{"gene":"TLE1","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1996,"finding":"TLE1 directly interacts with the WRPW motif of HES-1 (a mammalian Hairy-like protein), as demonstrated by yeast two-hybrid assay and GST pull-down assays, establishing a conserved Groucho/TLE–Hairy/HES interaction in mammals.","method":"Yeast two-hybrid assay; GST fusion protein pull-down assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — two orthogonal in vitro binding methods (Y2H and GST pull-down) in same study","pmids":["8687460"],"is_preprint":false},{"year":1996,"finding":"Groucho/TLE1 proteins are phosphorylated, and more slowly migrating (higher molecular mass) phosphorylated forms associate more strongly with the nuclear compartment; these higher-mass TLE1 forms are induced during neural determination of P19 cells, implicating phosphorylation in nuclear function.","method":"Subcellular fractionation; SDS-PAGE mobility shift; immunoblotting; P19 differentiation model","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — direct fractionation experiment with functional correlation, single lab","pmids":["8713081"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of the C-terminal WD40 repeat domain of human TLE1 was determined to 1.6 Å, revealing a seven-bladed β-propeller; the structure identifies protein-protein interaction sites, including an induced-fit binding site for Eh1 (Engrailed-homology 1) domain transcription factors, and confirms structural relationship to yeast Tup1 corepressor.","method":"X-ray crystallography at 1.6 Å resolution; missense mutation analysis in C. elegans UNC-37","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with functional mutation mapping","pmids":["12057191"],"is_preprint":false},{"year":2002,"finding":"TLE1 interacts with the intracellular region of gp130 (the shared IL-6 family cytokine signal transducer) through its Q domain, with the membrane-proximal Box1/Box2-containing region of gp130 being essential; demonstrated by yeast two-hybrid, GST pull-down, and co-immunoprecipitation.","method":"Yeast two-hybrid; GST pull-down; co-immunoprecipitation","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — three orthogonal binding methods, single lab","pmids":["12030375"],"is_preprint":false},{"year":2003,"finding":"TLE1 was identified as a binding partner of the oncoprotein Qin (a winged helix transcription factor) via yeast two-hybrid screen; TLE1 binding requires a WRPW motif and correlates with Qin-induced transformation of chicken embryo fibroblasts; Qin binding induces phosphorylation of TLE1.","method":"Yeast two-hybrid screen; mammalian two-hybrid; transformation assay in chicken embryo fibroblasts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal binding assays with functional transformation readout, single lab","pmids":["12660810"],"is_preprint":false},{"year":2003,"finding":"TLE1 was identified as an activation function-1 (AF-1) cofactor of the orphan nuclear receptor ERRγ; direct interaction was demonstrated by phage display biopanning and pull-down assay; surprisingly, TLE1 functioned as a coactivator (not repressor) of ERRγ in reporter gene assays.","method":"Phage display library biopanning; GST pull-down; reporter gene assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — binding plus functional reporter assay, single lab","pmids":["14651967"],"is_preprint":false},{"year":2004,"finding":"CaMKIIδ-mediated activation triggers PARP-1, a component of the Groucho/TLE1 corepressor complex, causing dismissal of the TLE corepressor complex from HES1-regulated promoters; CaMKIIδ also phosphorylates HES1 to permit coactivator recruitment, switching HES1 from a TLE1-dependent repressor to an activator of neurogenic gene programs.","method":"Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); reporter assays; pharmacological CaMKII activation; dominant-negative constructs","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, ChIP, reporter), high-citation foundational study","pmids":["15607978"],"is_preprint":false},{"year":2004,"finding":"Protein kinase CK2 phosphorylates TLE1 at serine 239 within the conserved CcN domain; this phosphorylation is required for TLE1 nuclear association, transcription repression activity, and its ability to inhibit cortical neural progenitor differentiation into neurons (mutation S239A reduces antineurogenic activity; S239E does not).","method":"In vivo phosphorylation assay; site-directed mutagenesis; cortical neural progenitor differentiation assay; immunocytochemistry","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis paired with cellular differentiation assay and multiple phosphorylation analyses","pmids":["15367661"],"is_preprint":false},{"year":2005,"finding":"TLE1 is expressed in postmitotic neurons of the adult rat brain, and its immunoreactivity is detected not only in nuclei but also in apical dendritic shafts of neocortical layer III/V pyramidal cells and Purkinje cell dendrites, indicating an unexpected extranuclear localization in differentiated neurons.","method":"Immunohistochemistry; confocal microscopy in adult rat brain sections","journal":"Brain research. Molecular brain research","confidence":"Medium","confidence_rationale":"Tier 3 — localization by immunohistochemistry, single study, no direct functional consequence tested","pmids":["16081186"],"is_preprint":false},{"year":2008,"finding":"TLE1 (and TLE4) function as tumor suppressors in myeloid leukemia: shRNA knockdown of TLE1 rescues AML1-ETO-expressing cells from cell-cycle arrest and apoptosis, while forced TLE1 expression causes apoptosis; genetic epistasis in zebrafish confirms cooperation between TLE loss and AML1-ETO in hematopoietic blast accumulation.","method":"shRNA knockdown; forced expression; cell proliferation/apoptosis assays; zebrafish genetic epistasis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple cell lines, loss-of-function and gain-of-function with defined phenotypes, and in vivo zebrafish model","pmids":["18258796"],"is_preprint":false},{"year":2008,"finding":"Point mutation L743F in the WD40 domain of TLE1 selectively blocks binding to Hes1 (WRPW motif) without disrupting binding to Engrailed1, FoxG1 (Eh1 motif), or Tcf3; this WRPW-binding is specifically required for TLE1-mediated inhibition of cortical neuron differentiation.","method":"Site-directed mutagenesis; co-immunoprecipitation; cortical neural progenitor differentiation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — structure-guided mutagenesis dissecting two interaction surfaces with specific cellular readout","pmids":["18611861"],"is_preprint":false},{"year":2008,"finding":"TLE1 undergoes promoter CpG island hypermethylation-associated silencing in diffuse large B-cell lymphoma and AML; reintroduction of TLE1 in hypermethylated cells causes growth inhibition in colony and xenograft assays, with effects mediated through transcriptional repression of Cyclin D1, CSF1R, and HES1.","method":"Bisulfite sequencing; colony formation assay; nude mouse xenograft; shRNA knockdown; gene expression analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple methods including in vivo xenograft, gain- and loss-of-function, target gene identification","pmids":["18519670"],"is_preprint":false},{"year":2009,"finding":"Cofactor-activated phosphorylation of TLE1 at Ser-286 (and nearby Ser-289, Ser-298) within the SP domain, induced by interaction with DNA-binding partners (e.g., Hes1), strengthens TLE1 chromatin association and is required for its anti-neurogenic activity; mutations at these sites impair cofactor-activated phosphorylation and weaken chromatin binding without disrupting partner interaction or DNA recruitment.","method":"Site-directed mutagenesis; mass spectrometry; biochemistry; primary cortical neural progenitor culture; immunocytochemistry","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 — MS identification of phosphorylation sites, mutagenesis, and cellular differentiation assay with orthogonal methods","pmids":["19956621"],"is_preprint":false},{"year":2010,"finding":"TLE1 associates with ribosomal RNA genes during mitosis and interphase through physical interaction with Runx2; TLE1 depletion relieves Runx2-mediated repression of rRNA transcription, increases active histone modifications at rRNA gene loci, and leads to increased global protein synthesis and cell proliferation.","method":"Co-immunoprecipitation; ChIP; siRNA knockdown; ribosomal RNA transcription assay; cell proliferation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, siRNA with multiple orthogonal phenotypic readouts","pmids":["20160071"],"is_preprint":false},{"year":2010,"finding":"TLE1 and TLE3 interact with HESX1 and can repress PROP1 transcription both in the presence and absence of HESX1 via direct protein-protein interaction; TLE1 and TLE3 show similar repressive efficiencies; constitutive HESX1 expression in thyrotrophs and gonadotrophs suppresses terminal differentiation in transgenic mice.","method":"Co-immunoprecipitation; reporter gene assay; transgenic mouse overexpression","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2–3 — binding and reporter assays plus in vivo transgenic, single lab","pmids":["20181723"],"is_preprint":false},{"year":2011,"finding":"TLE1 physically interacts with NOD2 (identified by yeast two-hybrid and confirmed by co-immunoprecipitation); TLE1 and NOD2 co-localize around the nuclear membrane; TLE1 inhibits NOD2-induced NF-κB activation in HEK293 cells, and TLE1 SNPs interact epistatically with NOD2 mutations in Crohn's disease susceptibility.","method":"Yeast two-hybrid; co-immunoprecipitation; co-localization; NF-κB reporter assay; genetic epistasis analysis","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — Y2H, reciprocal Co-IP, co-localization, and functional NF-κB assay with genetic epistasis","pmids":["21699783"],"is_preprint":false},{"year":2012,"finding":"TLE1 promotes anoikis resistance in breast cancer cells; TLE1 inhibits the Bit1 anoikis pathway by sequestering AES in the nucleus, reducing formation of the proapoptotic Bit1-AES cytoplasmic complex; cytoplasmic Bit1 causes nuclear TLE1 translocation to the cytoplasm and its degradation.","method":"Forced expression; siRNA knockdown; anoikis assay; subcellular fractionation; immunofluorescence; co-immunoprecipitation","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple functional assays with mechanistic follow-up, single lab","pmids":["22952044"],"is_preprint":false},{"year":2012,"finding":"TLE1 promotes neuronal survival in cerebellar granule neurons cooperatively with FoxG1; CK2 phosphorylation of TLE1 at Ser-239 and Ser-253 is required for its survival-promoting activity; PI3K-Akt signaling but not MEK-ERK or HDAC activity is required for TLE1-mediated neuroprotection.","method":"Ectopic expression; siRNA knockdown; pharmacological inhibitors; point mutant analysis; cerebellar granule neuron primary culture; cell viability assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple inhibitors and mutants with defined cellular survival readout, single lab","pmids":["22354967"],"is_preprint":false},{"year":2014,"finding":"TLE1 promotes epithelial-to-mesenchymal transition (EMT) in A549 lung cancer cells by transcriptionally repressing E-cadherin; TLE1 recruits histone deacetylase (HDAC) activity to the E-cadherin promoter; HDAC inhibitor TSA partially reverses TLE1-induced E-cadherin downregulation and cell migration.","method":"Forced expression; siRNA knockdown; cell migration assay; RT-PCR; ChIP; HDAC inhibitor treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus gain/loss-of-function with pharmacological rescue, single lab","pmids":["25446087"],"is_preprint":false},{"year":2014,"finding":"Grg1/TLE1 (the predominant Groucho in human β-cells) induces monohormonal β-cell identity and represses α-cell gene functions including glucagon and Arx expression; ectopic Grg3 in α-cells represses glucagon and, combined with Pdx1, induces glucose-responsive insulin secretion.","method":"Mouse genetic model (Grg3+/−); ectopic expression in pancreatic cell lines; gene expression profiling; insulin secretion assay","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic model plus gain-of-function with functional secretion readout, single lab","pmids":["24487024"],"is_preprint":false},{"year":2016,"finding":"Tle1-deficient mice display a chronic inflammatory phenotype with increased NF-κB phosphorylation and activation in macrophages, increased inflammatory cytokines in response to TLR agonists/LPS, decreased Hes1 expression, and accelerated melanoma xenograft growth; this establishes TLE1 as an in vivo negative regulator of NF-κB-mediated inflammation.","method":"Conditional Tle1 knockout mouse; macrophage stimulation assay; cytokine ELISA; NF-κB phosphorylation immunoblotting; xenograft tumor model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with multiple orthogonal inflammatory and molecular readouts","pmids":["26831087"],"is_preprint":false},{"year":2017,"finding":"TLE1 is phosphorylated by Ras-ERK pathway activation, which excludes TLE1 from the nucleus and attenuates its transcriptional repressor function; unphosphorylatable TLE1 blocks oncogenic H-Ras phenotypes in human mammary cells in vitro and in vivo, while phosphomimetic TLE1 has minimal repressive effects.","method":"Phosphorylation assays; nuclear exclusion/localization imaging; reporter gene assay; Drosophila transgenic model; mouse xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple systems (cell lines, transgenic Drosophila, mouse xenograft) with mutagenesis and functional readouts","pmids":["28192406"],"is_preprint":false},{"year":2017,"finding":"TLE1 suppresses E-cadherin transcription by interacting with and recruiting ZEB1 to the E-cadherin promoter, imposing histone deacetylation and gene silencing; ZEB1 is required for TLE1-mediated anoikis resistance and tumorigenicity in lung cancer cells in vivo.","method":"ChIP; co-immunoprecipitation; siRNA; forced expression; xenograft tumorigenicity assay","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrates promoter co-occupancy, co-IP shows TLE1-ZEB1 interaction, in vivo xenograft confirms functional consequence","pmids":["29069783"],"is_preprint":false},{"year":2017,"finding":"The crystal structure of a stapled peptide inhibitor complexed with the TLE1 WD40 domain was solved; the WRPW epitope binds the WD40 β-propeller, and the constrained cycFWRPW peptide binds TLE1 with ~5-fold higher Kd than the acyclic peptide due to a small shift of one side chain.","method":"Co-crystal structure; isothermal titration calorimetry (ITC); thermal shift assay","journal":"Chemistry","confidence":"High","confidence_rationale":"Tier 1 — co-crystal structure with biophysical binding validation","pmids":["28326635"],"is_preprint":false},{"year":2018,"finding":"FOXG1 and TLE1 form a complex that directly targets and represses specific genes in glioblastoma-initiating cells, including negative regulators of NOTCH signaling such as CHAC1; ChIP-Seq identified 150 direct FOXG1 targets, several shared with TLE1.","method":"ChIP-Seq; RNA-Seq; co-immunoprecipitation (implied by complex characterization)","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide ChIP-Seq with RNA-Seq validation, single lab","pmids":["29316219"],"is_preprint":false},{"year":2021,"finding":"A unique amino-terminal phosphorylation site present in TLE1 but absent from TLE3 confers distinct functional activity; mutating or reconstituting this site converts TLE1 activity toward TLE3-like behavior (and vice versa) in lung cancer drug sensitivity and adipocyte differentiation assays.","method":"Retroviral transduction; site-directed mutagenesis; paclitaxel sensitivity assay; adipocyte differentiation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — mutagenesis in two functional systems, single lab","pmids":["33571907"],"is_preprint":false}],"current_model":"TLE1 is a nuclear transcriptional corepressor that lacks intrinsic DNA-binding activity but is recruited to target gene promoters by a wide range of DNA-binding partners (including HES1, FOXG1, Runx2, HESX1, ZEB1, and Qin) via WRPW or Eh1 peptide motifs engaging its C-terminal WD40 β-propeller domain; once recruited, TLE1 mediates gene repression by associating with chromatin and recruiting histone deacetylases, and its activity is regulated by multiple phosphorylation events—CK2 phosphorylation at Ser-239 promotes nuclear retention and repressor function, while Ras-ERK pathway phosphorylation causes nuclear exclusion and loss of repression—enabling TLE1 to function as a context-dependent regulator of neurogenesis, hematopoiesis, inflammation (via NF-κB suppression), β-cell identity, EMT (through E-cadherin repression with ZEB1 and HDAC recruitment), and anoikis resistance."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing that mammalian TLE1 directly contacts HES1 via the WRPW motif resolved whether the Drosophila Groucho–Hairy corepressor mechanism was conserved in mammals and defined the founding protein-protein interaction mode.","evidence":"Yeast two-hybrid and GST pull-down with HES-1 and TLE1","pmids":["8687460"],"confidence":"High","gaps":["Binding affinity not quantified","Functional repression by the complex not demonstrated in this study","Other WRPW-containing partners not tested"]},{"year":1996,"claim":"Demonstrating that phosphorylated TLE1 isoforms preferentially associate with nuclei during neural differentiation first linked post-translational modification to TLE1 subcellular regulation.","evidence":"Subcellular fractionation and SDS-PAGE of P19 cell differentiation lysates","pmids":["8713081"],"confidence":"Medium","gaps":["Kinase identity unknown","Phosphorylation sites not mapped","Causality between phosphorylation and nuclear retention not tested"]},{"year":2002,"claim":"The 1.6 Å crystal structure of the TLE1 WD40 domain revealed a seven-bladed β-propeller with separate WRPW- and Eh1-binding surfaces, providing the structural framework for understanding how one corepressor engages multiple transcription-factor classes.","evidence":"X-ray crystallography with functional mutation mapping in C. elegans UNC-37","pmids":["12057191"],"confidence":"High","gaps":["Full-length TLE1 structure not determined","Eh1 peptide-bound co-crystal not yet obtained in this study","Oligomerization interface not resolved"]},{"year":2002,"claim":"Identifying the gp130 cytoplasmic domain as a TLE1 Q-domain interactor extended TLE1 function beyond classical transcription-factor partnerships to cytokine signaling scaffolds.","evidence":"Yeast two-hybrid, GST pull-down, and co-immunoprecipitation with gp130 truncations","pmids":["12030375"],"confidence":"Medium","gaps":["Functional consequence of gp130–TLE1 interaction on cytokine signaling not shown","Endogenous complex not validated","Specificity among TLE family members not tested"]},{"year":2003,"claim":"Discovery that the oncoprotein Qin recruits TLE1 through a WRPW motif and that this interaction correlates with transformation linked TLE1 for the first time to an oncogenic pathway.","evidence":"Yeast two-hybrid screen, mammalian two-hybrid, and chicken embryo fibroblast transformation assay","pmids":["12660810"],"confidence":"Medium","gaps":["Whether TLE1 is required for Qin transformation not tested by loss-of-function","Downstream target genes not identified","Relevance to human cancer unknown"]},{"year":2004,"claim":"Mapping CK2-mediated phosphorylation of TLE1 at Ser-239 as necessary for nuclear retention and anti-neurogenic repression established the first site-specific mechanism controlling TLE1 activity in a developmental context.","evidence":"In vivo phosphorylation, S239A/S239E mutagenesis, cortical progenitor differentiation assay","pmids":["15367661"],"confidence":"High","gaps":["Upstream signals activating CK2 in progenitors not identified","Whether CK2 phosphorylation also affects non-neuronal functions unknown","Interaction with chromatin not directly assayed"]},{"year":2004,"claim":"Showing that CaMKIIδ-activated PARP-1 dismisses TLE1 from HES1-bound promoters, switching HES1 from repressor to activator, revealed a regulated corepressor-exchange mechanism at neurogenic genes.","evidence":"Co-IP, ChIP, reporter assays, and dominant-negative CaMKII constructs","pmids":["15607978"],"confidence":"High","gaps":["Direct PARP-1 modification of TLE1 not demonstrated","Genome-wide scope of this switch unknown","Whether this mechanism operates outside neurogenesis not tested"]},{"year":2008,"claim":"Structure-guided L743F mutagenesis in the WD40 domain selectively ablated WRPW binding (HES1) without affecting Eh1 binding (FoxG1, Engrailed), functionally separating two corepressor recruitment modes and showing WRPW interaction is specifically required for anti-neurogenic activity.","evidence":"Site-directed mutagenesis, co-immunoprecipitation, cortical progenitor assay","pmids":["18611861"],"confidence":"High","gaps":["Eh1-specific mutation complementing L743F not generated","Effect on chromatin modification not tested","In vivo validation lacking"]},{"year":2008,"claim":"Demonstrating that TLE1 is epigenetically silenced by promoter hypermethylation in B-cell lymphoma and AML, and that its re-expression inhibits growth and represses Cyclin D1, CSF1R, and HES1, established TLE1 as a bona fide tumor suppressor in hematologic malignancies.","evidence":"Bisulfite sequencing, colony formation, nude mouse xenograft, shRNA, gene expression profiling","pmids":["18519670","18258796"],"confidence":"High","gaps":["Whether methylation-mediated silencing occurs in solid tumors not addressed","Direct promoter occupancy at Cyclin D1 not shown by ChIP","Patient outcome correlation not provided"]},{"year":2009,"claim":"Identification of cofactor-activated phosphorylation at Ser-286/289/298 by mass spectrometry, induced upon DNA-binding partner interaction, revealed a feed-forward mechanism whereby partner recruitment strengthens TLE1–chromatin association independently of DNA targeting.","evidence":"Mass spectrometry, site-directed mutagenesis, cortical progenitor differentiation assay","pmids":["19956621"],"confidence":"High","gaps":["Kinase responsible for cofactor-activated phosphorylation not identified","Whether this mechanism is universal across all TLE1 partners unknown","Chromatin substrate specificity not defined"]},{"year":2010,"claim":"Showing that TLE1 co-occupies ribosomal RNA gene loci with Runx2 and represses rRNA transcription linked the corepressor to ribosome biogenesis and global translational control, extending its roles beyond mRNA-encoding gene regulation.","evidence":"Co-IP, ChIP at rDNA loci, siRNA knockdown, rRNA transcription and cell proliferation assays","pmids":["20160071"],"confidence":"High","gaps":["Mechanism of TLE1-mediated histone deacetylation at rDNA not elucidated","Whether rRNA repression contributes to tumor suppression unknown","Mitotic bookmarking mechanism not resolved"]},{"year":2014,"claim":"Demonstrating that TLE1 is the predominant Groucho family member in β-cells and represses α-cell genes (glucagon, Arx) established TLE1 as a determinant of endocrine cell identity in the pancreas.","evidence":"Grg3 haploinsufficient mouse, ectopic expression in pancreatic cell lines, insulin secretion assay","pmids":["24487024"],"confidence":"Medium","gaps":["β-cell-specific TLE1 knockout not performed","Direct TLE1 ChIP at glucagon/Arx promoters not shown","Human β-cell relevance not demonstrated"]},{"year":2016,"claim":"Conditional Tle1 knockout mice exhibiting chronic NF-κB hyperactivation, elevated inflammatory cytokines, and accelerated tumor growth provided definitive in vivo evidence that TLE1 is a physiological brake on innate immune signaling.","evidence":"Conditional Tle1 KO mouse, macrophage stimulation, cytokine ELISA, NF-κB phospho-blot, melanoma xenograft","pmids":["26831087"],"confidence":"High","gaps":["Direct mechanism of NF-κB inhibition (chromatin vs. cytoplasmic sequestration) not resolved","Contribution of individual TLE1-partner interactions to inflammation unknown","Adaptive immune cell phenotype not characterized"]},{"year":2017,"claim":"Identifying Ras-ERK-mediated phosphorylation as the signal that excludes TLE1 from the nucleus resolved the long-standing question of how oncogenic signaling inactivates this corepressor, and showed that an unphosphorylatable TLE1 mutant blocks H-Ras-driven transformation.","evidence":"Phosphorylation assays, nuclear exclusion imaging, Drosophila transgenic, mouse xenograft","pmids":["28192406"],"confidence":"High","gaps":["Specific ERK phosphorylation sites on TLE1 not mapped","Relationship to CK2 and cofactor-activated phosphorylation not integrated","Whether nuclear exclusion targets TLE1 for degradation unknown"]},{"year":2017,"claim":"Demonstrating that TLE1 partners with ZEB1 to co-occupy the E-cadherin promoter and impose HDAC-dependent silencing unified TLE1's roles in EMT promotion and anoikis resistance through a single transcription-factor partnership.","evidence":"ChIP, co-IP, siRNA, forced expression, and xenograft tumorigenicity","pmids":["29069783"],"confidence":"High","gaps":["Which HDAC isoform is recruited not identified","Genome-wide ZEB1-TLE1 co-occupancy not mapped","Structural basis of TLE1–ZEB1 interaction unknown"]},{"year":2021,"claim":"Identifying a unique N-terminal phosphorylation site that distinguishes TLE1 from TLE3 functional activity clarified how paralog-specific post-translational modifications diversify Groucho family member output.","evidence":"Mutagenesis, paclitaxel sensitivity assay, and adipocyte differentiation assay","pmids":["33571907"],"confidence":"Medium","gaps":["Kinase responsible not identified","Phosphorylation site not mapped to a specific residue","In vivo relevance not tested"]},{"year":null,"claim":"Key unresolved questions include the identity of the HDAC isoform(s) directly recruited by TLE1, the full-length oligomeric structure, the precise ERK phosphorylation sites mediating nuclear exclusion, and whether TLE1's anti-inflammatory and tumor-suppressive activities can be pharmacologically enhanced.","evidence":"","pmids":[],"confidence":"Low","gaps":["Full-length TLE1 structure not determined","HDAC isoform specificity unresolved","ERK phosphorylation sites not mapped","No therapeutic-grade TLE1-modulating compound reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,6,7,10,11,18,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,20]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[12,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,7,8,16,21]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[12,13]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,7,10,11,18,22,24]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12,13,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,10,19]}],"complexes":["HES1–TLE1 corepressor complex","FOXG1–TLE1 corepressor complex","ZEB1–TLE1 corepressor complex","Runx2–TLE1 corepressor complex"],"partners":["HES1","FOXG1","ZEB1","RUNX2","HESX1","NOD2","AES","GP130"],"other_free_text":[]},"mechanistic_narrative":"TLE1 is a non-DNA-binding transcriptional corepressor that serves as a nexus for integrating diverse developmental, inflammatory, and oncogenic signals by bridging sequence-specific transcription factors to chromatin-modifying machinery. Its C-terminal WD40 β-propeller domain engages WRPW-motif partners (e.g., HES1) and Eh1-motif partners (e.g., FOXG1, Engrailed) through structurally distinct binding surfaces, and once recruited to target promoters it silences genes such as E-cadherin, Cyclin D1, and glucagon by recruiting histone deacetylase activity [PMID:12057191, PMID:18611861, PMID:25446087, PMID:24487024]. TLE1 repressor function is positively regulated by CK2 phosphorylation at Ser-239, which promotes nuclear retention and anti-neurogenic activity, and by cofactor-activated phosphorylation at Ser-286/289/298 that strengthens chromatin association, whereas Ras-ERK-mediated phosphorylation causes nuclear exclusion and loss of repression [PMID:15367661, PMID:19956621, PMID:28192406]. In vivo, TLE1 loss produces chronic NF-κB-driven inflammation and accelerated tumor growth, and its promoter is epigenetically silenced by CpG hypermethylation in hematologic malignancies, establishing TLE1 as a context-dependent tumor suppressor in myeloid leukemia and lymphoma [PMID:26831087, PMID:18519670, PMID:18258796]."},"prefetch_data":{"uniprot":{"accession":"Q04724","full_name":"Transducin-like enhancer protein 1","aliases":["E(Sp1) homolog","Enhancer of split groucho-like protein 1","ESG1"],"length_aa":770,"mass_kda":83.2,"function":"Transcriptional corepressor that binds to a number of transcription factors. Inhibits NF-kappa-B-regulated gene expression. Inhibits the transcriptional activation mediated by FOXA2, and by CTNNB1 and TCF family members in Wnt signaling. Enhances FOXG1/BF-1- and HES1-mediated transcriptional repression (By similarity). The effects of full-length TLE family members may be modulated by association with dominant-negative AES. Unusual function as coactivator for ESRRG","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q04724/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TLE1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TLE1","total_profiled":1310},"omim":[{"mim_id":"618645","title":"PHD FINGER PROTEIN 12; PHF12","url":"https://www.omim.org/entry/618645"},{"mim_id":"611882","title":"PROLINE-RICH NUCLEAR RECEPTOR COACTIVATOR 2; PNRC2","url":"https://www.omim.org/entry/611882"},{"mim_id":"611273","title":"SKI FAMILY TRANSCRIPTIONAL COREPRESSOR 1; SKOR1","url":"https://www.omim.org/entry/611273"},{"mim_id":"610331","title":"HES FAMILY bHLH TRANSCRIPTION FACTOR 6; 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pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23691400","citation_count":3,"is_preprint":false},{"pmid":"28248724","id":"PMC_28248724","title":"TLE-1-Positive Angiomatoid Fibrous Histiocytoma Mimicking Synovial Sarcoma.","date":"2019","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/28248724","citation_count":3,"is_preprint":false},{"pmid":"34673590","id":"PMC_34673590","title":"Expression of TLE1, INI1, β-catenin, Claudin1, CK7, CK19, SS18 and calponin in synovial sarcoma.","date":"2021","source":"Indian journal of pathology & microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34673590","citation_count":2,"is_preprint":false},{"pmid":"31614009","id":"PMC_31614009","title":"TLE1 expression fails to distinguish between synovial sarcoma, atypical fibroxanthoma, and dermatofibrosarcoma protuberans.","date":"2019","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31614009","citation_count":2,"is_preprint":false},{"pmid":"37668410","id":"PMC_37668410","title":"Expression of TLE1 in a Carcinoid Tumor of the Lung With Spindle Cell Morphology-A Potential Diagnostic Pitfall.","date":"2023","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/37668410","citation_count":2,"is_preprint":false},{"pmid":"30410809","id":"PMC_30410809","title":"TLE1 Positive Clear Cell Sarcoma of the Kidney: A Case Report and Review of the Literature.","date":"2018","source":"Case reports in pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30410809","citation_count":2,"is_preprint":false},{"pmid":"28744818","id":"PMC_28744818","title":"Epigenetic modification of TLE1 induce abnormal differentiation in diabetic mice intestinal epithelium.","date":"2017","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28744818","citation_count":2,"is_preprint":false},{"pmid":"27879218","id":"PMC_27879218","title":"Generation of a TLE1 homozygous knockout human embryonic stem cell line using CRISPR-Cas9.","date":"2016","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27879218","citation_count":2,"is_preprint":false},{"pmid":"31020273","id":"PMC_31020273","title":"A rare case of TLE1-positive sclerosing epithelioid fibrosarcoma expanding the differential diagnosis of TLE1-positive tumors: a case report.","date":"2019","source":"AME case reports","url":"https://pubmed.ncbi.nlm.nih.gov/31020273","citation_count":2,"is_preprint":false},{"pmid":"39423627","id":"PMC_39423627","title":"ESG performance and green innovation of Chinese enterprises: Based on the perspective of financing constraints.","date":"2024","source":"Journal of environmental management","url":"https://pubmed.ncbi.nlm.nih.gov/39423627","citation_count":2,"is_preprint":false},{"pmid":"29490565","id":"PMC_29490565","title":"TLE1 Expression in Malignant Rhabdoid Tumor and Atypical Teratoid/Rhabdoid Tumor.","date":"2018","source":"Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society","url":"https://pubmed.ncbi.nlm.nih.gov/29490565","citation_count":1,"is_preprint":false},{"pmid":"36945158","id":"PMC_36945158","title":"Expression of TLE-1 in Gastrointestinal Stromal Tumour and Its Relationship to Clinicopathological Parameters.","date":"2023","source":"Journal of the College of Physicians and Surgeons--Pakistan : JCPSP","url":"https://pubmed.ncbi.nlm.nih.gov/36945158","citation_count":1,"is_preprint":false},{"pmid":"39781042","id":"PMC_39781042","title":"TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing.","date":"2024","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/39781042","citation_count":1,"is_preprint":false},{"pmid":"41403958","id":"PMC_41403958","title":"CN-VEFD: A visual emotion feature dataset for Chinese ESG reports.","date":"2025","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/41403958","citation_count":0,"is_preprint":false},{"pmid":"40335446","id":"PMC_40335446","title":"Differential Expression of TLE1 in Small Round Cell Tumors: A Proposed Solution for Challenging Differentials Impacting Treatment Strategies.","date":"2025","source":"International journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40335446","citation_count":0,"is_preprint":false},{"pmid":"41933729","id":"PMC_41933729","title":"\"Molecular insights into the bactericidal toxin Tle1 of Pseudomonas aeruginosa: Interaction with VgrG, its adaptor, and its immunity protein\".","date":"2026","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41933729","citation_count":0,"is_preprint":false},{"pmid":"21183761","id":"PMC_21183761","title":"Expression, purification, crystallization, and preliminary X-ray diffraction analysis of the human TLE1 Q domain.","date":"2010","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/21183761","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49136,"output_tokens":5943,"usd":0.118277},"stage2":{"model":"claude-opus-4-6","input_tokens":9639,"output_tokens":3977,"usd":0.22143},"total_usd":0.339707,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"TLE1 directly interacts with the WRPW motif of HES-1 (a mammalian Hairy-like protein), as demonstrated by yeast two-hybrid assay and GST pull-down assays, establishing a conserved Groucho/TLE–Hairy/HES interaction in mammals.\",\n      \"method\": \"Yeast two-hybrid assay; GST fusion protein pull-down assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — two orthogonal in vitro binding methods (Y2H and GST pull-down) in same study\",\n      \"pmids\": [\"8687460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Groucho/TLE1 proteins are phosphorylated, and more slowly migrating (higher molecular mass) phosphorylated forms associate more strongly with the nuclear compartment; these higher-mass TLE1 forms are induced during neural determination of P19 cells, implicating phosphorylation in nuclear function.\",\n      \"method\": \"Subcellular fractionation; SDS-PAGE mobility shift; immunoblotting; P19 differentiation model\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct fractionation experiment with functional correlation, single lab\",\n      \"pmids\": [\"8713081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of the C-terminal WD40 repeat domain of human TLE1 was determined to 1.6 Å, revealing a seven-bladed β-propeller; the structure identifies protein-protein interaction sites, including an induced-fit binding site for Eh1 (Engrailed-homology 1) domain transcription factors, and confirms structural relationship to yeast Tup1 corepressor.\",\n      \"method\": \"X-ray crystallography at 1.6 Å resolution; missense mutation analysis in C. elegans UNC-37\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional mutation mapping\",\n      \"pmids\": [\"12057191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TLE1 interacts with the intracellular region of gp130 (the shared IL-6 family cytokine signal transducer) through its Q domain, with the membrane-proximal Box1/Box2-containing region of gp130 being essential; demonstrated by yeast two-hybrid, GST pull-down, and co-immunoprecipitation.\",\n      \"method\": \"Yeast two-hybrid; GST pull-down; co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — three orthogonal binding methods, single lab\",\n      \"pmids\": [\"12030375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TLE1 was identified as a binding partner of the oncoprotein Qin (a winged helix transcription factor) via yeast two-hybrid screen; TLE1 binding requires a WRPW motif and correlates with Qin-induced transformation of chicken embryo fibroblasts; Qin binding induces phosphorylation of TLE1.\",\n      \"method\": \"Yeast two-hybrid screen; mammalian two-hybrid; transformation assay in chicken embryo fibroblasts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays with functional transformation readout, single lab\",\n      \"pmids\": [\"12660810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TLE1 was identified as an activation function-1 (AF-1) cofactor of the orphan nuclear receptor ERRγ; direct interaction was demonstrated by phage display biopanning and pull-down assay; surprisingly, TLE1 functioned as a coactivator (not repressor) of ERRγ in reporter gene assays.\",\n      \"method\": \"Phage display library biopanning; GST pull-down; reporter gene assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — binding plus functional reporter assay, single lab\",\n      \"pmids\": [\"14651967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CaMKIIδ-mediated activation triggers PARP-1, a component of the Groucho/TLE1 corepressor complex, causing dismissal of the TLE corepressor complex from HES1-regulated promoters; CaMKIIδ also phosphorylates HES1 to permit coactivator recruitment, switching HES1 from a TLE1-dependent repressor to an activator of neurogenic gene programs.\",\n      \"method\": \"Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); reporter assays; pharmacological CaMKII activation; dominant-negative constructs\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, ChIP, reporter), high-citation foundational study\",\n      \"pmids\": [\"15607978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Protein kinase CK2 phosphorylates TLE1 at serine 239 within the conserved CcN domain; this phosphorylation is required for TLE1 nuclear association, transcription repression activity, and its ability to inhibit cortical neural progenitor differentiation into neurons (mutation S239A reduces antineurogenic activity; S239E does not).\",\n      \"method\": \"In vivo phosphorylation assay; site-directed mutagenesis; cortical neural progenitor differentiation assay; immunocytochemistry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis paired with cellular differentiation assay and multiple phosphorylation analyses\",\n      \"pmids\": [\"15367661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TLE1 is expressed in postmitotic neurons of the adult rat brain, and its immunoreactivity is detected not only in nuclei but also in apical dendritic shafts of neocortical layer III/V pyramidal cells and Purkinje cell dendrites, indicating an unexpected extranuclear localization in differentiated neurons.\",\n      \"method\": \"Immunohistochemistry; confocal microscopy in adult rat brain sections\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization by immunohistochemistry, single study, no direct functional consequence tested\",\n      \"pmids\": [\"16081186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TLE1 (and TLE4) function as tumor suppressors in myeloid leukemia: shRNA knockdown of TLE1 rescues AML1-ETO-expressing cells from cell-cycle arrest and apoptosis, while forced TLE1 expression causes apoptosis; genetic epistasis in zebrafish confirms cooperation between TLE loss and AML1-ETO in hematopoietic blast accumulation.\",\n      \"method\": \"shRNA knockdown; forced expression; cell proliferation/apoptosis assays; zebrafish genetic epistasis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell lines, loss-of-function and gain-of-function with defined phenotypes, and in vivo zebrafish model\",\n      \"pmids\": [\"18258796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Point mutation L743F in the WD40 domain of TLE1 selectively blocks binding to Hes1 (WRPW motif) without disrupting binding to Engrailed1, FoxG1 (Eh1 motif), or Tcf3; this WRPW-binding is specifically required for TLE1-mediated inhibition of cortical neuron differentiation.\",\n      \"method\": \"Site-directed mutagenesis; co-immunoprecipitation; cortical neural progenitor differentiation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structure-guided mutagenesis dissecting two interaction surfaces with specific cellular readout\",\n      \"pmids\": [\"18611861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TLE1 undergoes promoter CpG island hypermethylation-associated silencing in diffuse large B-cell lymphoma and AML; reintroduction of TLE1 in hypermethylated cells causes growth inhibition in colony and xenograft assays, with effects mediated through transcriptional repression of Cyclin D1, CSF1R, and HES1.\",\n      \"method\": \"Bisulfite sequencing; colony formation assay; nude mouse xenograft; shRNA knockdown; gene expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including in vivo xenograft, gain- and loss-of-function, target gene identification\",\n      \"pmids\": [\"18519670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cofactor-activated phosphorylation of TLE1 at Ser-286 (and nearby Ser-289, Ser-298) within the SP domain, induced by interaction with DNA-binding partners (e.g., Hes1), strengthens TLE1 chromatin association and is required for its anti-neurogenic activity; mutations at these sites impair cofactor-activated phosphorylation and weaken chromatin binding without disrupting partner interaction or DNA recruitment.\",\n      \"method\": \"Site-directed mutagenesis; mass spectrometry; biochemistry; primary cortical neural progenitor culture; immunocytochemistry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — MS identification of phosphorylation sites, mutagenesis, and cellular differentiation assay with orthogonal methods\",\n      \"pmids\": [\"19956621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TLE1 associates with ribosomal RNA genes during mitosis and interphase through physical interaction with Runx2; TLE1 depletion relieves Runx2-mediated repression of rRNA transcription, increases active histone modifications at rRNA gene loci, and leads to increased global protein synthesis and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation; ChIP; siRNA knockdown; ribosomal RNA transcription assay; cell proliferation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, siRNA with multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"20160071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TLE1 and TLE3 interact with HESX1 and can repress PROP1 transcription both in the presence and absence of HESX1 via direct protein-protein interaction; TLE1 and TLE3 show similar repressive efficiencies; constitutive HESX1 expression in thyrotrophs and gonadotrophs suppresses terminal differentiation in transgenic mice.\",\n      \"method\": \"Co-immunoprecipitation; reporter gene assay; transgenic mouse overexpression\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — binding and reporter assays plus in vivo transgenic, single lab\",\n      \"pmids\": [\"20181723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TLE1 physically interacts with NOD2 (identified by yeast two-hybrid and confirmed by co-immunoprecipitation); TLE1 and NOD2 co-localize around the nuclear membrane; TLE1 inhibits NOD2-induced NF-κB activation in HEK293 cells, and TLE1 SNPs interact epistatically with NOD2 mutations in Crohn's disease susceptibility.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; co-localization; NF-κB reporter assay; genetic epistasis analysis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Y2H, reciprocal Co-IP, co-localization, and functional NF-κB assay with genetic epistasis\",\n      \"pmids\": [\"21699783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TLE1 promotes anoikis resistance in breast cancer cells; TLE1 inhibits the Bit1 anoikis pathway by sequestering AES in the nucleus, reducing formation of the proapoptotic Bit1-AES cytoplasmic complex; cytoplasmic Bit1 causes nuclear TLE1 translocation to the cytoplasm and its degradation.\",\n      \"method\": \"Forced expression; siRNA knockdown; anoikis assay; subcellular fractionation; immunofluorescence; co-immunoprecipitation\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple functional assays with mechanistic follow-up, single lab\",\n      \"pmids\": [\"22952044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TLE1 promotes neuronal survival in cerebellar granule neurons cooperatively with FoxG1; CK2 phosphorylation of TLE1 at Ser-239 and Ser-253 is required for its survival-promoting activity; PI3K-Akt signaling but not MEK-ERK or HDAC activity is required for TLE1-mediated neuroprotection.\",\n      \"method\": \"Ectopic expression; siRNA knockdown; pharmacological inhibitors; point mutant analysis; cerebellar granule neuron primary culture; cell viability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple inhibitors and mutants with defined cellular survival readout, single lab\",\n      \"pmids\": [\"22354967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TLE1 promotes epithelial-to-mesenchymal transition (EMT) in A549 lung cancer cells by transcriptionally repressing E-cadherin; TLE1 recruits histone deacetylase (HDAC) activity to the E-cadherin promoter; HDAC inhibitor TSA partially reverses TLE1-induced E-cadherin downregulation and cell migration.\",\n      \"method\": \"Forced expression; siRNA knockdown; cell migration assay; RT-PCR; ChIP; HDAC inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus gain/loss-of-function with pharmacological rescue, single lab\",\n      \"pmids\": [\"25446087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Grg1/TLE1 (the predominant Groucho in human β-cells) induces monohormonal β-cell identity and represses α-cell gene functions including glucagon and Arx expression; ectopic Grg3 in α-cells represses glucagon and, combined with Pdx1, induces glucose-responsive insulin secretion.\",\n      \"method\": \"Mouse genetic model (Grg3+/−); ectopic expression in pancreatic cell lines; gene expression profiling; insulin secretion assay\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model plus gain-of-function with functional secretion readout, single lab\",\n      \"pmids\": [\"24487024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tle1-deficient mice display a chronic inflammatory phenotype with increased NF-κB phosphorylation and activation in macrophages, increased inflammatory cytokines in response to TLR agonists/LPS, decreased Hes1 expression, and accelerated melanoma xenograft growth; this establishes TLE1 as an in vivo negative regulator of NF-κB-mediated inflammation.\",\n      \"method\": \"Conditional Tle1 knockout mouse; macrophage stimulation assay; cytokine ELISA; NF-κB phosphorylation immunoblotting; xenograft tumor model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with multiple orthogonal inflammatory and molecular readouts\",\n      \"pmids\": [\"26831087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TLE1 is phosphorylated by Ras-ERK pathway activation, which excludes TLE1 from the nucleus and attenuates its transcriptional repressor function; unphosphorylatable TLE1 blocks oncogenic H-Ras phenotypes in human mammary cells in vitro and in vivo, while phosphomimetic TLE1 has minimal repressive effects.\",\n      \"method\": \"Phosphorylation assays; nuclear exclusion/localization imaging; reporter gene assay; Drosophila transgenic model; mouse xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple systems (cell lines, transgenic Drosophila, mouse xenograft) with mutagenesis and functional readouts\",\n      \"pmids\": [\"28192406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TLE1 suppresses E-cadherin transcription by interacting with and recruiting ZEB1 to the E-cadherin promoter, imposing histone deacetylation and gene silencing; ZEB1 is required for TLE1-mediated anoikis resistance and tumorigenicity in lung cancer cells in vivo.\",\n      \"method\": \"ChIP; co-immunoprecipitation; siRNA; forced expression; xenograft tumorigenicity assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates promoter co-occupancy, co-IP shows TLE1-ZEB1 interaction, in vivo xenograft confirms functional consequence\",\n      \"pmids\": [\"29069783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The crystal structure of a stapled peptide inhibitor complexed with the TLE1 WD40 domain was solved; the WRPW epitope binds the WD40 β-propeller, and the constrained cycFWRPW peptide binds TLE1 with ~5-fold higher Kd than the acyclic peptide due to a small shift of one side chain.\",\n      \"method\": \"Co-crystal structure; isothermal titration calorimetry (ITC); thermal shift assay\",\n      \"journal\": \"Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — co-crystal structure with biophysical binding validation\",\n      \"pmids\": [\"28326635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXG1 and TLE1 form a complex that directly targets and represses specific genes in glioblastoma-initiating cells, including negative regulators of NOTCH signaling such as CHAC1; ChIP-Seq identified 150 direct FOXG1 targets, several shared with TLE1.\",\n      \"method\": \"ChIP-Seq; RNA-Seq; co-immunoprecipitation (implied by complex characterization)\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-Seq with RNA-Seq validation, single lab\",\n      \"pmids\": [\"29316219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A unique amino-terminal phosphorylation site present in TLE1 but absent from TLE3 confers distinct functional activity; mutating or reconstituting this site converts TLE1 activity toward TLE3-like behavior (and vice versa) in lung cancer drug sensitivity and adipocyte differentiation assays.\",\n      \"method\": \"Retroviral transduction; site-directed mutagenesis; paclitaxel sensitivity assay; adipocyte differentiation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mutagenesis in two functional systems, single lab\",\n      \"pmids\": [\"33571907\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TLE1 is a nuclear transcriptional corepressor that lacks intrinsic DNA-binding activity but is recruited to target gene promoters by a wide range of DNA-binding partners (including HES1, FOXG1, Runx2, HESX1, ZEB1, and Qin) via WRPW or Eh1 peptide motifs engaging its C-terminal WD40 β-propeller domain; once recruited, TLE1 mediates gene repression by associating with chromatin and recruiting histone deacetylases, and its activity is regulated by multiple phosphorylation events—CK2 phosphorylation at Ser-239 promotes nuclear retention and repressor function, while Ras-ERK pathway phosphorylation causes nuclear exclusion and loss of repression—enabling TLE1 to function as a context-dependent regulator of neurogenesis, hematopoiesis, inflammation (via NF-κB suppression), β-cell identity, EMT (through E-cadherin repression with ZEB1 and HDAC recruitment), and anoikis resistance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TLE1 is a non-DNA-binding transcriptional corepressor that serves as a nexus for integrating diverse developmental, inflammatory, and oncogenic signals by bridging sequence-specific transcription factors to chromatin-modifying machinery. Its C-terminal WD40 β-propeller domain engages WRPW-motif partners (e.g., HES1) and Eh1-motif partners (e.g., FOXG1, Engrailed) through structurally distinct binding surfaces, and once recruited to target promoters it silences genes such as E-cadherin, Cyclin D1, and glucagon by recruiting histone deacetylase activity [PMID:12057191, PMID:18611861, PMID:25446087, PMID:24487024]. TLE1 repressor function is positively regulated by CK2 phosphorylation at Ser-239, which promotes nuclear retention and anti-neurogenic activity, and by cofactor-activated phosphorylation at Ser-286/289/298 that strengthens chromatin association, whereas Ras-ERK-mediated phosphorylation causes nuclear exclusion and loss of repression [PMID:15367661, PMID:19956621, PMID:28192406]. In vivo, TLE1 loss produces chronic NF-κB-driven inflammation and accelerated tumor growth, and its promoter is epigenetically silenced by CpG hypermethylation in hematologic malignancies, establishing TLE1 as a context-dependent tumor suppressor in myeloid leukemia and lymphoma [PMID:26831087, PMID:18519670, PMID:18258796].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that mammalian TLE1 directly contacts HES1 via the WRPW motif resolved whether the Drosophila Groucho–Hairy corepressor mechanism was conserved in mammals and defined the founding protein-protein interaction mode.\",\n      \"evidence\": \"Yeast two-hybrid and GST pull-down with HES-1 and TLE1\",\n      \"pmids\": [\"8687460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding affinity not quantified\", \"Functional repression by the complex not demonstrated in this study\", \"Other WRPW-containing partners not tested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating that phosphorylated TLE1 isoforms preferentially associate with nuclei during neural differentiation first linked post-translational modification to TLE1 subcellular regulation.\",\n      \"evidence\": \"Subcellular fractionation and SDS-PAGE of P19 cell differentiation lysates\",\n      \"pmids\": [\"8713081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase identity unknown\", \"Phosphorylation sites not mapped\", \"Causality between phosphorylation and nuclear retention not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The 1.6 Å crystal structure of the TLE1 WD40 domain revealed a seven-bladed β-propeller with separate WRPW- and Eh1-binding surfaces, providing the structural framework for understanding how one corepressor engages multiple transcription-factor classes.\",\n      \"evidence\": \"X-ray crystallography with functional mutation mapping in C. elegans UNC-37\",\n      \"pmids\": [\"12057191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length TLE1 structure not determined\", \"Eh1 peptide-bound co-crystal not yet obtained in this study\", \"Oligomerization interface not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying the gp130 cytoplasmic domain as a TLE1 Q-domain interactor extended TLE1 function beyond classical transcription-factor partnerships to cytokine signaling scaffolds.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, and co-immunoprecipitation with gp130 truncations\",\n      \"pmids\": [\"12030375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of gp130–TLE1 interaction on cytokine signaling not shown\", \"Endogenous complex not validated\", \"Specificity among TLE family members not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that the oncoprotein Qin recruits TLE1 through a WRPW motif and that this interaction correlates with transformation linked TLE1 for the first time to an oncogenic pathway.\",\n      \"evidence\": \"Yeast two-hybrid screen, mammalian two-hybrid, and chicken embryo fibroblast transformation assay\",\n      \"pmids\": [\"12660810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TLE1 is required for Qin transformation not tested by loss-of-function\", \"Downstream target genes not identified\", \"Relevance to human cancer unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping CK2-mediated phosphorylation of TLE1 at Ser-239 as necessary for nuclear retention and anti-neurogenic repression established the first site-specific mechanism controlling TLE1 activity in a developmental context.\",\n      \"evidence\": \"In vivo phosphorylation, S239A/S239E mutagenesis, cortical progenitor differentiation assay\",\n      \"pmids\": [\"15367661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating CK2 in progenitors not identified\", \"Whether CK2 phosphorylation also affects non-neuronal functions unknown\", \"Interaction with chromatin not directly assayed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that CaMKIIδ-activated PARP-1 dismisses TLE1 from HES1-bound promoters, switching HES1 from repressor to activator, revealed a regulated corepressor-exchange mechanism at neurogenic genes.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays, and dominant-negative CaMKII constructs\",\n      \"pmids\": [\"15607978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PARP-1 modification of TLE1 not demonstrated\", \"Genome-wide scope of this switch unknown\", \"Whether this mechanism operates outside neurogenesis not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Structure-guided L743F mutagenesis in the WD40 domain selectively ablated WRPW binding (HES1) without affecting Eh1 binding (FoxG1, Engrailed), functionally separating two corepressor recruitment modes and showing WRPW interaction is specifically required for anti-neurogenic activity.\",\n      \"evidence\": \"Site-directed mutagenesis, co-immunoprecipitation, cortical progenitor assay\",\n      \"pmids\": [\"18611861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Eh1-specific mutation complementing L743F not generated\", \"Effect on chromatin modification not tested\", \"In vivo validation lacking\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that TLE1 is epigenetically silenced by promoter hypermethylation in B-cell lymphoma and AML, and that its re-expression inhibits growth and represses Cyclin D1, CSF1R, and HES1, established TLE1 as a bona fide tumor suppressor in hematologic malignancies.\",\n      \"evidence\": \"Bisulfite sequencing, colony formation, nude mouse xenograft, shRNA, gene expression profiling\",\n      \"pmids\": [\"18519670\", \"18258796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether methylation-mediated silencing occurs in solid tumors not addressed\", \"Direct promoter occupancy at Cyclin D1 not shown by ChIP\", \"Patient outcome correlation not provided\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of cofactor-activated phosphorylation at Ser-286/289/298 by mass spectrometry, induced upon DNA-binding partner interaction, revealed a feed-forward mechanism whereby partner recruitment strengthens TLE1–chromatin association independently of DNA targeting.\",\n      \"evidence\": \"Mass spectrometry, site-directed mutagenesis, cortical progenitor differentiation assay\",\n      \"pmids\": [\"19956621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for cofactor-activated phosphorylation not identified\", \"Whether this mechanism is universal across all TLE1 partners unknown\", \"Chromatin substrate specificity not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that TLE1 co-occupies ribosomal RNA gene loci with Runx2 and represses rRNA transcription linked the corepressor to ribosome biogenesis and global translational control, extending its roles beyond mRNA-encoding gene regulation.\",\n      \"evidence\": \"Co-IP, ChIP at rDNA loci, siRNA knockdown, rRNA transcription and cell proliferation assays\",\n      \"pmids\": [\"20160071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TLE1-mediated histone deacetylation at rDNA not elucidated\", \"Whether rRNA repression contributes to tumor suppression unknown\", \"Mitotic bookmarking mechanism not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that TLE1 is the predominant Groucho family member in β-cells and represses α-cell genes (glucagon, Arx) established TLE1 as a determinant of endocrine cell identity in the pancreas.\",\n      \"evidence\": \"Grg3 haploinsufficient mouse, ectopic expression in pancreatic cell lines, insulin secretion assay\",\n      \"pmids\": [\"24487024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"β-cell-specific TLE1 knockout not performed\", \"Direct TLE1 ChIP at glucagon/Arx promoters not shown\", \"Human β-cell relevance not demonstrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Conditional Tle1 knockout mice exhibiting chronic NF-κB hyperactivation, elevated inflammatory cytokines, and accelerated tumor growth provided definitive in vivo evidence that TLE1 is a physiological brake on innate immune signaling.\",\n      \"evidence\": \"Conditional Tle1 KO mouse, macrophage stimulation, cytokine ELISA, NF-κB phospho-blot, melanoma xenograft\",\n      \"pmids\": [\"26831087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of NF-κB inhibition (chromatin vs. cytoplasmic sequestration) not resolved\", \"Contribution of individual TLE1-partner interactions to inflammation unknown\", \"Adaptive immune cell phenotype not characterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying Ras-ERK-mediated phosphorylation as the signal that excludes TLE1 from the nucleus resolved the long-standing question of how oncogenic signaling inactivates this corepressor, and showed that an unphosphorylatable TLE1 mutant blocks H-Ras-driven transformation.\",\n      \"evidence\": \"Phosphorylation assays, nuclear exclusion imaging, Drosophila transgenic, mouse xenograft\",\n      \"pmids\": [\"28192406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ERK phosphorylation sites on TLE1 not mapped\", \"Relationship to CK2 and cofactor-activated phosphorylation not integrated\", \"Whether nuclear exclusion targets TLE1 for degradation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that TLE1 partners with ZEB1 to co-occupy the E-cadherin promoter and impose HDAC-dependent silencing unified TLE1's roles in EMT promotion and anoikis resistance through a single transcription-factor partnership.\",\n      \"evidence\": \"ChIP, co-IP, siRNA, forced expression, and xenograft tumorigenicity\",\n      \"pmids\": [\"29069783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which HDAC isoform is recruited not identified\", \"Genome-wide ZEB1-TLE1 co-occupancy not mapped\", \"Structural basis of TLE1–ZEB1 interaction unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying a unique N-terminal phosphorylation site that distinguishes TLE1 from TLE3 functional activity clarified how paralog-specific post-translational modifications diversify Groucho family member output.\",\n      \"evidence\": \"Mutagenesis, paclitaxel sensitivity assay, and adipocyte differentiation assay\",\n      \"pmids\": [\"33571907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible not identified\", \"Phosphorylation site not mapped to a specific residue\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the HDAC isoform(s) directly recruited by TLE1, the full-length oligomeric structure, the precise ERK phosphorylation sites mediating nuclear exclusion, and whether TLE1's anti-inflammatory and tumor-suppressive activities can be pharmacologically enhanced.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Full-length TLE1 structure not determined\", \"HDAC isoform specificity unresolved\", \"ERK phosphorylation sites not mapped\", \"No therapeutic-grade TLE1-modulating compound reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6, 7, 10, 11, 18, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 20]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 7, 8, 16, 21]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [12, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 7, 10, 11, 18, 22, 24]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12, 13, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 10, 19]}\n    ],\n    \"complexes\": [\n      \"HES1–TLE1 corepressor complex\",\n      \"FOXG1–TLE1 corepressor complex\",\n      \"ZEB1–TLE1 corepressor complex\",\n      \"Runx2–TLE1 corepressor complex\"\n    ],\n    \"partners\": [\n      \"HES1\",\n      \"FOXG1\",\n      \"ZEB1\",\n      \"RUNX2\",\n      \"HESX1\",\n      \"NOD2\",\n      \"AES\",\n      \"GP130\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}