{"gene":"TGIF2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2001,"finding":"TGIF2 recruits histone deacetylase 1 (HDAC1) to repress transcription. Unlike TGIF1, TGIF2 cannot interact with the corepressor CtBP. TGIF2 binds DNA via its homeodomain at TGIF binding sites and represses transcription. TGIF2 also interacts directly with TGFβ-activated Smads to repress TGFβ-responsive transcription.","method":"Co-immunoprecipitation, reporter gene assays, DNA-binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and reporter assays, foundational study replicated in subsequent work, multiple orthogonal methods","pmids":["11427533"],"is_preprint":false},{"year":2000,"finding":"TGIF2 protein contains a putative nuclear localization signal and translocates to the nucleus, as confirmed by transfection of epitope-tagged cDNA. TGIF2 is a TALE-superclass homeodomain protein.","method":"Subcellular localization by transfection and imaging of epitope-tagged protein","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with epitope tag, single lab, confirmed by nuclear localization signal analysis","pmids":["11006116"],"is_preprint":false},{"year":2006,"finding":"TGIF2 interacts with the transcriptional corepressor mSin3, providing an additional repression mechanism. Both full-length and a shorter splice variant (lacking 39 amino acids) of mouse Tgif2 are functional transcriptional repressors that can repress TGFβ-dependent and -independent transcription. The Tgif2 gene contains a retained intron within its coding sequence.","method":"Co-immunoprecipitation, reporter gene assays, RT-PCR splice variant analysis","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and reporter assays, single lab, multiple orthogonal methods","pmids":["16436215"],"is_preprint":false},{"year":2010,"finding":"Tgif1 and Tgif2 together are required for gastrulation; double-null mouse embryos fail to gastrulate. Genetic reduction of Nodal dosage partially rescues the gastrulation and left-right asymmetry defects in embryos lacking all Tgif function, establishing that Tgifs limit the transcriptional response to Nodal/TGFβ signaling during early embryogenesis. Extra-embryonic Tgif function (single wild-type allele of Tgif1 in extra-embryonic tissue) is sufficient to allow gastrulation.","method":"Conditional knockout mouse genetics, genetic epistasis (Nodal dosage reduction), embryo phenotype analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with conditional knockouts and Nodal dosage rescue, multiple allele combinations tested","pmids":["20040491"],"is_preprint":false},{"year":2016,"finding":"Loss of both Tgif1 and Tgif2 in mice results in holoprosencephaly and defects in left-right asymmetry. The combination of Tgif1 and Tgif2 mutations increases severity and penetrance of posterior axial transformation phenotype. Tgif1/Tgif2 regulate axial patterning and Hoxc6 expression, and reduced TGIF function sensitizes embryos to retinoic acid effects.","method":"Mouse knockout genetics, embryo phenotypic analysis, gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function with defined phenotype and gene expression readout, single lab","pmids":["27187787"],"is_preprint":false},{"year":2017,"finding":"TGIF1 directly binds to a conserved consensus TGIF site 5' of the Evi5l gene and represses its expression. Loss of both Tgif1 and Tgif2 increases Evi5l (a RabGAP) expression, which reduces primary cilia number. Reducing Evi5l expression in double-null MEFs partially restores cilium numbers and Shh pathway transcriptional response, placing Tgif1/2 upstream of Evi5l in ciliogenesis regulation.","method":"Chromatin immunoprecipitation, transcriptome profiling, shRNA knockdown, primary MEF analysis, Shh pathway reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, transcriptomics, genetic epistasis (Evi5l rescue), and functional cilia readout; multiple orthogonal methods in single lab","pmids":["27956704"],"is_preprint":false},{"year":2017,"finding":"TGIF2 acts as a developmental regulator sufficient to drive liver-to-pancreas fate conversion. Expression of Tgif2 in hepatocytes causes transcriptional remodelling that represses hepatic identity and induces a pancreatic progenitor-like phenotype both ex vivo and in vivo in adult mouse hepatocytes.","method":"Forced expression in hepatocytes (ex vivo and in vivo mouse), transcriptome profiling, lineage marker analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo and ex vivo forced expression with transcriptome readout, multiple orthogonal methods confirming fate conversion","pmids":["28193997"],"is_preprint":false},{"year":2019,"finding":"EGFR/RAS/ERK signaling phosphorylates TGIF2 and increases its protein stability. Phosphorylation of TGIF2 is required for its pro-stemness functions in lung adenocarcinoma, as phosphorylation-deficient TGIF2 mutants lose these activities. TGIF2 binds the OCT4 promoter and promotes OCT4 expression.","method":"Phosphorylation-deficient mutant analysis, ChIP assay, xenograft mouse models, in vitro cell biology assays","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phosphorylation sites, ChIP, in vivo xenograft, single lab","pmids":["31871777"],"is_preprint":false},{"year":2018,"finding":"Nuclear PKM2 promotes post-translational degradation of TGIF2 protein via the ubiquitin-proteasome system during EMT in oral squamous cell carcinoma cells. TGIF2 protein and mRNA expression were discordant in EMT-induced cells, and proteasome inhibition with MG132 blocked TGIF2 protein loss.","method":"Western blot mRNA/protein discordance analysis, proteasome inhibitor (MG132) rescue assay, PKM2 knockdown","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proteasome inhibitor rescue and PKM2 knockdown, single lab, two supporting methods but limited mechanistic depth","pmids":["30333907"],"is_preprint":false},{"year":2017,"finding":"TGIF2 represses Smad pathway activity, and its restoration in miR-181a-overexpressing prostate cancer cells inhibits Smad2/3 phosphorylation, nuclear localization of Smad2/3, and EMT processes, confirming TGIF2 functions as a repressor of the Smad pathway in this context.","method":"TGIF2 overexpression rescue, Smad2/3 nuclear localization immunostaining, Western blot for EMT markers","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, rescue experiment with Western blot and immunostaining, limited mechanistic depth","pmids":["29164579"],"is_preprint":false},{"year":2022,"finding":"TGIF2 forms a transcriptional complex with DDX17, SMAD3, and the JAG1 intracellular domain (JICD1) to increase SOX2 expression, driving oncogenic transformation and stemness in astrocytes. This was identified by proteomics, ChIP-seq, and transcriptome analysis.","method":"Co-immunoprecipitation/proteomics, ChIP-seq, transcriptome profiling","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics, ChIP-seq, and transcriptome used together; single lab but multiple orthogonal methods","pmids":["36417870"],"is_preprint":false},{"year":2023,"finding":"Phosphorylation of TGIF2 by EGFR/ERK signaling is required to recruit HDAC1 to the E-cadherin promoter, suppressing E-cadherin transcription and promoting EMT. Phosphorylation-deficient TGIF2 mutants fail to recruit HDAC1 and cannot promote migration/EMT. HDAC1 inhibition blocks TGIF2 phosphorylation-induced EMT.","method":"Co-immunoprecipitation, dual-luciferase reporter assay, ChIP assay, phosphorylation-deficient mutant analysis, xenograft mouse models","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, luciferase reporter, and mutagenesis in single lab with in vivo validation","pmids":["36647029"],"is_preprint":false},{"year":2020,"finding":"TGIF2 directly binds to the FCMR gene promoter and represses FCMR expression, thereby promoting cervical cancer cell proliferation and metastasis. This was confirmed by luciferase assay, and rescue experiments showed simultaneous FCMR knockdown partially reversed the inhibition caused by TGIF2 knockdown.","method":"Luciferase reporter assay, ChIP (implied by promoter binding), shRNA knockdown, rescue experiments, xenograft mouse model","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase assay for promoter binding, single lab, limited mechanistic follow-up","pmids":["32572908"],"is_preprint":false},{"year":2022,"finding":"LSD1 histone demethylase binds the TGIF2 promoter and is associated with reduced H3K4me1 monomethylation at the TGIF2 locus, potentially mediating TGIF2 downregulation. Adenovirus-mediated TGIF2 overexpression activated the Wnt/β-catenin signaling pathway in mouse hippocampal neurons and suppressed neuronal apoptosis.","method":"ChIP-qPCR, adenovirus-mediated overexpression, gene set enrichment analysis, ENCODE database validation","journal":"Brain and behavior","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP-qPCR and overexpression, single lab, pathway activation inferred from downstream marker analysis","pmids":["35592894"],"is_preprint":false},{"year":2016,"finding":"Tgif2 participates in photoreceptor cell fate determination in the early mouse retina: knockdown decreases rod photoreceptors and increases cones in retinal explants, while overexpression (conditional knock-in) causes abnormal cone nuclear localization in the outer nuclear layer without affecting cone function.","method":"shRNA knockdown in retinal explants, conditional knock-in mouse model, electroretinography, histological analysis","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function in vivo with defined cellular phenotype, single lab","pmids":["27639517"],"is_preprint":false},{"year":2025,"finding":"TGIF2 controls neural stem cell (NSC) fate maintenance by interacting with the SIN3A/HDAC repressor complex to suppress neuronal differentiation genes. TGIF2 is identified as the major regulator of neurogenic priming in cortical NSCs, restraining neuronal differentiation gene activation. This was demonstrated by in vitro and in vivo experiments in the mouse cerebral cortex.","method":"RNA-seq, ATAC-seq, Co-immunoprecipitation with SIN3A/HDAC complex, in vitro and in vivo overexpression/knockdown experiments in mouse NSCs","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiomics (RNA-seq, ATAC-seq) plus Co-IP with repressor complex and in vivo validation; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.02.13.635953"],"is_preprint":true},{"year":2025,"finding":"TGIF2 transcriptionally upregulates HMGB3 expression in esophageal squamous cell carcinoma, as demonstrated by luciferase reporter and ChIP assays. HMGB3 then activates TGF-β signaling through interaction with TLR3, promoting proliferation and metastasis.","method":"Luciferase reporter assay, ChIP assay, Co-immunoprecipitation, RNA sequencing","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter and ChIP for direct transcriptional regulation, Co-IP for protein interactions, single lab","pmids":["41716633"],"is_preprint":false},{"year":2025,"finding":"Smad2 cooperates with TGIF2 to co-regulate the SOX2 promoter in pancreatic cancer. TGIF2 promotes SOX2, Slug, CD44, and EGFR/MAPK signaling, and SOX2-driven transactivation of EGFR/MAPK promotes TGIF2 nuclear translocation, forming a positive feedback loop. TGIF2 nuclear translocation was demonstrated in vitro.","method":"ChIP assay (SOX2 promoter co-occupancy), Co-immunoprecipitation, subcellular fractionation/localization, in vivo xenograft","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP for complex formation at SOX2 promoter, feedback loop validated in vitro, single lab","pmids":["39781447"],"is_preprint":false}],"current_model":"TGIF2 is a TALE-superclass homeodomain transcriptional repressor that recruits HDAC1 and mSin3 (but not CtBP) to repress both TGFβ/Nodal-Smad-dependent and DNA-bound target gene transcription; its repressive activity is regulated by EGFR/ERK-mediated phosphorylation, which stabilizes TGIF2 and enables HDAC1 recruitment to specific promoters (e.g., E-cadherin), while it also forms transcriptional complexes with partners such as SMAD3, DDX17, and SIN3A/HDAC to control cell fate decisions in development (gastrulation, neurogenesis, pancreas vs. liver identity, retinal photoreceptor fate) and cancer progression."},"narrative":{"mechanistic_narrative":"TGIF2 is a TALE-superclass homeodomain transcriptional repressor that limits TGFβ/Nodal signaling and shapes cell-fate decisions across development and cancer [PMID:11427533, PMID:20040491]. It binds DNA at TGIF consensus sites through its homeodomain and represses target transcription, and it independently binds TGFβ-activated Smads to dampen Smad-dependent transcription; repression is executed by recruitment of HDAC1 and the mSin3 corepressor, but, unlike TGIF1, TGIF2 does not engage CtBP [PMID:11427533, PMID:16436215]. In vivo, Tgif1 and Tgif2 act redundantly to restrain the transcriptional response to Nodal during gastrulation and left-right patterning — double-null embryos fail to gastrulate and develop holoprosencephaly, and Nodal dosage reduction rescues these defects — and they also repress the RabGAP Evi5l to permit ciliogenesis and Shh signaling [PMID:20040491, PMID:27187787, PMID:27956704]. As a fate determinant, TGIF2 is sufficient to convert hepatocytes toward a pancreatic progenitor identity, governs rod-versus-cone photoreceptor specification, and maintains neural stem cell identity by partnering with the SIN3A/HDAC complex to suppress neuronal differentiation genes [PMID:28193997, PMID:27639517, PMID:bio_10.1101_2025.02.13.635953]. In cancer, TGIF2 activity is gated post-translationally: EGFR/RAS/ERK signaling phosphorylates and stabilizes TGIF2, enabling HDAC1 recruitment to the E-cadherin promoter to drive EMT and promoting OCT4 expression and stemness, while nuclear PKM2 routes TGIF2 to ubiquitin-proteasome degradation [PMID:31871777, PMID:30333907, PMID:36647029]. Beyond repression, TGIF2 also acts within transcriptional complexes with SMAD3, DDX17, and the JAG1 intracellular domain, and cooperates with Smad2, to activate SOX2 and drive oncogenic stemness in glioma and pancreatic cancer [PMID:36417870, PMID:39781447].","teleology":[{"year":2000,"claim":"Establishing that TGIF2 is a nuclear TALE-homeodomain protein defined where it acts and assigned it to a transcription-factor class.","evidence":"Subcellular localization of epitope-tagged TGIF2 and NLS analysis","pmids":["11006116"],"confidence":"Medium","gaps":["No DNA target or interacting partner defined","Single-lab localization without endogenous protein"]},{"year":2001,"claim":"Defining TGIF2's core repressive mechanism showed it works both by direct DNA binding and by binding activated Smads, recruiting HDAC1 but not CtBP — distinguishing it from TGIF1.","evidence":"Co-IP, DNA-binding assays, and reporter assays","pmids":["11427533"],"confidence":"High","gaps":["Endogenous target genes not identified","Structural basis of Smad interaction unknown"]},{"year":2006,"claim":"Identifying mSin3 as an additional corepressor and characterizing functional splice variants broadened the repression machinery and showed both isoforms repress TGFβ-dependent and -independent transcription.","evidence":"Co-IP, reporter assays, RT-PCR splice variant analysis","pmids":["16436215"],"confidence":"Medium","gaps":["Promoter-specific targeting of mSin3 vs HDAC1 not resolved","Functional difference between isoforms unclear"]},{"year":2010,"claim":"Genetic epistasis established the in vivo purpose of TGIF function: Tgif1/Tgif2 together limit Nodal/TGFβ signaling required for gastrulation and left-right asymmetry.","evidence":"Conditional knockout mouse genetics with Nodal dosage rescue","pmids":["20040491"],"confidence":"High","gaps":["Direct target genes mediating the Nodal restraint not defined","Tissue-specific contribution of TGIF2 vs TGIF1 not separated"]},{"year":2016,"claim":"Loss-of-function studies extended TGIF roles to axial patterning/holoprosencephaly and to photoreceptor fate, showing context-dependent developmental functions.","evidence":"Mouse knockouts, retinal explant knockdown, and conditional knock-in with gene expression analysis","pmids":["27187787","27639517"],"confidence":"Medium","gaps":["Direct transcriptional targets in retina and axial tissue not fully mapped","Mechanism of rod/cone choice unresolved"]},{"year":2017,"claim":"Three studies established TGIF as an instructive fate regulator: it represses Evi5l to enable ciliogenesis/Shh signaling, and forced TGIF2 reprograms hepatocytes toward pancreatic identity, while a Smad-repressor role was reaffirmed in prostate cancer.","evidence":"ChIP, transcriptomics, Evi5l rescue, forced hepatocyte expression in vivo, and miR-181a/TGIF2 rescue with Smad2/3 readout","pmids":["27956704","28193997","29164579"],"confidence":"High","gaps":["How TGIF2 reorganizes chromatin during lineage conversion unknown","Prostate cancer Smad-repression evidence is low-confidence and lacks direct target genes"]},{"year":2018,"claim":"Discovery that nuclear PKM2 drives proteasomal degradation of TGIF2 during EMT revealed post-translational control of TGIF2 abundance.","evidence":"mRNA/protein discordance, MG132 rescue, and PKM2 knockdown","pmids":["30333907"],"confidence":"Medium","gaps":["E3 ligase mediating TGIF2 ubiquitination not identified","Whether PKM2 acts directly on TGIF2 unresolved"]},{"year":2019,"claim":"Linking EGFR/RAS/ERK phosphorylation to TGIF2 stability and OCT4 activation showed signaling-dependent activation of pro-stemness TGIF2 function.","evidence":"Phospho-deficient mutants, ChIP, and xenografts in lung adenocarcinoma","pmids":["31871777"],"confidence":"Medium","gaps":["Specific phosphosites and responsible kinase not fully defined","How phosphorylation switches TGIF2 from repressor to OCT4 activator unclear"]},{"year":2022,"claim":"Demonstrating that TGIF2 assembles activating complexes (with DDX17, SMAD3, JICD1) at SOX2 reframed it as also a transcriptional activator in oncogenic stemness.","evidence":"Proteomics/Co-IP, ChIP-seq, transcriptome profiling in astrocytes; plus LSD1-mediated TGIF2 promoter regulation in neurons","pmids":["36417870","35592894"],"confidence":"Medium","gaps":["What determines repressor vs activator behavior of TGIF2 not defined","Neuronal Wnt/β-catenin link is low-confidence and indirect"]},{"year":2023,"claim":"Mechanistic dissection showed ERK phosphorylation of TGIF2 is required to recruit HDAC1 to the E-cadherin promoter, directly coupling signaling, corepressor recruitment, and EMT.","evidence":"Co-IP, ChIP, luciferase, phospho-deficient mutants, and xenografts","pmids":["36647029"],"confidence":"Medium","gaps":["Generalizability of phospho-dependent HDAC1 recruitment to other promoters untested","Phosphosite identity not pinpointed"]},{"year":2025,"claim":"Recent work consolidated dual context-dependent roles: SIN3A/HDAC-dependent maintenance of neural stem cell identity, and Smad2/SOX2 feedback plus HMGB3 upregulation driving cancer progression.","evidence":"RNA-seq/ATAC-seq and Co-IP in NSCs (preprint); ChIP, Co-IP, subcellular fractionation in pancreatic and esophageal cancer","pmids":["bio_10.1101_2025.02.13.635953","39781447","41716633"],"confidence":"Medium","gaps":["NSC findings remain a preprint awaiting peer review","Determinants of TGIF2 nuclear translocation in the SOX2 feedback loop not fully defined"]},{"year":null,"claim":"What molecular switch toggles TGIF2 between HDAC1/SIN3A-mediated repression and SMAD3/DDX17/SOX2-mediated activation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TGIF2-corepressor vs TGIF2-coactivator complexes","Specific phosphosites and kinases controlling the switch not mapped","Genome-wide direct target catalog incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,6,7,10,11,16,17]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,5,7,11,12,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,9,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,10,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4,6,14,15]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,2,11,15]}],"complexes":["SIN3A/HDAC complex","TGIF2-DDX17-SMAD3-JICD1 complex"],"partners":["HDAC1","SIN3A","SMAD3","SMAD2","DDX17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9GZN2","full_name":"Homeobox protein TGIF2","aliases":["5'-TG-3'-interacting factor 2","TGF-beta-induced transcription factor 2","TGFB-induced factor 2"],"length_aa":237,"mass_kda":25.9,"function":"Transcriptional repressor, which probably repress transcription by binding directly the 5'-CTGTCAA-3' DNA sequence or by interacting with TGF-beta activated SMAD proteins. Probably represses transcription via the recruitment of histone deacetylase proteins","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9GZN2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TGIF2","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TGIF2","total_profiled":1310},"omim":[{"mim_id":"611172","title":"MICRO RNA 34A; MIR34A","url":"https://www.omim.org/entry/611172"},{"mim_id":"607294","title":"TRANSFORMING GROWTH FACTOR-BETA-INDUCED FACTOR 2; TGIF2","url":"https://www.omim.org/entry/607294"},{"mim_id":"602630","title":"TRANSFORMING GROWTH FACTOR-BETA-INDUCED FACTOR 1; TGIF1","url":"https://www.omim.org/entry/602630"},{"mim_id":"300411","title":"TRANSFORMING GROWTH FACTOR-BETA-INDUCED FACTOR 2-LIKE, X-LINKED; TGIF2LX","url":"https://www.omim.org/entry/300411"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TGIF2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9GZN2","domains":[{"cath_id":"1.10.10.60","chopping":"26-89","consensus_level":"high","plddt":96.7022,"start":26,"end":89}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZN2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZN2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9GZN2-F1-predicted_aligned_error_v6.png","plddt_mean":68.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TGIF2","jax_strain_url":"https://www.jax.org/strain/search?query=TGIF2"},"sequence":{"accession":"Q9GZN2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9GZN2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9GZN2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9GZN2"}},"corpus_meta":[{"pmid":"11427533","id":"PMC_11427533","title":"TGIF2 interacts with histone deacetylase 1 and represses transcription.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11427533","citation_count":118,"is_preprint":false},{"pmid":"11006116","id":"PMC_11006116","title":"Amplification and overexpression of TGIF2, a novel homeobox gene of the TALE superclass, in ovarian cancer cell lines.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11006116","citation_count":91,"is_preprint":false},{"pmid":"20040491","id":"PMC_20040491","title":"Tgif1 and Tgif2 regulate Nodal signaling and are required for gastrulation.","date":"2010","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20040491","citation_count":56,"is_preprint":false},{"pmid":"31871777","id":"PMC_31871777","title":"TGIF2 promotes the progression of lung adenocarcinoma by bridging EGFR/RAS/ERK signaling to cancer cell stemness.","date":"2019","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31871777","citation_count":43,"is_preprint":false},{"pmid":"31008529","id":"PMC_31008529","title":"Polycomb complex mediated epigenetic reprogramming alters TGF-β signaling via a novel EZH2/miR-490/TGIF2 axis thereby inducing migration and EMT potential in glioblastomas.","date":"2019","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31008529","citation_count":39,"is_preprint":false},{"pmid":"29164579","id":"PMC_29164579","title":"MiR-181a promotes epithelial to mesenchymal transition of prostate cancer cells by targeting TGIF2.","date":"2017","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29164579","citation_count":39,"is_preprint":false},{"pmid":"28193997","id":"PMC_28193997","title":"Stepwise reprogramming of liver cells to a pancreas progenitor state by the transcriptional regulator Tgif2.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28193997","citation_count":38,"is_preprint":false},{"pmid":"29431269","id":"PMC_29431269","title":"MiR-129-5p inhibits glioma cell progression in vitro and in vivo by targeting TGIF2.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29431269","citation_count":36,"is_preprint":false},{"pmid":"26464633","id":"PMC_26464633","title":"MicroRNA-34a inhibits tumor invasion and metastasis in gastric cancer by targeting Tgif2.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26464633","citation_count":32,"is_preprint":false},{"pmid":"27448300","id":"PMC_27448300","title":"MiR-541-3p reverses cancer progression by directly targeting TGIF2 in non-small cell lung cancer.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27448300","citation_count":32,"is_preprint":false},{"pmid":"30333907","id":"PMC_30333907","title":"Nuclear PKM2 promotes the progression of oral squamous cell carcinoma by inducing EMT and post-translationally repressing TGIF2.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/30333907","citation_count":29,"is_preprint":false},{"pmid":"28078014","id":"PMC_28078014","title":"MiRNA-34a overexpression inhibits multiple myeloma cancer stem cell growth in mice by suppressing TGIF2.","date":"2016","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/28078014","citation_count":28,"is_preprint":false},{"pmid":"16436215","id":"PMC_16436215","title":"The Tgif2 gene contains a retained intron within the coding sequence.","date":"2006","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16436215","citation_count":27,"is_preprint":false},{"pmid":"33714261","id":"PMC_33714261","title":"Circ-RNF13, as an oncogene, regulates malignant progression of HBV-associated hepatocellular carcinoma cells and HBV infection through ceRNA pathway of circ-RNF13/miR-424-5p/TGIF2.","date":"2021","source":"Bosnian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33714261","citation_count":26,"is_preprint":false},{"pmid":"29895719","id":"PMC_29895719","title":"miR-34 inhibits growth and promotes apoptosis of osteosarcoma in nude mice through targetly regulating TGIF2 expression.","date":"2018","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/29895719","citation_count":23,"is_preprint":false},{"pmid":"31793741","id":"PMC_31793741","title":"Long noncoding RNA SNHG7 contributes to cell proliferation, migration, invasion and epithelial to mesenchymal transition in non-small cell lung cancer by regulating miR-449a/TGIF2 axis.","date":"2019","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31793741","citation_count":22,"is_preprint":false},{"pmid":"28454497","id":"PMC_28454497","title":"MicroRNA-34a alleviates steroid-induced avascular necrosis of femoral head by targeting Tgif2 through OPG/RANK/RANKL signaling pathway.","date":"2017","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/28454497","citation_count":19,"is_preprint":false},{"pmid":"32541687","id":"PMC_32541687","title":"microRNA-181c-5p promotes the formation of insulin-producing cells from human induced pluripotent stem cells by targeting smad7 and TGIF2.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32541687","citation_count":19,"is_preprint":false},{"pmid":"32495888","id":"PMC_32495888","title":"Sevoflurane impedes the progression of glioma through modulating the circular RNA has_circ_0012129/miR-761/TGIF2 axis.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32495888","citation_count":18,"is_preprint":false},{"pmid":"34741437","id":"PMC_34741437","title":"Circular RNA circCPA4 promotes tumorigenesis by regulating miR-214-3p/TGIF2 in lung cancer.","date":"2021","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34741437","citation_count":17,"is_preprint":false},{"pmid":"36417870","id":"PMC_36417870","title":"The oncogenic JAG1 intracellular domain is a transcriptional cofactor that acts in concert with DDX17/SMAD3/TGIF2.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36417870","citation_count":17,"is_preprint":false},{"pmid":"36740902","id":"PMC_36740902","title":"Hsa_circ_0063329 inhibits prostate cancer growth and metastasis by modulating the miR-605-5p/tgif2 axis.","date":"2023","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/36740902","citation_count":16,"is_preprint":false},{"pmid":"27956704","id":"PMC_27956704","title":"Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l.","date":"2017","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27956704","citation_count":13,"is_preprint":false},{"pmid":"36982885","id":"PMC_36982885","title":"MiR-424/TGIF2-Mediated Pro-Fibrogenic Responses in Oral Submucous Fibrosis.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36982885","citation_count":12,"is_preprint":false},{"pmid":"33275259","id":"PMC_33275259","title":"Sevoflurane induction alleviates the progression of gastric cancer by upregulating the miR-34a/TGIF2 axis.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33275259","citation_count":11,"is_preprint":false},{"pmid":"30584331","id":"PMC_30584331","title":"MALAT1 promotes proliferation, migration, and invasion of MG63 cells by upregulation of TGIF2 via negatively regulating miR-129.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30584331","citation_count":11,"is_preprint":false},{"pmid":"32572908","id":"PMC_32572908","title":"TGIF2 promotes cervical cancer metastasis by negatively regulating FCMR.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32572908","citation_count":10,"is_preprint":false},{"pmid":"35592894","id":"PMC_35592894","title":"Downregulation of TGIF2 is possibly correlated with neuronal apoptosis and autism-like symptoms in mice.","date":"2022","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/35592894","citation_count":10,"is_preprint":false},{"pmid":"36647029","id":"PMC_36647029","title":"Phosphorylation of TGIF2 represents a therapeutic target that drives EMT and metastasis of lung adenocarcinoma.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36647029","citation_count":9,"is_preprint":false},{"pmid":"34965271","id":"PMC_34965271","title":"HIV-1 Vpr protein upregulates microRNA-210-5p expression to induce G2 arrest by targeting TGIF2.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34965271","citation_count":9,"is_preprint":false},{"pmid":"27187787","id":"PMC_27187787","title":"Tgif1 and Tgif2 Regulate Axial Patterning in Mouse.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27187787","citation_count":8,"is_preprint":false},{"pmid":"39781447","id":"PMC_39781447","title":"Smad2 Cooperating with TGIF2 Contributes to EMT and Cancer Stem Cells Properties in Pancreatic Cancer via Co-Targeting SOX2.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39781447","citation_count":7,"is_preprint":false},{"pmid":"34187170","id":"PMC_34187170","title":"LncRNA X inactive-specific transcript promotes osteoclast differentiation through Tgif2 by acting as a ceRNA of miR-590-3p in a murine model.","date":"2021","source":"Regenerative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34187170","citation_count":7,"is_preprint":false},{"pmid":"34471941","id":"PMC_34471941","title":"Circular RNA circMMP1 Contributes to the Progression of Glioma Through Regulating TGIF2 Expression by Sponging miR-195-5p.","date":"2021","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34471941","citation_count":4,"is_preprint":false},{"pmid":"27639517","id":"PMC_27639517","title":"Role of transcription factor Tgif2 in photoreceptor differentiation in the mouse retina.","date":"2016","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/27639517","citation_count":3,"is_preprint":false},{"pmid":"40168772","id":"PMC_40168772","title":"FBLN2 inhibits gastric cancer proliferation and metastasis via the TGFβ/TGIF2 pathway.","date":"2025","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/40168772","citation_count":1,"is_preprint":false},{"pmid":"41716633","id":"PMC_41716633","title":"TGIF2-mediated HMGB3 overexpression promotes esophageal squamous cell carcinoma proliferation and metastasis through TLR3/TGF-β signaling.","date":"2025","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41716633","citation_count":0,"is_preprint":false},{"pmid":"39530347","id":"PMC_39530347","title":"RETRACTION: MiR-129-5p Inhibits Glioma Cell Progression In Vitro and In Vivo by Targeting TGIF2.","date":"2024","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39530347","citation_count":0,"is_preprint":false},{"pmid":"38983641","id":"PMC_38983641","title":"Retraction: MicroRNA-34a alleviates steroid-induced avascular necrosis of femoral head by targeting Tgif2 through OPG/RANK/RANKL signaling pathway.","date":"2024","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/38983641","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.13.635953","title":"TGIF2 is a major regulator of neural stem cell fate and neurogenic priming","date":"2025-02-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.13.635953","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22619,"output_tokens":4440,"usd":0.067228,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12425,"output_tokens":3887,"usd":0.07965,"stage2_stop_reason":"end_turn"},"total_usd":0.146878,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"TGIF2 recruits histone deacetylase 1 (HDAC1) to repress transcription. Unlike TGIF1, TGIF2 cannot interact with the corepressor CtBP. TGIF2 binds DNA via its homeodomain at TGIF binding sites and represses transcription. TGIF2 also interacts directly with TGFβ-activated Smads to repress TGFβ-responsive transcription.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays, DNA-binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and reporter assays, foundational study replicated in subsequent work, multiple orthogonal methods\",\n      \"pmids\": [\"11427533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TGIF2 protein contains a putative nuclear localization signal and translocates to the nucleus, as confirmed by transfection of epitope-tagged cDNA. TGIF2 is a TALE-superclass homeodomain protein.\",\n      \"method\": \"Subcellular localization by transfection and imaging of epitope-tagged protein\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with epitope tag, single lab, confirmed by nuclear localization signal analysis\",\n      \"pmids\": [\"11006116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TGIF2 interacts with the transcriptional corepressor mSin3, providing an additional repression mechanism. Both full-length and a shorter splice variant (lacking 39 amino acids) of mouse Tgif2 are functional transcriptional repressors that can repress TGFβ-dependent and -independent transcription. The Tgif2 gene contains a retained intron within its coding sequence.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays, RT-PCR splice variant analysis\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and reporter assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16436215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Tgif1 and Tgif2 together are required for gastrulation; double-null mouse embryos fail to gastrulate. Genetic reduction of Nodal dosage partially rescues the gastrulation and left-right asymmetry defects in embryos lacking all Tgif function, establishing that Tgifs limit the transcriptional response to Nodal/TGFβ signaling during early embryogenesis. Extra-embryonic Tgif function (single wild-type allele of Tgif1 in extra-embryonic tissue) is sufficient to allow gastrulation.\",\n      \"method\": \"Conditional knockout mouse genetics, genetic epistasis (Nodal dosage reduction), embryo phenotype analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with conditional knockouts and Nodal dosage rescue, multiple allele combinations tested\",\n      \"pmids\": [\"20040491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of both Tgif1 and Tgif2 in mice results in holoprosencephaly and defects in left-right asymmetry. The combination of Tgif1 and Tgif2 mutations increases severity and penetrance of posterior axial transformation phenotype. Tgif1/Tgif2 regulate axial patterning and Hoxc6 expression, and reduced TGIF function sensitizes embryos to retinoic acid effects.\",\n      \"method\": \"Mouse knockout genetics, embryo phenotypic analysis, gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function with defined phenotype and gene expression readout, single lab\",\n      \"pmids\": [\"27187787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TGIF1 directly binds to a conserved consensus TGIF site 5' of the Evi5l gene and represses its expression. Loss of both Tgif1 and Tgif2 increases Evi5l (a RabGAP) expression, which reduces primary cilia number. Reducing Evi5l expression in double-null MEFs partially restores cilium numbers and Shh pathway transcriptional response, placing Tgif1/2 upstream of Evi5l in ciliogenesis regulation.\",\n      \"method\": \"Chromatin immunoprecipitation, transcriptome profiling, shRNA knockdown, primary MEF analysis, Shh pathway reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, transcriptomics, genetic epistasis (Evi5l rescue), and functional cilia readout; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"27956704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TGIF2 acts as a developmental regulator sufficient to drive liver-to-pancreas fate conversion. Expression of Tgif2 in hepatocytes causes transcriptional remodelling that represses hepatic identity and induces a pancreatic progenitor-like phenotype both ex vivo and in vivo in adult mouse hepatocytes.\",\n      \"method\": \"Forced expression in hepatocytes (ex vivo and in vivo mouse), transcriptome profiling, lineage marker analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo and ex vivo forced expression with transcriptome readout, multiple orthogonal methods confirming fate conversion\",\n      \"pmids\": [\"28193997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EGFR/RAS/ERK signaling phosphorylates TGIF2 and increases its protein stability. Phosphorylation of TGIF2 is required for its pro-stemness functions in lung adenocarcinoma, as phosphorylation-deficient TGIF2 mutants lose these activities. TGIF2 binds the OCT4 promoter and promotes OCT4 expression.\",\n      \"method\": \"Phosphorylation-deficient mutant analysis, ChIP assay, xenograft mouse models, in vitro cell biology assays\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phosphorylation sites, ChIP, in vivo xenograft, single lab\",\n      \"pmids\": [\"31871777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nuclear PKM2 promotes post-translational degradation of TGIF2 protein via the ubiquitin-proteasome system during EMT in oral squamous cell carcinoma cells. TGIF2 protein and mRNA expression were discordant in EMT-induced cells, and proteasome inhibition with MG132 blocked TGIF2 protein loss.\",\n      \"method\": \"Western blot mRNA/protein discordance analysis, proteasome inhibitor (MG132) rescue assay, PKM2 knockdown\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proteasome inhibitor rescue and PKM2 knockdown, single lab, two supporting methods but limited mechanistic depth\",\n      \"pmids\": [\"30333907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TGIF2 represses Smad pathway activity, and its restoration in miR-181a-overexpressing prostate cancer cells inhibits Smad2/3 phosphorylation, nuclear localization of Smad2/3, and EMT processes, confirming TGIF2 functions as a repressor of the Smad pathway in this context.\",\n      \"method\": \"TGIF2 overexpression rescue, Smad2/3 nuclear localization immunostaining, Western blot for EMT markers\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, rescue experiment with Western blot and immunostaining, limited mechanistic depth\",\n      \"pmids\": [\"29164579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TGIF2 forms a transcriptional complex with DDX17, SMAD3, and the JAG1 intracellular domain (JICD1) to increase SOX2 expression, driving oncogenic transformation and stemness in astrocytes. This was identified by proteomics, ChIP-seq, and transcriptome analysis.\",\n      \"method\": \"Co-immunoprecipitation/proteomics, ChIP-seq, transcriptome profiling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics, ChIP-seq, and transcriptome used together; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36417870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Phosphorylation of TGIF2 by EGFR/ERK signaling is required to recruit HDAC1 to the E-cadherin promoter, suppressing E-cadherin transcription and promoting EMT. Phosphorylation-deficient TGIF2 mutants fail to recruit HDAC1 and cannot promote migration/EMT. HDAC1 inhibition blocks TGIF2 phosphorylation-induced EMT.\",\n      \"method\": \"Co-immunoprecipitation, dual-luciferase reporter assay, ChIP assay, phosphorylation-deficient mutant analysis, xenograft mouse models\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, luciferase reporter, and mutagenesis in single lab with in vivo validation\",\n      \"pmids\": [\"36647029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TGIF2 directly binds to the FCMR gene promoter and represses FCMR expression, thereby promoting cervical cancer cell proliferation and metastasis. This was confirmed by luciferase assay, and rescue experiments showed simultaneous FCMR knockdown partially reversed the inhibition caused by TGIF2 knockdown.\",\n      \"method\": \"Luciferase reporter assay, ChIP (implied by promoter binding), shRNA knockdown, rescue experiments, xenograft mouse model\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase assay for promoter binding, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"32572908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LSD1 histone demethylase binds the TGIF2 promoter and is associated with reduced H3K4me1 monomethylation at the TGIF2 locus, potentially mediating TGIF2 downregulation. Adenovirus-mediated TGIF2 overexpression activated the Wnt/β-catenin signaling pathway in mouse hippocampal neurons and suppressed neuronal apoptosis.\",\n      \"method\": \"ChIP-qPCR, adenovirus-mediated overexpression, gene set enrichment analysis, ENCODE database validation\",\n      \"journal\": \"Brain and behavior\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP-qPCR and overexpression, single lab, pathway activation inferred from downstream marker analysis\",\n      \"pmids\": [\"35592894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tgif2 participates in photoreceptor cell fate determination in the early mouse retina: knockdown decreases rod photoreceptors and increases cones in retinal explants, while overexpression (conditional knock-in) causes abnormal cone nuclear localization in the outer nuclear layer without affecting cone function.\",\n      \"method\": \"shRNA knockdown in retinal explants, conditional knock-in mouse model, electroretinography, histological analysis\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function in vivo with defined cellular phenotype, single lab\",\n      \"pmids\": [\"27639517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGIF2 controls neural stem cell (NSC) fate maintenance by interacting with the SIN3A/HDAC repressor complex to suppress neuronal differentiation genes. TGIF2 is identified as the major regulator of neurogenic priming in cortical NSCs, restraining neuronal differentiation gene activation. This was demonstrated by in vitro and in vivo experiments in the mouse cerebral cortex.\",\n      \"method\": \"RNA-seq, ATAC-seq, Co-immunoprecipitation with SIN3A/HDAC complex, in vitro and in vivo overexpression/knockdown experiments in mouse NSCs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiomics (RNA-seq, ATAC-seq) plus Co-IP with repressor complex and in vivo validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.02.13.635953\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGIF2 transcriptionally upregulates HMGB3 expression in esophageal squamous cell carcinoma, as demonstrated by luciferase reporter and ChIP assays. HMGB3 then activates TGF-β signaling through interaction with TLR3, promoting proliferation and metastasis.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, Co-immunoprecipitation, RNA sequencing\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter and ChIP for direct transcriptional regulation, Co-IP for protein interactions, single lab\",\n      \"pmids\": [\"41716633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Smad2 cooperates with TGIF2 to co-regulate the SOX2 promoter in pancreatic cancer. TGIF2 promotes SOX2, Slug, CD44, and EGFR/MAPK signaling, and SOX2-driven transactivation of EGFR/MAPK promotes TGIF2 nuclear translocation, forming a positive feedback loop. TGIF2 nuclear translocation was demonstrated in vitro.\",\n      \"method\": \"ChIP assay (SOX2 promoter co-occupancy), Co-immunoprecipitation, subcellular fractionation/localization, in vivo xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP for complex formation at SOX2 promoter, feedback loop validated in vitro, single lab\",\n      \"pmids\": [\"39781447\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TGIF2 is a TALE-superclass homeodomain transcriptional repressor that recruits HDAC1 and mSin3 (but not CtBP) to repress both TGFβ/Nodal-Smad-dependent and DNA-bound target gene transcription; its repressive activity is regulated by EGFR/ERK-mediated phosphorylation, which stabilizes TGIF2 and enables HDAC1 recruitment to specific promoters (e.g., E-cadherin), while it also forms transcriptional complexes with partners such as SMAD3, DDX17, and SIN3A/HDAC to control cell fate decisions in development (gastrulation, neurogenesis, pancreas vs. liver identity, retinal photoreceptor fate) and cancer progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TGIF2 is a TALE-superclass homeodomain transcriptional repressor that limits TGF\\u03b2/Nodal signaling and shapes cell-fate decisions across development and cancer [#0, #3]. It binds DNA at TGIF consensus sites through its homeodomain and represses target transcription, and it independently binds TGF\\u03b2-activated Smads to dampen Smad-dependent transcription; repression is executed by recruitment of HDAC1 and the mSin3 corepressor, but, unlike TGIF1, TGIF2 does not engage CtBP [#0, #2]. In vivo, Tgif1 and Tgif2 act redundantly to restrain the transcriptional response to Nodal during gastrulation and left-right patterning \\u2014 double-null embryos fail to gastrulate and develop holoprosencephaly, and Nodal dosage reduction rescues these defects \\u2014 and they also repress the RabGAP Evi5l to permit ciliogenesis and Shh signaling [#3, #4, #5]. As a fate determinant, TGIF2 is sufficient to convert hepatocytes toward a pancreatic progenitor identity, governs rod-versus-cone photoreceptor specification, and maintains neural stem cell identity by partnering with the SIN3A/HDAC complex to suppress neuronal differentiation genes [#6, #14, #15]. In cancer, TGIF2 activity is gated post-translationally: EGFR/RAS/ERK signaling phosphorylates and stabilizes TGIF2, enabling HDAC1 recruitment to the E-cadherin promoter to drive EMT and promoting OCT4 expression and stemness, while nuclear PKM2 routes TGIF2 to ubiquitin-proteasome degradation [#7, #8, #11]. Beyond repression, TGIF2 also acts within transcriptional complexes with SMAD3, DDX17, and the JAG1 intracellular domain, and cooperates with Smad2, to activate SOX2 and drive oncogenic stemness in glioma and pancreatic cancer [#10, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that TGIF2 is a nuclear TALE-homeodomain protein defined where it acts and assigned it to a transcription-factor class.\",\n      \"evidence\": \"Subcellular localization of epitope-tagged TGIF2 and NLS analysis\",\n      \"pmids\": [\"11006116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No DNA target or interacting partner defined\", \"Single-lab localization without endogenous protein\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defining TGIF2's core repressive mechanism showed it works both by direct DNA binding and by binding activated Smads, recruiting HDAC1 but not CtBP \\u2014 distinguishing it from TGIF1.\",\n      \"evidence\": \"Co-IP, DNA-binding assays, and reporter assays\",\n      \"pmids\": [\"11427533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous target genes not identified\", \"Structural basis of Smad interaction unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying mSin3 as an additional corepressor and characterizing functional splice variants broadened the repression machinery and showed both isoforms repress TGF\\u03b2-dependent and -independent transcription.\",\n      \"evidence\": \"Co-IP, reporter assays, RT-PCR splice variant analysis\",\n      \"pmids\": [\"16436215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter-specific targeting of mSin3 vs HDAC1 not resolved\", \"Functional difference between isoforms unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic epistasis established the in vivo purpose of TGIF function: Tgif1/Tgif2 together limit Nodal/TGF\\u03b2 signaling required for gastrulation and left-right asymmetry.\",\n      \"evidence\": \"Conditional knockout mouse genetics with Nodal dosage rescue\",\n      \"pmids\": [\"20040491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes mediating the Nodal restraint not defined\", \"Tissue-specific contribution of TGIF2 vs TGIF1 not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Loss-of-function studies extended TGIF roles to axial patterning/holoprosencephaly and to photoreceptor fate, showing context-dependent developmental functions.\",\n      \"evidence\": \"Mouse knockouts, retinal explant knockdown, and conditional knock-in with gene expression analysis\",\n      \"pmids\": [\"27187787\", \"27639517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets in retina and axial tissue not fully mapped\", \"Mechanism of rod/cone choice unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Three studies established TGIF as an instructive fate regulator: it represses Evi5l to enable ciliogenesis/Shh signaling, and forced TGIF2 reprograms hepatocytes toward pancreatic identity, while a Smad-repressor role was reaffirmed in prostate cancer.\",\n      \"evidence\": \"ChIP, transcriptomics, Evi5l rescue, forced hepatocyte expression in vivo, and miR-181a/TGIF2 rescue with Smad2/3 readout\",\n      \"pmids\": [\"27956704\", \"28193997\", \"29164579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TGIF2 reorganizes chromatin during lineage conversion unknown\", \"Prostate cancer Smad-repression evidence is low-confidence and lacks direct target genes\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that nuclear PKM2 drives proteasomal degradation of TGIF2 during EMT revealed post-translational control of TGIF2 abundance.\",\n      \"evidence\": \"mRNA/protein discordance, MG132 rescue, and PKM2 knockdown\",\n      \"pmids\": [\"30333907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating TGIF2 ubiquitination not identified\", \"Whether PKM2 acts directly on TGIF2 unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking EGFR/RAS/ERK phosphorylation to TGIF2 stability and OCT4 activation showed signaling-dependent activation of pro-stemness TGIF2 function.\",\n      \"evidence\": \"Phospho-deficient mutants, ChIP, and xenografts in lung adenocarcinoma\",\n      \"pmids\": [\"31871777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphosites and responsible kinase not fully defined\", \"How phosphorylation switches TGIF2 from repressor to OCT4 activator unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that TGIF2 assembles activating complexes (with DDX17, SMAD3, JICD1) at SOX2 reframed it as also a transcriptional activator in oncogenic stemness.\",\n      \"evidence\": \"Proteomics/Co-IP, ChIP-seq, transcriptome profiling in astrocytes; plus LSD1-mediated TGIF2 promoter regulation in neurons\",\n      \"pmids\": [\"36417870\", \"35592894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What determines repressor vs activator behavior of TGIF2 not defined\", \"Neuronal Wnt/\\u03b2-catenin link is low-confidence and indirect\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mechanistic dissection showed ERK phosphorylation of TGIF2 is required to recruit HDAC1 to the E-cadherin promoter, directly coupling signaling, corepressor recruitment, and EMT.\",\n      \"evidence\": \"Co-IP, ChIP, luciferase, phospho-deficient mutants, and xenografts\",\n      \"pmids\": [\"36647029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability of phospho-dependent HDAC1 recruitment to other promoters untested\", \"Phosphosite identity not pinpointed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Recent work consolidated dual context-dependent roles: SIN3A/HDAC-dependent maintenance of neural stem cell identity, and Smad2/SOX2 feedback plus HMGB3 upregulation driving cancer progression.\",\n      \"evidence\": \"RNA-seq/ATAC-seq and Co-IP in NSCs (preprint); ChIP, Co-IP, subcellular fractionation in pancreatic and esophageal cancer\",\n      \"pmids\": [\"bio_10.1101_2025.02.13.635953\", \"39781447\", \"41716633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NSC findings remain a preprint awaiting peer review\", \"Determinants of TGIF2 nuclear translocation in the SOX2 feedback loop not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What molecular switch toggles TGIF2 between HDAC1/SIN3A-mediated repression and SMAD3/DDX17/SOX2-mediated activation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TGIF2-corepressor vs TGIF2-coactivator complexes\", \"Specific phosphosites and kinases controlling the switch not mapped\", \"Genome-wide direct target catalog incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 6, 7, 10, 11, 16, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 5, 7, 11, 12, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 9, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 10, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4, 6, 14, 15]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 2, 11, 15]}\n    ],\n    \"complexes\": [\"SIN3A/HDAC complex\", \"TGIF2-DDX17-SMAD3-JICD1 complex\"],\n    \"partners\": [\"HDAC1\", \"SIN3A\", \"SMAD3\", \"SMAD2\", \"DDX17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}