinct optimal binding sequences and that promoter context (presence of a GTTTC/G element) switches it between repressor and activator, explaining its dual transcriptional behavior.\",\n      \"evidence\": \"CASTing site selection, zinc-finger mutagenesis, and transient reporter assays\",\n      \"pmids\": [\"7588776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors mediating the activator vs repressor switch not yet identified\", \"Homeodomain function beyond zinc-finger interaction unclear\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed ZEB1 represses muscle differentiation by occupying E-boxes and is displaced by accumulating myogenic bHLH factors, providing a developmental logic for its repressive role.\",\n      \"evidence\": \"DNA binding, reporter assays, and overexpression differentiation assays targeting MEF-2\",\n      \"pmids\": [\"9233803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Corepressor identity not yet defined\", \"Direct vs competitive displacement mechanism not fully resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified the corepressor machinery—NC2 and CtBP via PLDLS motifs—and separable lineage-specific repressor domains, defining how ZEB1 silences transcription mechanistically.\",\n      \"evidence\": \"In vitro transcription reconstitution, yeast two-hybrid, PLDLS-motif mutagenesis, and domain-swap reporter assays\",\n      \"pmids\": [\"9418848\", \"10359772\", \"10567522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NC2 and CtBP act on the same or distinct target sets unresolved\", \"Chromatin-level consequences not characterized in this era\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Distinguished ZEB1 from ZEB2 functionally, showing ZEB1 recruits p300 to promote Smad-dependent activation whereas ZEB2 recruits CtBP to repress, establishing cofactor choice as the determinant of opposing signaling outputs.\",\n      \"evidence\": \"Reciprocal Co-IP, reporter assays, and in vivo Xenopus developmental epistasis\",\n      \"pmids\": [\"12743039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal determining p300 vs CtBP recruitment unknown\", \"Structural basis of p300 interaction not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated through in vivo ChIP that ZEB1 directly represses tissue-specific targets (p73, SEMA3F, MITF) to control proliferation, dedifferentiation, and tumor invasion, generalizing its repressive program.\",\n      \"evidence\": \"ChIP, shRNA/dominant-negative knockdown, and heterozygous mouse mutants\",\n      \"pmids\": [\"11713281\", \"19177200\", \"19515996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide target catalog still incomplete\", \"Cofactor requirements at these loci not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected ZEB1 to the DNA-damage response, showing ATM phosphorylates and stabilizes ZEB1, which then promotes USP7-mediated CHK1 deubiquitylation and radioresistance—a non-transcriptional protein-stabilizing role.\",\n      \"evidence\": \"ATM kinase assay, Co-IP, CHK1 ubiquitination assay, and in vivo radioresistance models\",\n      \"pmids\": [\"25086746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ATM phosphosite(s) on ZEB1 not mapped here\", \"Relationship between this function and ZEB1's transcriptional output unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Used genome-wide ChIP-seq and DNA-binding mutants to separate ZEB1's direct repression from Lef1-dependent indirect activation, mechanistically resolving its dual activator/repressor function at the chromatin level.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, ZEB1 DNA-binding mutants, Lef1 Co-IP, and in vivo invasion assays\",\n      \"pmids\": [\"29903919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ZEB1 is recruited by Lef1 without direct DNA binding not fully defined\", \"Generalizability across tissues untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established ZEB1 as a direct transcriptional activator of metabolic genes (PFKM, PHGDH) via non-canonical promoter sites, revealing its role in glycolytic and serine-synthesis reprogramming with in vivo rescue validation.\",\n      \"evidence\": \"ChIP, luciferase assays, metabolic flux/isotope tracing, conditional KO mice, and PFKM/PHGDH rescue experiments\",\n      \"pmids\": [\"33897890\", \"37331567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors enabling activation at non-canonical sites not identified\", \"Whether these activation events require the acidic activation domain untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined O-GlcNAcylation at Ser555 as a modification controlling ZEB1 nuclear translocation and lipogenic-gene activation, adding a metabolic-sensing PTM layer to ZEB1 regulation.\",\n      \"evidence\": \"Site-specific Ser555 mutagenesis, O-GlcNAcylation assay, subcellular fractionation, and ChIP for FASN/FADS2\",\n      \"pmids\": [\"35844792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme(s) adding/removing the O-GlcNAc mark not identified\", \"Interplay with phosphorylation not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped the deubiquitinase/E3 network (USP22, USP43, USP10/MEK-ERK) and YAP/EP300 cofactor complexes controlling ZEB1 stability and chromatin activity, showing protein turnover is a major control node for ZEB1 output.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, domain-mapping Co-IP, H3K27Ac/H2Bub ChIP, phosphosite mutagenesis, and in vivo metastasis models\",\n      \"pmids\": [\"36906615\", \"33391437\", \"36940483\", \"37166352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cognate E3 ligase(s) for ZEB1 not fully identified\", \"Hierarchy among competing DUBs in a given cell type unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Conditional in vivo deletions across hematopoietic/leukemic stem cells, endothelium, osteoclasts, and T cells established ZEB1's physiological and tumor-suppressive/context-dependent roles beyond cancer-cell EMT.\",\n      \"evidence\": \"Tissue-specific conditional KO mice with transcriptomics, ChIP, metabolic flux, lineage tracing, and disease-model rescues (AML, osteoporosis, EAE, PAH)\",\n      \"pmids\": [\"33108352\", \"31974363\", \"36843552\", \"34433042\", \"36166408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect targets in each tissue not exhaustively mapped\", \"Reconciling tumor-suppressive (LSC) and oncogenic (EMT) roles mechanistically unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZEB1 integrates competing post-translational modifications, cofactor choice, and DNA-binding context into a single cell-type-specific transcriptional decision remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM state to activator vs repressor switching\", \"Cognate E3 ligases and the full cofactor selection logic not defined\", \"Structural basis of zinc-finger/homeodomain cooperation not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 4, 6, 24, 31]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 2, 6, 24]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 24, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 34]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 4, 6, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 25, 28, 41]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [31, 38, 34, 39]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 30, 44]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 20, 36, 43]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CtBP\", \"p300\", \"USP7\", \"Lef1\", \"YAP1\", \"EP300\", \"USP22\", \"ID2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}