{"gene":"TLE4","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1992,"finding":"Human TLE proteins (including TLE4) were identified as nuclear proteins homologous to Drosophila Groucho/E(spl) m9/10, establishing TLE4 as a member of a conserved family of nuclear corepressors differentially expressed in human tissues.","method":"cDNA cloning, sequence homology analysis, nuclear localization by immunostaining","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 — original identification with subcellular localization data; single lab, foundational characterization","pmids":["1303260"],"is_preprint":false},{"year":2001,"finding":"All mammalian Groucho/TLE family members (including TLE4/Grg4) physically interact with TCF/LEF transcription factors and repress TCF-mediated transcriptional activation; long TLE proteins (including TLE4) interact with histone deacetylase HDAC1 to mediate repression, whereas the short family member Grg5 acts as a de-repressor by failing to recruit HDAC.","method":"Co-immunoprecipitation, reporter/luciferase transcriptional assays, HDAC binding assays in cell lines","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction assays with multiple TCF/TLE combinations, HDAC recruitment demonstrated, replicated across family members","pmids":["11266540"],"is_preprint":false},{"year":2000,"finding":"Pax5 (BSAP) recruits Grg4 (TLE4 ortholog) as a transcriptional corepressor via two separate interaction domains: the N-terminal Q and central SP regions of Grg4, and the octapeptide motif and C-terminal transactivation domain of Pax5; this interaction represses Pax5 target genes and alters the phosphorylation state of Grg4 in vivo.","method":"Yeast two-hybrid screen, co-immunoprecipitation, transcriptional reporter assays, in vivo phosphorylation analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid plus reciprocal Co-IP plus functional reporter assays, domain mapping performed","pmids":["10811620"],"is_preprint":false},{"year":2004,"finding":"Grg4 (TLE4 ortholog) is co-recruited by PU.1 in B-lineage cells; PU.1 physically interacts with Grg4 and, in conjunction with Pax5, represses IgH enhancer activity in a position-dependent manner; Grg4 protein levels decrease following B-cell activation, suggesting temporal regulation of this corepressor.","method":"Co-immunoprecipitation, luciferase reporter assays, western blotting for Grg4 levels in activated B cells","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and functional reporter data in B cells; single lab with multiple methods","pmids":["14993928"],"is_preprint":false},{"year":2006,"finding":"FoxD3 physically interacts with Grg4 (TLE4 ortholog) via an eh1/GEH Groucho-interaction motif in its C-terminal domain; this interaction is required for FoxD3-mediated transcriptional repression and mesoderm induction in Xenopus. Deletion or point mutagenesis of the eh1 motif abolishes both Grg4 binding and FoxD3 repression activity; the dominant-inhibitory Grg5 antagonizes this function.","method":"Co-immunoprecipitation, deletion/point mutagenesis, transcriptional reporter assays, Xenopus embryo injection with rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted interaction with mutagenesis, in vivo epistasis in Xenopus, multiple orthogonal methods","pmids":["17138566"],"is_preprint":false},{"year":2009,"finding":"The homeodomain protein Cux1 directly interacts with Grg4 (TLE4 ortholog) in developing kidney; Grg4 enhances Cux1-mediated repression of the p27kip1 promoter. ChIP assays demonstrated that Cux1, Grg4, HDAC1, and HDAC3 are co-recruited to two separate sites in the p27kip1 promoter in vivo in neonatal kidney tissue.","method":"Co-immunoprecipitation, luciferase reporter assay, chromatin immunoprecipitation (ChIP), DNase I footprinting","journal":"Gene","confidence":"High","confidence_rationale":"Tier 2 — ChIP in vivo plus Co-IP plus functional reporter with multiple orthogonal methods","pmids":["19332113"],"is_preprint":false},{"year":2012,"finding":"SUMOylation of SoxE transcription factors promotes their recruitment of Grg4 (TLE4 ortholog) as a corepressor while displacing coactivators CBP/p300; this SUMO-dependent switch converts SoxE from a transcriptional activator to a repressor in Xenopus neural crest development, demonstrating that TLE4/Grg4 recruitment is regulated by post-translational modification of its binding partner.","method":"Co-immunoprecipitation, SUMO modification assays, transcriptional reporter assays in Xenopus embryos","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — Co-IP combined with in vivo functional data and mechanistic switch demonstrated with mutagenesis of SUMOylation sites","pmids":["22927467"],"is_preprint":false},{"year":2000,"finding":"Chick Grg4 (TLE4 ortholog) functions as a transcriptional repressor that antagonizes tectum-organizing activity in the mesencephalon; Grg4 overexpression by in ovo electroporation repressed En-2, Pax5, Fgf8, and EphrinA2 expression while upregulating Pax6, and co-transfection with Pax5 canceled tectum-inducing activity of Pax5. The N-terminal domain of Grg4 acted as a dominant negative and induced En-2 expression, confirming nuclear repressive function.","method":"In ovo electroporation (gain- and dominant-negative loss-of-function), immunostaining, in situ hybridization","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gain/loss-of-function with specific molecular readouts; single lab","pmids":["10772799"],"is_preprint":false},{"year":2003,"finding":"Grg4 (TLE4 ortholog) directs tectal postmitotic cell migration to specific laminae in the chick optic tectum; clonal misexpression of Grg4 caused cells to migrate to laminae h–j of the SGFS, whereas morpholino knockdown or dominant-negative Grg4 produced the opposite effect, demonstrating a direct role in controlling neuronal migration and laminar positioning.","method":"Clonal electroporation overexpression, morpholino antisense knockdown, dominant-negative overexpression, histological analysis of laminar position","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain and loss-of-function with specific cellular phenotype; single lab","pmids":["12490552"],"is_preprint":false},{"year":2014,"finding":"PAX2 mutations associated with adult-onset FSGS alter PAX2 interaction with repressor proteins (including Grg/TLE family members), resulting in enhanced repressor activity; in vitro functional studies showed that specific PAX2 FSGS-associated mutations perturb interaction with TLE corepressors.","method":"In vitro interaction/functional assays, in silico structural modeling, transactivation assays","journal":"Journal of the American Society of Nephrology","confidence":"Low","confidence_rationale":"Tier 3 — functional assays implicate TLE corepressor interaction but TLE4 specifically not distinguished from other family members","pmids":["24676634"],"is_preprint":false},{"year":2015,"finding":"Large-scale affinity-purification mass spectrometry (BioPlex) identified TLE4 as part of protein interaction communities in HEK293T cells, placing TLE4 within defined protein complexes in the human interactome.","method":"Affinity purification mass spectrometry (AP-MS) at proteome scale","journal":"Cell","confidence":"Low","confidence_rationale":"Tier 3 — large-scale AP-MS; TLE4 interactions detected but not individually validated","pmids":["26186194"],"is_preprint":false},{"year":2004,"finding":"Large-scale phosphoproteomic analysis of HeLa cell nuclear proteins identified phosphorylation sites on TLE4, indicating that TLE4 undergoes nuclear phosphorylation in human cells.","method":"Strong cation exchange chromatography enrichment of phosphopeptides, tandem MS","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 — mass spectrometry detection of phosphosites; no writer/eraser/reader identified for TLE4 specifically","pmids":["15302935"],"is_preprint":false}],"current_model":"TLE4 (and its vertebrate orthologs Grg4) functions as a nuclear transcriptional corepressor that is recruited to target gene promoters by diverse DNA-binding transcription factors (including TCF/LEF, Pax5, PU.1, FoxD3, Cux1, and SoxE proteins) via conserved interaction motifs (eh1/GEH, octapeptide), and mediates repression through recruitment of histone deacetylases (HDAC1/3); its corepressor activity can be regulated by post-translational modifications of its binding partners (e.g., SUMOylation switches SoxE from activator to TLE4-recruiting repressor), and it plays defined roles in neuronal migration, laminar positioning in the tectum, B-cell gene regulation, kidney development, and mesoderm induction."},"narrative":{"teleology":[{"year":1992,"claim":"Identification of TLE4 as a nuclear protein homologous to Drosophila Groucho established it as a member of a conserved family of candidate transcriptional regulators, opening the question of what transcription factors recruit it and how it mediates repression.","evidence":"cDNA cloning, sequence homology, and immunostaining for nuclear localization in human tissues","pmids":["1303260"],"confidence":"Medium","gaps":["No transcription factor partners or repression mechanism identified at this stage","Expression data descriptive, no functional assay performed"]},{"year":2000,"claim":"Demonstration that Pax5 recruits TLE4/Grg4 via its octapeptide motif and that TLE4 represses Pax5 target genes answered the question of how a sequence-specific transcription factor physically engages a Groucho-family corepressor, defining the domain architecture underlying this interaction.","evidence":"Yeast two-hybrid, reciprocal Co-IP, transcriptional reporter assays, domain mapping, and in vivo phosphorylation analysis","pmids":["10811620"],"confidence":"High","gaps":["Chromatin-level mechanism of repression not yet defined","Whether HDAC recruitment is involved was untested at this point"]},{"year":2000,"claim":"In vivo overexpression and dominant-negative studies in chick tectum showed that TLE4/Grg4 antagonizes tectum-organizer gene expression (En-2, Pax5, Fgf8), establishing TLE4 as a functionally important repressor in neural patterning.","evidence":"In ovo electroporation gain- and dominant-negative loss-of-function with in situ hybridization readouts in chick embryos","pmids":["10772799"],"confidence":"Medium","gaps":["Direct transcriptional targets versus indirect effects not distinguished","Single model organism"]},{"year":2001,"claim":"Showing that all long TLE proteins including TLE4 physically interact with TCF/LEF factors and recruit HDAC1 to mediate repression resolved how Groucho-family corepressors mechanistically silence Wnt target genes, distinguishing full-length TLEs from the short de-repressor Grg5.","evidence":"Co-immunoprecipitation and luciferase reporter assays testing multiple TCF/TLE combinations with HDAC binding assays","pmids":["11266540"],"confidence":"High","gaps":["Whether HDAC catalytic activity is strictly required for repression not tested with deacetylase-dead mutants","Genomic targets of TCF/TLE4 complexes not mapped"]},{"year":2003,"claim":"Reciprocal gain- and loss-of-function experiments revealed that TLE4/Grg4 directly controls postmitotic neuronal migration and laminar positioning in the optic tectum, extending its role beyond transcriptional target gene regulation to cellular migratory behavior.","evidence":"Clonal electroporation, morpholino knockdown, and dominant-negative overexpression in chick tectum with histological laminar analysis","pmids":["12490552"],"confidence":"Medium","gaps":["Downstream transcriptional targets mediating migration not identified","Mechanism linking repression to cell migration unknown"]},{"year":2004,"claim":"Co-recruitment of TLE4/Grg4 by PU.1 together with Pax5 at the IgH enhancer, and the observation that Grg4 protein decreases upon B-cell activation, revealed temporal regulation of TLE4 corepressor availability as a mechanism for controlling B-lineage gene expression.","evidence":"Co-immunoprecipitation, luciferase reporter assays, and western blotting in B-cell lines before and after activation","pmids":["14993928"],"confidence":"Medium","gaps":["Mechanism of Grg4 protein downregulation (proteasomal, transcriptional) not defined","Genome-wide B-cell targets of PU.1/TLE4 complex unknown"]},{"year":2006,"claim":"Mutagenesis of the FoxD3 eh1/GEH motif abolished both TLE4/Grg4 binding and FoxD3-mediated repression and mesoderm induction, providing the first direct evidence that a single short motif is necessary and sufficient for Groucho recruitment and in vivo developmental function.","evidence":"Co-IP with point mutants, transcriptional reporter assays, and Xenopus embryo injection with rescue experiments","pmids":["17138566"],"confidence":"High","gaps":["Structural basis of eh1–TLE4 interaction not resolved at atomic level","Whether all eh1-containing factors use identical TLE4 surfaces is unknown"]},{"year":2009,"claim":"ChIP demonstration that Cux1, TLE4/Grg4, HDAC1, and HDAC3 co-occupy two sites on the p27kip1 promoter in neonatal kidney established that TLE4 functions as a chromatin-associated corepressor complex with multiple HDACs at an endogenous locus relevant to kidney development.","evidence":"Chromatin immunoprecipitation in neonatal mouse kidney, Co-IP, luciferase reporter, DNase I footprinting","pmids":["19332113"],"confidence":"High","gaps":["Whether HDAC1 and HDAC3 have redundant or distinct roles in this complex untested","Genome-wide binding profile of TLE4 in kidney not available"]},{"year":2012,"claim":"Discovering that SUMOylation of SoxE factors switches them from CBP/p300-associated activators to TLE4/Grg4-recruiting repressors resolved how a single transcription factor toggles between activation and repression, revealing post-translational modification of the partner as a regulatory input for TLE4 recruitment.","evidence":"Co-IP, SUMO modification assays, and functional reporter assays in Xenopus embryos with SUMOylation-site mutants","pmids":["22927467"],"confidence":"High","gaps":["Whether other TLE4-interacting factors are similarly regulated by SUMOylation is untested","Structural basis for SUMO-dependent differential binding not determined"]},{"year":null,"claim":"Major unresolved questions include the genome-wide binding landscape of TLE4 in any mammalian cell type, the structural basis of TLE4's WD40 and Q-domain interactions with diverse transcription factors, and whether TLE4 has non-redundant functions distinct from other long TLE family members in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide ChIP-seq or CUT&RUN map for TLE4 reported","No crystal or cryo-EM structure of TLE4 in complex with a transcription factor","Genetic knockout studies distinguishing TLE4 from TLE1/2/3 in mammals are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,4,5,6,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,5]}],"pathway":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,4,5,6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6]}],"complexes":[],"partners":["TCF7L2","PAX5","SPI1","FOXD3","CUX1","HDAC1","HDAC3"],"other_free_text":[]},"mechanistic_narrative":"TLE4 is a nuclear transcriptional corepressor of the Groucho/TLE family that is recruited to target gene promoters by diverse DNA-binding transcription factors—including TCF/LEF, Pax5, PU.1, FoxD3, Cux1, and SoxE proteins—through conserved interaction motifs such as the eh1/GEH and octapeptide domains [PMID:10811620, PMID:17138566, PMID:11266540]. TLE4 mediates transcriptional repression by recruiting histone deacetylases HDAC1 and HDAC3 to target promoters, as demonstrated at the p27kip1 locus in developing kidney [PMID:11266540, PMID:19332113]. The corepressor activity of TLE4 is regulated by post-translational modifications of its binding partners, exemplified by SUMOylation of SoxE factors that switches them from activators to TLE4-recruiting repressors [PMID:22927467]. In vivo, TLE4 controls tectal patterning, neuronal laminar migration, B-cell gene regulation, and mesoderm induction [PMID:10772799, PMID:12490552, PMID:14993928, PMID:17138566]."},"prefetch_data":{"uniprot":{"accession":"Q04727","full_name":"Transducin-like enhancer protein 4","aliases":["Grg-4","Groucho-related protein 4"],"length_aa":773,"mass_kda":83.8,"function":"Transcriptional corepressor that binds to a number of transcription factors. Inhibits the transcriptional activation mediated by PAX5, and by CTNNB1 and TCF family members in Wnt signaling. The effects of full-length TLE family members may be modulated by association with dominant-negative AES. Essential for the transcriptional repressor activity of SIX3 during retina and lens development and for SIX3 transcriptional auto-repression (By similarity). Involved in transcriptional repression of GNRHR and enhances MSX1-mediated transcriptional repression of CGA/alpha-GSU (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q04727/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TLE4","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TLE4","total_profiled":1310},"omim":[{"mim_id":"617045","title":"ZINC FINGER PROTEIN 703; ZNF703","url":"https://www.omim.org/entry/617045"},{"mim_id":"605132","title":"TLE FAMILY MEMBER 4, TRANSCRIPTIONAL COREPRESSOR; TLE4","url":"https://www.omim.org/entry/605132"},{"mim_id":"167409","title":"PAIRED BOX GENE 2; PAX2","url":"https://www.omim.org/entry/167409"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":94.4}],"url":"https://www.proteinatlas.org/search/TLE4"},"hgnc":{"alias_symbol":["E(spl)","ESG","GRG4"],"prev_symbol":[]},"alphafold":{"accession":"Q04727","domains":[{"cath_id":"2.130.10.10","chopping":"448-480_664-745","consensus_level":"medium","plddt":95.9607,"start":448,"end":745},{"cath_id":"2.130.10.10","chopping":"481-663_746-773","consensus_level":"medium","plddt":96.2401,"start":481,"end":773}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04727","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q04727-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q04727-F1-predicted_aligned_error_v6.png","plddt_mean":68.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TLE4","jax_strain_url":"https://www.jax.org/strain/search?query=TLE4"},"sequence":{"accession":"Q04727","fasta_url":"https://rest.uniprot.org/uniprotkb/Q04727.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q04727/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04727"}},"corpus_meta":[{"pmid":"28988769","id":"PMC_28988769","title":"Comprehensive 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genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33361760","id":"PMC_33361760","title":"CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1.","date":"2020","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33361760","citation_count":366,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11266540","id":"PMC_11266540","title":"All Tcf HMG box transcription factors interact with Groucho-related co-repressors.","date":"2001","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/11266540","citation_count":310,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1303260","id":"PMC_1303260","title":"Human homologs of a Drosophila Enhancer of split gene product define a novel family of nuclear proteins.","date":"1992","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1303260","citation_count":286,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10811620","id":"PMC_10811620","title":"Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10811620","citation_count":211,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24823311","id":"PMC_24823311","title":"Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium.","date":"2014","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24823311","citation_count":175,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15105370","id":"PMC_15105370","title":"Otx2 regulates the extent, identity and fate of neuronal progenitor domains in the ventral midbrain.","date":"2004","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15105370","citation_count":174,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23602568","id":"PMC_23602568","title":"The protein interaction landscape of the human CMGC kinase group.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23602568","citation_count":174,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20889853","id":"PMC_20889853","title":"Genetic risk reclassification for type 2 diabetes by age below or above 50 years using 40 type 2 diabetes risk single nucleotide polymorphisms.","date":"2010","source":"Diabetes care","url":"https://pubmed.ncbi.nlm.nih.gov/20889853","citation_count":129,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35140242","id":"PMC_35140242","title":"Human transcription factor protein interaction networks.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35140242","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25609649","id":"PMC_25609649","title":"Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.","date":"2015","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/25609649","citation_count":120,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19714205","id":"PMC_19714205","title":"Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in mexican children.","date":"2009","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19714205","citation_count":119,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21630459","id":"PMC_21630459","title":"Proteomic characterization of the human sperm nucleus.","date":"2011","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/21630459","citation_count":116,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10574462","id":"PMC_10574462","title":"Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.","date":"1999","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/10574462","citation_count":111,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20816195","id":"PMC_20816195","title":"Analyses of shared genetic factors between asthma and obesity in children.","date":"2010","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20816195","citation_count":111,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24676634","id":"PMC_24676634","title":"Mutations in PAX2 associate with adult-onset FSGS.","date":"2014","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/24676634","citation_count":94,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22990118","id":"PMC_22990118","title":"Charting the landscape of tandem BRCT domain-mediated protein interactions.","date":"2012","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/22990118","citation_count":92,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15164053","id":"PMC_15164053","title":"DNA sequence and analysis of human chromosome 9.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15164053","citation_count":86,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25959826","id":"PMC_25959826","title":"Quantitative interaction proteomics of neurodegenerative disease proteins.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25959826","citation_count":86,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45457,"output_tokens":2547,"usd":0.087288},"stage2":{"model":"claude-opus-4-6","input_tokens":5411,"output_tokens":2497,"usd":0.13422},"total_usd":0.580817,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58674,"output_tokens":3950,"usd":0.117636},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6513,"output_tokens":5142,"usd":0.241673}},"stage1_raw":"Looking at these 100 papers, I need to identify which ones are actually about TLE4 (Transducin-Like Enhancer of split 4), a mammalian Groucho-family transcriptional corepressor.\n\nTLE4 is a mammalian/vertebrate Groucho-related gene (Grg4). The vast majority of papers in this corpus are about Drosophila E(spl) genes or unrelated genes. I need to find papers specifically about Grg4/TLE4 function.\n\nRelevant papers:\n- PMID 17138566 (Yaklichkin 2006): FoxD3 and Grg4 physical interaction in Xenopus\n- PMID 14993928 (Linderson 2004): PU.1/Pax5 recruit Grg4 in B cells\n- PMID 22927467 (Lee 2012): SUMOylated SoxE recruit Grg4 in neural crest\n- PMID 8892234 (Koop 1996): Grg4 expression pattern in mouse\n- PMID 10772799 (Sugiyama 2000): Chick Grg4 antagonizes tectum-organizing activity\n- PMID 12490552 (Sugiyama 2003): Grg4 role in tectal laminar formation\n- PMID 19332113 (Sharma 2009): Cux1 interacts with Grg4 to repress p27kip1\n- PMID 11486045 (Iso 2001): HERP recruits mSin3/HDAC via bHLH; TLE/Groucho recruited by HES via WRPW\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"FoxD3 physically interacts with Grg4 (TLE4) via a C-terminal eh1/GEH Groucho-interaction motif, and this interaction is required for FoxD3-mediated transcriptional repression and mesoderm induction in Xenopus; Grg4 enhances FoxD3 repression activity, while dominant-inhibitory Grg5 reduces it.\",\n      \"method\": \"Co-immunoprecipitation, structure-function mutagenesis of the eh1/GEH motif, luciferase reporter repression assays, Xenopus gain- and loss-of-function experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal physical interaction plus mutagenesis plus functional rescue in vivo, moderate evidence from single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17138566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PU.1 physically interacts with and recruits Grg4 (TLE4) as a transcriptional corepressor; in combination with Pax5, PU.1-recruited Grg4 represses B-cell-specific enhancer (IgH HS1,2 and J-chain promoter) activity in a position-dependent manner; Grg4 levels decrease following B-cell activation, suggesting temporal regulation.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assays, transient transfection in B-cell lines\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct physical interaction plus functional repression assay, but single lab with limited orthogonal validation\",\n      \"pmids\": [\"14993928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUMOylation of SoxE transcription factors promotes their recruitment of Grg4 (TLE4) as a corepressor while displacing coactivators CBP/p300; SUMOylated SoxE–Grg4 complexes function as transcriptional repressors in the neural crest, demonstrating that SUMO modification switches SoxE from activator to repressor mode via Grg4 recruitment.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, reporter transcription assays, in vivo Xenopus neural crest gain- and loss-of-function\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction plus functional epistasis plus in vivo developmental readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"22927467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Murine Grg4 (TLE4) transcripts are detected in proliferating epithelial tissues undergoing mesenchymal induction, overlapping with Grg3, Notch1, and Hes1, but also expressed in the CNS and somites in cells adjacent to those expressing other neurogenic gene homologues, suggesting a role in later stages of cell differentiation.\",\n      \"method\": \"In situ hybridization and Northern blot expression analysis during mouse embryogenesis\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization without direct functional consequence established\",\n      \"pmids\": [\"8892234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Chick Grg4 (TLE4) overexpression in the mesencephalon represses expression of tectum-organizing molecules (En-2, Pax5, Fgf8, EphrinA2) and upregulates Pax6, antagonizing tectum-inducing activity of Pax5; dominant-negative N-terminal Grg4 domains induced En-2 expression, indicating Grg4 acts as a transcriptional repressor against organizing molecules in tectal development.\",\n      \"method\": \"In ovo electroporation-based gain-of-function, dominant-negative constructs, in situ hybridization for downstream targets in chick\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain- and loss-of-function with defined molecular readouts, single lab\",\n      \"pmids\": [\"10772799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Grg4 (TLE4) expression in the tectal ventricular layer coincides with a change in postmitotic cell migration pattern; clonal misexpression of Grg4 redirects tectal postmitotic cells to migrate to laminae h–j of the SGFS, while morpholino knockdown or dominant-negative Grg4 produces the opposite effect, establishing Grg4 as a regulator of tectal laminar fate through control of cell migration.\",\n      \"method\": \"In ovo electroporation misexpression, antisense morpholino knockdown, dominant-negative constructs, histological laminar analysis in chick optic tectum\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with specific laminar phenotype readout, single lab\",\n      \"pmids\": [\"12490552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cux1 directly interacts with Grg4 (TLE4) and, together with HDAC1 and HDAC3, forms a repressor complex on the p27kip1 promoter; Grg4 enhances Cux1-mediated repression of p27kip1 promoter activity, and all components bind the p27kip1 promoter in neonatal kidney tissue in vivo.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP) in vivo, DNase I footprinting, luciferase reporter assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct physical interaction confirmed by Co-IP, in vivo ChIP, footprinting, and functional reporter assay in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"19332113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HES/E(spl) proteins recruit TLE/Groucho corepressors (including the TLE4 mammalian family) via a conserved C-terminal WRPW tetrapeptide motif to mediate transcriptional repression downstream of Notch signaling; in contrast, HERP proteins lack a functional WRPW and instead use their bHLH domain to recruit mSin3/HDAC1 and N-CoR for repression.\",\n      \"method\": \"Transcriptional repression assays, domain deletion/mutagenesis, co-immunoprecipitation of corepressor complexes, DNA binding assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of corepressor recruitment with mutagenesis and interaction assays, but focuses primarily on HERP; TLE/Groucho role inferred from HES-WRPW motif studies\",\n      \"pmids\": [\"11486045\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TLE4 (Grg4) is a transcriptional corepressor of the Groucho family that is recruited to target gene promoters by diverse DNA-binding transcription factors—including HES proteins (via WRPW motif), FoxD3, Cux1, PU.1/Pax5, and SUMOylated SoxE—where it assembles repressor complexes with HDACs to silence target genes (e.g., p27kip1) and control cell fate decisions in B-cell differentiation, mesoderm induction, neural crest development, and brain laminar patterning.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\nThe target gene is TLE4 (Transducin-Like Enhancer of split 4), a human Groucho/TLE family transcriptional corepressor.\n\n**Main corpus (100 papers):** The vast majority describe Drosophila E(spl) complex genes (HLH repressors), Notch signaling, HES/HERP family members, zebrafish her genes, or completely unrelated topics (cancer genomics, cochlear physiology, COVID, plant genes, bacterial genes). None of these are about the canonical human TLE4 protein. A few mention Grg4/Groucho-related proteins:\n\n- Paper [53]: FoxD3 and Grg4 in Xenopus — Grg4 is the Xenopus ortholog of TLE4. KEEP.\n- Paper [59]: Grg4 and PU.1/Pax5 in B cells — Grg4 = TLE4 ortholog/homolog. KEEP.\n- Paper [63]: SUMOylated SoxE factors recruit Grg4 — Grg4 = TLE4. KEEP.\n- Paper [72]: Chick Grg4 antagonizing tectum-organizing activity — Grg4 = TLE4. KEEP.\n- Paper [77]: Role of Grg4 in tectal laminar formation — Grg4 = TLE4. KEEP.\n- Paper [83]: Cux1 interacts with Grg4 in kidney — Grg4 = TLE4. KEEP.\n\nAll others in main corpus: EXCLUDE (alias collisions, unrelated biology, plant SPL genes, bacterial esg, cochlear physiology, COVID, etc.)\n\n**Additional gene2pubmed papers (30 papers):**\n- [15]: Human TLE family characterized — human TLE genes including TLE4. KEEP.\n- [14]: Tcf factors interact with Groucho/TLE family — includes TLE4. KEEP.\n- [16]: Pax5 interacts with Grg4 — TLE4 ortholog. KEEP.\n- [3]: BioPlex — large-scale interactome, TLE4 identified as interactor. KEEP (mass spec interactome).\n- [4]: BioPlex 2.0 — same. KEEP.\n- [9]: BioPlex 3.0 — same. KEEP.\n- [5]: HuRI — binary interactome. KEEP.\n- [21]: Human TF protein interaction networks — TLE4 interactions. KEEP.\n- [22]: Proteomic analyses of TF complexes — may include TLE4. KEEP.\n- [27]: PAX2 mutations/FSGS — mentions TLE4 interaction with PAX2 repressor activity. KEEP.\n- [2]: HeLa phosphoproteomics — identifies TLE4 phosphorylation sites. KEEP.\n- [19]: CMGC kinase interactome — TLE4 may appear. KEEP.\n- [1], [8], [12], [25]: cDNA sequencing/characterization — sequence data only, no mechanism. EXCLUDE.\n- [6], [20], [17], [23], [26]: GWAS/epidemiology. EXCLUDE.\n- [7]: m6A methylation — unrelated. EXCLUDE.\n- [10]: GO phylogenetic propagation — no mechanism. EXCLUDE.\n- [11]: mRNA granules BioID — TLE4 may appear peripherally. Low relevance. EXCLUDE.\n- [13]: CircRNA-SORE — unrelated. EXCLUDE.\n- [18]: Otx2 in midbrain — mentions Grg4 in passing. Low. EXCLUDE.\n- [24]: Sperm nuclear proteome — TLE4 detected. No mechanism. EXCLUDE.\n- [28]: BRCT domain interactions — unrelated to TLE4 mechanism. EXCLUDE.\n- [29]: Chromosome 9 sequence — no mechanism. EXCLUDE.\n- [30]: Neurodegenerative protein interactomes — not TLE4-focused. EXCLUDE.\n\nNow extracting discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"Human TLE proteins (including TLE4) were identified as nuclear proteins homologous to Drosophila Groucho/E(spl) m9/10, establishing TLE4 as a member of a conserved family of nuclear corepressors differentially expressed in human tissues.\",\n      \"method\": \"cDNA cloning, sequence homology analysis, nuclear localization by immunostaining\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — original identification with subcellular localization data; single lab, foundational characterization\",\n      \"pmids\": [\"1303260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"All mammalian Groucho/TLE family members (including TLE4/Grg4) physically interact with TCF/LEF transcription factors and repress TCF-mediated transcriptional activation; long TLE proteins (including TLE4) interact with histone deacetylase HDAC1 to mediate repression, whereas the short family member Grg5 acts as a de-repressor by failing to recruit HDAC.\",\n      \"method\": \"Co-immunoprecipitation, reporter/luciferase transcriptional assays, HDAC binding assays in cell lines\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction assays with multiple TCF/TLE combinations, HDAC recruitment demonstrated, replicated across family members\",\n      \"pmids\": [\"11266540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Pax5 (BSAP) recruits Grg4 (TLE4 ortholog) as a transcriptional corepressor via two separate interaction domains: the N-terminal Q and central SP regions of Grg4, and the octapeptide motif and C-terminal transactivation domain of Pax5; this interaction represses Pax5 target genes and alters the phosphorylation state of Grg4 in vivo.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, transcriptional reporter assays, in vivo phosphorylation analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus reciprocal Co-IP plus functional reporter assays, domain mapping performed\",\n      \"pmids\": [\"10811620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Grg4 (TLE4 ortholog) is co-recruited by PU.1 in B-lineage cells; PU.1 physically interacts with Grg4 and, in conjunction with Pax5, represses IgH enhancer activity in a position-dependent manner; Grg4 protein levels decrease following B-cell activation, suggesting temporal regulation of this corepressor.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assays, western blotting for Grg4 levels in activated B cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and functional reporter data in B cells; single lab with multiple methods\",\n      \"pmids\": [\"14993928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FoxD3 physically interacts with Grg4 (TLE4 ortholog) via an eh1/GEH Groucho-interaction motif in its C-terminal domain; this interaction is required for FoxD3-mediated transcriptional repression and mesoderm induction in Xenopus. Deletion or point mutagenesis of the eh1 motif abolishes both Grg4 binding and FoxD3 repression activity; the dominant-inhibitory Grg5 antagonizes this function.\",\n      \"method\": \"Co-immunoprecipitation, deletion/point mutagenesis, transcriptional reporter assays, Xenopus embryo injection with rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted interaction with mutagenesis, in vivo epistasis in Xenopus, multiple orthogonal methods\",\n      \"pmids\": [\"17138566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The homeodomain protein Cux1 directly interacts with Grg4 (TLE4 ortholog) in developing kidney; Grg4 enhances Cux1-mediated repression of the p27kip1 promoter. ChIP assays demonstrated that Cux1, Grg4, HDAC1, and HDAC3 are co-recruited to two separate sites in the p27kip1 promoter in vivo in neonatal kidney tissue.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, chromatin immunoprecipitation (ChIP), DNase I footprinting\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP in vivo plus Co-IP plus functional reporter with multiple orthogonal methods\",\n      \"pmids\": [\"19332113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUMOylation of SoxE transcription factors promotes their recruitment of Grg4 (TLE4 ortholog) as a corepressor while displacing coactivators CBP/p300; this SUMO-dependent switch converts SoxE from a transcriptional activator to a repressor in Xenopus neural crest development, demonstrating that TLE4/Grg4 recruitment is regulated by post-translational modification of its binding partner.\",\n      \"method\": \"Co-immunoprecipitation, SUMO modification assays, transcriptional reporter assays in Xenopus embryos\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP combined with in vivo functional data and mechanistic switch demonstrated with mutagenesis of SUMOylation sites\",\n      \"pmids\": [\"22927467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Chick Grg4 (TLE4 ortholog) functions as a transcriptional repressor that antagonizes tectum-organizing activity in the mesencephalon; Grg4 overexpression by in ovo electroporation repressed En-2, Pax5, Fgf8, and EphrinA2 expression while upregulating Pax6, and co-transfection with Pax5 canceled tectum-inducing activity of Pax5. The N-terminal domain of Grg4 acted as a dominant negative and induced En-2 expression, confirming nuclear repressive function.\",\n      \"method\": \"In ovo electroporation (gain- and dominant-negative loss-of-function), immunostaining, in situ hybridization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain/loss-of-function with specific molecular readouts; single lab\",\n      \"pmids\": [\"10772799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Grg4 (TLE4 ortholog) directs tectal postmitotic cell migration to specific laminae in the chick optic tectum; clonal misexpression of Grg4 caused cells to migrate to laminae h–j of the SGFS, whereas morpholino knockdown or dominant-negative Grg4 produced the opposite effect, demonstrating a direct role in controlling neuronal migration and laminar positioning.\",\n      \"method\": \"Clonal electroporation overexpression, morpholino antisense knockdown, dominant-negative overexpression, histological analysis of laminar position\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain and loss-of-function with specific cellular phenotype; single lab\",\n      \"pmids\": [\"12490552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PAX2 mutations associated with adult-onset FSGS alter PAX2 interaction with repressor proteins (including Grg/TLE family members), resulting in enhanced repressor activity; in vitro functional studies showed that specific PAX2 FSGS-associated mutations perturb interaction with TLE corepressors.\",\n      \"method\": \"In vitro interaction/functional assays, in silico structural modeling, transactivation assays\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional assays implicate TLE corepressor interaction but TLE4 specifically not distinguished from other family members\",\n      \"pmids\": [\"24676634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Large-scale affinity-purification mass spectrometry (BioPlex) identified TLE4 as part of protein interaction communities in HEK293T cells, placing TLE4 within defined protein complexes in the human interactome.\",\n      \"method\": \"Affinity purification mass spectrometry (AP-MS) at proteome scale\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — large-scale AP-MS; TLE4 interactions detected but not individually validated\",\n      \"pmids\": [\"26186194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Large-scale phosphoproteomic analysis of HeLa cell nuclear proteins identified phosphorylation sites on TLE4, indicating that TLE4 undergoes nuclear phosphorylation in human cells.\",\n      \"method\": \"Strong cation exchange chromatography enrichment of phosphopeptides, tandem MS\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mass spectrometry detection of phosphosites; no writer/eraser/reader identified for TLE4 specifically\",\n      \"pmids\": [\"15302935\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TLE4 (and its vertebrate orthologs Grg4) functions as a nuclear transcriptional corepressor that is recruited to target gene promoters by diverse DNA-binding transcription factors (including TCF/LEF, Pax5, PU.1, FoxD3, Cux1, and SoxE proteins) via conserved interaction motifs (eh1/GEH, octapeptide), and mediates repression through recruitment of histone deacetylases (HDAC1/3); its corepressor activity can be regulated by post-translational modifications of its binding partners (e.g., SUMOylation switches SoxE from activator to TLE4-recruiting repressor), and it plays defined roles in neuronal migration, laminar positioning in the tectum, B-cell gene regulation, kidney development, and mesoderm induction.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TLE4 (Grg4) is a Groucho-family transcriptional corepressor recruited to gene promoters by diverse DNA-binding transcription factors to silence target genes and control cell fate decisions during development and differentiation. It is recruited by HES proteins via a WRPW motif downstream of Notch signaling [PMID:11486045], by FoxD3 via an eh1/GEH motif to mediate mesoderm induction [PMID:17138566], by SUMOylated SoxE factors to switch neural crest gene regulation from activation to repression [PMID:22927467], and by PU.1/Pax5 to repress B-cell-specific enhancers [PMID:14993928]. At target promoters such as p27kip1, TLE4 assembles a repressor complex with Cux1, HDAC1, and HDAC3, directly coupling its recruitment to histone deacetylase-dependent gene silencing [PMID:19332113]. In the developing brain, TLE4 controls laminar cell fate by redirecting postmitotic neuronal migration in the optic tectum [PMID:12490552].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Before any functional data, expression mapping established that TLE4 transcripts localize to proliferating epithelia undergoing mesenchymal induction and to the CNS, positioning TLE4 as a potential regulator of cell differentiation decisions.\",\n      \"evidence\": \"In situ hybridization and Northern blot during mouse embryogenesis\",\n      \"pmids\": [\"8892234\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Expression pattern alone; no functional consequence demonstrated\", \"No loss-of-function or gain-of-function analysis\", \"Correlation with Notch/Hes expression not tested functionally\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Gain- and loss-of-function experiments in the chick tectum demonstrated that TLE4 acts as a transcriptional repressor of tectum-organizing molecules (En-2, Pax5, Fgf8, EphrinA2), establishing its role as an active repressor in brain patterning rather than a passive marker.\",\n      \"evidence\": \"In ovo electroporation overexpression and dominant-negative constructs with in situ hybridization readout in chick mesencephalon\",\n      \"pmids\": [\"10772799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA-binding transcription factor that recruits TLE4 at these promoters not identified\", \"Endogenous loss-of-function (knockout) not performed\", \"Corepressor complex composition at tectal targets unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mechanistic dissection of HES versus HERP repression revealed that HES proteins recruit TLE/Groucho corepressors via a conserved WRPW motif, establishing TLE4 as a downstream effector of Notch-HES signaling.\",\n      \"evidence\": \"Transcriptional repression assays, domain mutagenesis, and co-immunoprecipitation of corepressor complexes\",\n      \"pmids\": [\"11486045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Study focused primarily on HERP; TLE4's specific participation inferred from family membership and WRPW motif studies\", \"No ChIP demonstrating TLE4 occupancy at HES target promoters\", \"No in vivo Notch-dependent phenotype tied specifically to TLE4\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Clonal misexpression and knockdown experiments showed that TLE4 regulates laminar fate of postmitotic neurons in the optic tectum by controlling migration to specific sublayers, linking its corepressor activity to a discrete developmental cell-fate output.\",\n      \"evidence\": \"In ovo electroporation, antisense morpholino knockdown, dominant-negative constructs, and histological laminar analysis in chick optic tectum\",\n      \"pmids\": [\"12490552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets mediating the laminar migration phenotype not identified\", \"Whether TLE4 acts through HES or other recruiters in this context is unknown\", \"Mammalian validation of the laminar patterning role absent\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"PU.1 was identified as a direct recruiter of TLE4, and the PU.1–TLE4 complex, in combination with Pax5, represses B-cell-specific enhancers; TLE4 protein levels decrease upon B-cell activation, suggesting temporal regulation of corepressor availability controls B-cell gene expression.\",\n      \"evidence\": \"Co-immunoprecipitation, luciferase reporter assays, and transient transfection in B-cell lines\",\n      \"pmids\": [\"14993928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ChIP confirming TLE4 occupancy at endogenous IgH or J-chain loci\", \"Mechanism of TLE4 downregulation upon B-cell activation not determined\", \"Redundancy with other TLE family members in B cells not assessed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"FoxD3 was shown to recruit TLE4 through an eh1/GEH motif, and this interaction is essential for FoxD3-mediated transcriptional repression and mesoderm induction, revealing a Groucho-interaction motif distinct from WRPW as a recruitment mechanism.\",\n      \"evidence\": \"Co-immunoprecipitation, eh1/GEH motif mutagenesis, luciferase reporter assays, Xenopus gain- and loss-of-function experiments\",\n      \"pmids\": [\"17138566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous genomic targets of FoxD3–TLE4 complexes in mesoderm not identified\", \"Whether TLE4 or other Groucho paralogs are functionally redundant with FoxD3 not resolved\", \"Mammalian validation of the FoxD3–TLE4 interaction not performed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The identification of a Cux1–TLE4–HDAC1/3 complex on the p27kip1 promoter in vivo provided the first defined endogenous target promoter and revealed that TLE4 functions within an HDAC-containing repressor complex, linking TLE4 recruitment to a specific chromatin-modifying mechanism.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP in neonatal kidney, DNase I footprinting, luciferase reporter assays\",\n      \"pmids\": [\"19332113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HDAC enzymatic activity is strictly required for TLE4-dependent repression at p27kip1 not tested with HDAC inhibitors in this context\", \"Genome-wide set of Cux1–TLE4 co-occupied promoters unknown\", \"Structural basis of TLE4–Cux1 interaction not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"SUMOylation of SoxE factors was shown to switch them from activators to repressors by promoting TLE4 recruitment and displacing CBP/p300, demonstrating that post-translational modification of the recruiting transcription factor can regulate TLE4 corepressor engagement.\",\n      \"evidence\": \"Co-immunoprecipitation, pulldown assays, reporter transcription assays, Xenopus neural crest gain- and loss-of-function\",\n      \"pmids\": [\"22927467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SUMO-dependent TLE4 recruitment involves a direct SUMO–TLE4 interaction or an indirect conformational change is not resolved\", \"Neural crest target genes repressed by the SUMOylated SoxE–TLE4 complex not identified\", \"Mammalian relevance of this switch in neural crest development not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A genome-wide map of TLE4 chromatin occupancy in any mammalian cell type is lacking, the structural basis for how TLE4 distinguishes among its multiple recruiting transcription factors is unresolved, and functional redundancy among TLE family members has not been systematically addressed.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide ChIP-seq or CUT&RUN for TLE4 reported\", \"No crystal or cryo-EM structure of TLE4 in complex with any partner\", \"Genetic redundancy with TLE1–3 in mammalian development not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 4, 5]}\n    ],\n    \"complexes\": [\n      \"Cux1–TLE4–HDAC1/3 repressor complex\"\n    ],\n    \"partners\": [\n      \"CUX1\",\n      \"FOXD3\",\n      \"SPI1\",\n      \"PAX5\",\n      \"HDAC1\",\n      \"HDAC3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"TLE4 is a nuclear transcriptional corepressor of the Groucho/TLE family that is recruited to target gene promoters by diverse DNA-binding transcription factors—including TCF/LEF, Pax5, PU.1, FoxD3, Cux1, and SoxE proteins—through conserved interaction motifs such as the eh1/GEH and octapeptide domains [PMID:10811620, PMID:17138566, PMID:11266540]. TLE4 mediates transcriptional repression by recruiting histone deacetylases HDAC1 and HDAC3 to target promoters, as demonstrated at the p27kip1 locus in developing kidney [PMID:11266540, PMID:19332113]. The corepressor activity of TLE4 is regulated by post-translational modifications of its binding partners, exemplified by SUMOylation of SoxE factors that switches them from activators to TLE4-recruiting repressors [PMID:22927467]. In vivo, TLE4 controls tectal patterning, neuronal laminar migration, B-cell gene regulation, and mesoderm induction [PMID:10772799, PMID:12490552, PMID:14993928, PMID:17138566].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Identification of TLE4 as a nuclear protein homologous to Drosophila Groucho established it as a member of a conserved family of candidate transcriptional regulators, opening the question of what transcription factors recruit it and how it mediates repression.\",\n      \"evidence\": \"cDNA cloning, sequence homology, and immunostaining for nuclear localization in human tissues\",\n      \"pmids\": [\"1303260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No transcription factor partners or repression mechanism identified at this stage\", \"Expression data descriptive, no functional assay performed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstration that Pax5 recruits TLE4/Grg4 via its octapeptide motif and that TLE4 represses Pax5 target genes answered the question of how a sequence-specific transcription factor physically engages a Groucho-family corepressor, defining the domain architecture underlying this interaction.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, transcriptional reporter assays, domain mapping, and in vivo phosphorylation analysis\",\n      \"pmids\": [\"10811620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin-level mechanism of repression not yet defined\", \"Whether HDAC recruitment is involved was untested at this point\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"In vivo overexpression and dominant-negative studies in chick tectum showed that TLE4/Grg4 antagonizes tectum-organizer gene expression (En-2, Pax5, Fgf8), establishing TLE4 as a functionally important repressor in neural patterning.\",\n      \"evidence\": \"In ovo electroporation gain- and dominant-negative loss-of-function with in situ hybridization readouts in chick embryos\",\n      \"pmids\": [\"10772799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets versus indirect effects not distinguished\", \"Single model organism\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing that all long TLE proteins including TLE4 physically interact with TCF/LEF factors and recruit HDAC1 to mediate repression resolved how Groucho-family corepressors mechanistically silence Wnt target genes, distinguishing full-length TLEs from the short de-repressor Grg5.\",\n      \"evidence\": \"Co-immunoprecipitation and luciferase reporter assays testing multiple TCF/TLE combinations with HDAC binding assays\",\n      \"pmids\": [\"11266540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HDAC catalytic activity is strictly required for repression not tested with deacetylase-dead mutants\", \"Genomic targets of TCF/TLE4 complexes not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Reciprocal gain- and loss-of-function experiments revealed that TLE4/Grg4 directly controls postmitotic neuronal migration and laminar positioning in the optic tectum, extending its role beyond transcriptional target gene regulation to cellular migratory behavior.\",\n      \"evidence\": \"Clonal electroporation, morpholino knockdown, and dominant-negative overexpression in chick tectum with histological laminar analysis\",\n      \"pmids\": [\"12490552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream transcriptional targets mediating migration not identified\", \"Mechanism linking repression to cell migration unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Co-recruitment of TLE4/Grg4 by PU.1 together with Pax5 at the IgH enhancer, and the observation that Grg4 protein decreases upon B-cell activation, revealed temporal regulation of TLE4 corepressor availability as a mechanism for controlling B-lineage gene expression.\",\n      \"evidence\": \"Co-immunoprecipitation, luciferase reporter assays, and western blotting in B-cell lines before and after activation\",\n      \"pmids\": [\"14993928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Grg4 protein downregulation (proteasomal, transcriptional) not defined\", \"Genome-wide B-cell targets of PU.1/TLE4 complex unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mutagenesis of the FoxD3 eh1/GEH motif abolished both TLE4/Grg4 binding and FoxD3-mediated repression and mesoderm induction, providing the first direct evidence that a single short motif is necessary and sufficient for Groucho recruitment and in vivo developmental function.\",\n      \"evidence\": \"Co-IP with point mutants, transcriptional reporter assays, and Xenopus embryo injection with rescue experiments\",\n      \"pmids\": [\"17138566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of eh1–TLE4 interaction not resolved at atomic level\", \"Whether all eh1-containing factors use identical TLE4 surfaces is unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"ChIP demonstration that Cux1, TLE4/Grg4, HDAC1, and HDAC3 co-occupy two sites on the p27kip1 promoter in neonatal kidney established that TLE4 functions as a chromatin-associated corepressor complex with multiple HDACs at an endogenous locus relevant to kidney development.\",\n      \"evidence\": \"Chromatin immunoprecipitation in neonatal mouse kidney, Co-IP, luciferase reporter, DNase I footprinting\",\n      \"pmids\": [\"19332113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HDAC1 and HDAC3 have redundant or distinct roles in this complex untested\", \"Genome-wide binding profile of TLE4 in kidney not available\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovering that SUMOylation of SoxE factors switches them from CBP/p300-associated activators to TLE4/Grg4-recruiting repressors resolved how a single transcription factor toggles between activation and repression, revealing post-translational modification of the partner as a regulatory input for TLE4 recruitment.\",\n      \"evidence\": \"Co-IP, SUMO modification assays, and functional reporter assays in Xenopus embryos with SUMOylation-site mutants\",\n      \"pmids\": [\"22927467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other TLE4-interacting factors are similarly regulated by SUMOylation is untested\", \"Structural basis for SUMO-dependent differential binding not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the genome-wide binding landscape of TLE4 in any mammalian cell type, the structural basis of TLE4's WD40 and Q-domain interactions with diverse transcription factors, and whether TLE4 has non-redundant functions distinct from other long TLE family members in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide ChIP-seq or CUT&RUN map for TLE4 reported\", \"No crystal or cryo-EM structure of TLE4 in complex with a transcription factor\", \"Genetic knockout studies distinguishing TLE4 from TLE1/2/3 in mammals are lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 4, 5, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TCF7L2\", \"PAX5\", \"SPI1\", \"FOXD3\", \"CUX1\", \"HDAC1\", \"HDAC3\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I placed a GO localization term inside the pathway array. Let me fix that.\n\n```json\n{\n  \"mechanistic_narrative\": \"TLE4 is a nuclear transcriptional corepressor of the Groucho/TLE family that is recruited to target gene promoters by diverse DNA-binding transcription factors—including TCF/LEF, Pax5, PU.1, FoxD3, Cux1, and SoxE proteins—through conserved interaction motifs such as the eh1/GEH and octapeptide domains [PMID:10811620, PMID:17138566, PMID:11266540]. TLE4 mediates transcriptional repression by recruiting histone deacetylases HDAC1 and HDAC3 to target promoters, as demonstrated at the p27kip1 locus in developing kidney [PMID:11266540, PMID:19332113]. The corepressor activity of TLE4 is regulated by post-translational modifications of its binding partners, exemplified by SUMOylation of SoxE factors that switches them from activators to TLE4-recruiting repressors [PMID:22927467]. In vivo, TLE4 controls tectal patterning, neuronal laminar migration, B-cell gene regulation, and mesoderm induction [PMID:10772799, PMID:12490552, PMID:14993928, PMID:17138566].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Identification of TLE4 as a nuclear protein homologous to Drosophila Groucho established it as a member of a conserved family of candidate transcriptional regulators, opening the question of what transcription factors recruit it and how it mediates repression.\",\n      \"evidence\": \"cDNA cloning, sequence homology, and immunostaining for nuclear localization in human tissues\",\n      \"pmids\": [\"1303260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No transcription factor partners or repression mechanism identified at this stage\", \"Expression data descriptive, no functional assay performed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstration that Pax5 recruits TLE4/Grg4 via its octapeptide motif and that TLE4 represses Pax5 target genes answered the question of how a sequence-specific transcription factor physically engages a Groucho-family corepressor, defining the domain architecture underlying this interaction.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, transcriptional reporter assays, domain mapping, and in vivo phosphorylation analysis\",\n      \"pmids\": [\"10811620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin-level mechanism of repression not yet defined\", \"Whether HDAC recruitment is involved was untested at this point\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"In vivo overexpression and dominant-negative studies in chick tectum showed that TLE4/Grg4 antagonizes tectum-organizer gene expression (En-2, Pax5, Fgf8), establishing TLE4 as a functionally important repressor in neural patterning.\",\n      \"evidence\": \"In ovo electroporation gain- and dominant-negative loss-of-function with in situ hybridization readouts in chick embryos\",\n      \"pmids\": [\"10772799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets versus indirect effects not distinguished\", \"Single model organism\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing that all long TLE proteins including TLE4 physically interact with TCF/LEF factors and recruit HDAC1 to mediate repression resolved how Groucho-family corepressors mechanistically silence Wnt target genes, distinguishing full-length TLEs from the short de-repressor Grg5.\",\n      \"evidence\": \"Co-immunoprecipitation and luciferase reporter assays testing multiple TCF/TLE combinations with HDAC binding assays\",\n      \"pmids\": [\"11266540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HDAC catalytic activity is strictly required for repression not tested with deacetylase-dead mutants\", \"Genomic targets of TCF/TLE4 complexes not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Reciprocal gain- and loss-of-function experiments revealed that TLE4/Grg4 directly controls postmitotic neuronal migration and laminar positioning in the optic tectum, extending its role beyond transcriptional target gene regulation to cellular migratory behavior.\",\n      \"evidence\": \"Clonal electroporation, morpholino knockdown, and dominant-negative overexpression in chick tectum with histological laminar analysis\",\n      \"pmids\": [\"12490552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream transcriptional targets mediating migration not identified\", \"Mechanism linking repression to cell migration unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Co-recruitment of TLE4/Grg4 by PU.1 together with Pax5 at the IgH enhancer, and the observation that Grg4 protein decreases upon B-cell activation, revealed temporal regulation of TLE4 corepressor availability as a mechanism for controlling B-lineage gene expression.\",\n      \"evidence\": \"Co-immunoprecipitation, luciferase reporter assays, and western blotting in B-cell lines before and after activation\",\n      \"pmids\": [\"14993928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Grg4 protein downregulation (proteasomal, transcriptional) not defined\", \"Genome-wide B-cell targets of PU.1/TLE4 complex unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mutagenesis of the FoxD3 eh1/GEH motif abolished both TLE4/Grg4 binding and FoxD3-mediated repression and mesoderm induction, providing the first direct evidence that a single short motif is necessary and sufficient for Groucho recruitment and in vivo developmental function.\",\n      \"evidence\": \"Co-IP with point mutants, transcriptional reporter assays, and Xenopus embryo injection with rescue experiments\",\n      \"pmids\": [\"17138566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of eh1–TLE4 interaction not resolved at atomic level\", \"Whether all eh1-containing factors use identical TLE4 surfaces is unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"ChIP demonstration that Cux1, TLE4/Grg4, HDAC1, and HDAC3 co-occupy two sites on the p27kip1 promoter in neonatal kidney established that TLE4 functions as a chromatin-associated corepressor complex with multiple HDACs at an endogenous locus relevant to kidney development.\",\n      \"evidence\": \"Chromatin immunoprecipitation in neonatal mouse kidney, Co-IP, luciferase reporter, DNase I footprinting\",\n      \"pmids\": [\"19332113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HDAC1 and HDAC3 have redundant or distinct roles in this complex untested\", \"Genome-wide binding profile of TLE4 in kidney not available\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovering that SUMOylation of SoxE factors switches them from CBP/p300-associated activators to TLE4/Grg4-recruiting repressors resolved how a single transcription factor toggles between activation and repression, revealing post-translational modification of the partner as a regulatory input for TLE4 recruitment.\",\n      \"evidence\": \"Co-IP, SUMO modification assays, and functional reporter assays in Xenopus embryos with SUMOylation-site mutants\",\n      \"pmids\": [\"22927467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other TLE4-interacting factors are similarly regulated by SUMOylation is untested\", \"Structural basis for SUMO-dependent differential binding not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the genome-wide binding landscape of TLE4 in any mammalian cell type, the structural basis of TLE4's WD40 and Q-domain interactions with diverse transcription factors, and whether TLE4 has non-redundant functions distinct from other long TLE family members in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide ChIP-seq or CUT&RUN map for TLE4 reported\", \"No crystal or cryo-EM structure of TLE4 in complex with a transcription factor\", \"Genetic knockout studies distinguishing TLE4 from TLE1/2/3 in mammals are lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 4, 5, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TCF7L2\", \"PAX5\", \"SPI1\", \"FOXD3\", \"CUX1\", \"HDAC1\", \"HDAC3\"],\n    \"other_free_text\": []\n  }\n}\n```"}