{"gene":"TLE3","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2011,"finding":"TLE3 is a direct transcriptional target of PPARγ that participates in a feed-forward loop during adipocyte differentiation; TLE3 enhances PPARγ activity and functions synergistically with PPARγ on its target promoters to stimulate adipogenesis, while simultaneously antagonizing TCF4 activation by β-catenin to inhibit Wnt target gene expression.","method":"Chromatin immunoprecipitation, reporter assays, transgenic mouse model, gain/loss-of-function in preadipocytes","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter assays, transgenic mice), replicated functional consequences across systems","pmids":["21459326"],"is_preprint":false},{"year":2013,"finding":"TLE3 acts as a white adipose-selective cofactor that reciprocally opposes the brown-selective cofactor Prdm16; TLE3 disrupts the physical interaction between Prdm16 and PPARγ, and occupancy of TLE3 and Prdm16 on certain promoters is mutually exclusive. Conditional adipose-specific TLE3 knockout enhances thermogenesis in inguinal white adipose depots.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, conditional knockout mouse model, gene expression profiling","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating disruption of Prdm16-PPARγ interaction, confirmed with conditional KO mouse and multiple gene expression analyses","pmids":["23473036"],"is_preprint":false},{"year":2018,"finding":"The E3 ubiquitin ligase RNF6 binds and ubiquitinates TLE3, promoting its proteasomal degradation. RNF6-mediated loss of TLE3 suppresses TLE3 association with TCF4/LEF, enabling β-catenin recruitment to TCF4/LEF and consequent activation of Wnt/β-catenin signaling.","method":"Co-immunoprecipitation, ubiquitination assay, rescue experiments with TLE3 restoration, colorectal cancer cell lines and mouse xenograft models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, rescue experiments with TLE3 restoration, consistent in vitro and in vivo data in single lab","pmids":["29374067"],"is_preprint":false},{"year":2019,"finding":"TLE3 inhibits mitochondrial gene expression in beige adipocytes by occupying distal enhancers near nuclear-encoded mitochondrial genes. TLE3 interacts with the EBF2 transcription factor and blocks its ability to promote the thermogenic transcriptional program; conditional adipocyte-specific TLE3 deletion promotes mitochondrial oxidative metabolism and improves glucose control.","method":"Chromatin immunoprecipitation with deep sequencing (ChIP-seq), co-immunoprecipitation, conditional knockout mouse model, metabolic phenotyping","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, Co-IP, and conditional KO with defined metabolic phenotype, multiple orthogonal methods in single lab","pmids":["31123067"],"is_preprint":false},{"year":2019,"finding":"In prostate cancer cells, TLE3 co-occupies the glucocorticoid receptor (GR) locus with AR, repressing GR expression. Loss of TLE3 confers resistance to AR antagonists by enabling upregulation of GR, which rescues expression of androgen-responsive genes under enzalutamide treatment; GR inhibition re-sensitizes TLE3-knockout cells to enzalutamide.","method":"Genome-wide CRISPR-Cas9 screen, ChIP, gene expression analysis, pharmacological rescue experiments in LNCaP cells","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen plus ChIP and pharmacological rescue, multiple orthogonal methods in single study","pmids":["31855178"],"is_preprint":false},{"year":2014,"finding":"TLE3 interacts with FoxA1 and is recruited to regulatory elements of ERα target genes in the absence of estrogen in breast cancer MCF-7 cells. TLE3 also interacts with HDAC2 to maintain chromatin at basal acetylation levels, preventing ligand-independent activation. At the TFF1 gene, TLE3 recruitment is FoxA1-dependent and prevents ERα and RNA Pol II recruitment.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, knockdown experiments, reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional reporter assays in same study, multiple orthogonal methods","pmids":["25223786"],"is_preprint":false},{"year":2017,"finding":"TLE3 represses myogenic differentiation by interfering with the association between the bHLH domain of MyoD and E proteins; this disruption is mediated through the glutamine- and serine/proline-rich domains of TLE3. Elevated TLE3 in activated satellite cells suppresses differentiation, while reduced TLE3 promotes myogenesis.","method":"Co-immunoprecipitation, domain deletion/mapping, overexpression and shRNA knockdown in satellite cells and C2C12 cells, myogenic differentiation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping Co-IP establishing mechanism, combined with loss/gain-of-function differentiation assays","pmids":["28607151"],"is_preprint":false},{"year":2012,"finding":"Grg3/TLE3 is expressed in Ngn3+ endocrine progenitor descendants in the pancreas and is required for delamination of endocrine progenitors from the trunk epithelium by suppressing E-cadherin gene expression. Grg3-null pancreatic explants show drastically reduced differentiation of all endocrine cell types.","method":"Grg3 knockout mouse embryo explant culture, in situ hybridization, immunostaining, gene expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined cellular phenotype (delamination defect) and molecular mechanism (E-cadherin suppression)","pmids":["22434868"],"is_preprint":false},{"year":2013,"finding":"TLE3 suppresses osteoblast differentiation of bone marrow stromal cells by repressing Runx2 transcriptional activity via HDACs; this repression is rescued by HDAC inhibitor TSA. TLE3 overexpression also suppresses ALP activity and OSE2-luciferase activity induced by Runx2.","method":"Overexpression and shRNA knockdown in bone marrow stromal cells, ALP activity assay, OSE2-luciferase reporter assay, HDAC inhibitor rescue experiment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional reporter and rescue assays in single lab but no direct interaction between TLE3 and Runx2 demonstrated by Co-IP","pmids":["23880346"],"is_preprint":false},{"year":2013,"finding":"TLE3 is required for development of trophoblast giant cells lining maternal blood spaces in the mouse placenta; Tle3-null mice die in utero with placental defects. TLE3 expression overlaps with Notch2 in trophoblast giant cell subtypes, and Tle3 and Notch2 mutants share overlapping phenotypic features, suggesting TLE3 mediates some Notch2 signaling effects in this context.","method":"Tle3-knockout mouse generation, histological and molecular analysis, comparison with Notch2 mutants","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic KO with defined developmental phenotype; Notch2 epistasis is inferred from phenotypic comparison, not direct molecular interaction assay","pmids":["23954203"],"is_preprint":false},{"year":2020,"finding":"TLE3 interacts with the transcription factor Hhex to promote memory B cell development; both Hhex and Tle3 were identified in an inducible CRISPR-Cas9 screen for MBC differentiation, and TLE3 co-immunoprecipitates with Hhex.","method":"Inducible CRISPR-Cas9 screen, co-immunoprecipitation, single-cell RNA sequencing, conditional knockout","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen plus Co-IP plus scRNA-seq and conditional KO, multiple orthogonal methods identifying TLE3-Hhex interaction","pmids":["32601467"],"is_preprint":false},{"year":2021,"finding":"FOXC1 interacts with RUNX1 through Forkhead and Runt domains, respectively, and stabilizes association of RUNX1, HDAC1, and TLE3 at enhancers near myeloid differentiation genes, limiting enhancer activity. FOXC1 knockdown causes loss of this repressor complex from enhancers, gain of CEBPA binding, and upregulation of nearby differentiation genes.","method":"Integrated proteomics, co-immunoprecipitation, ChIP-seq, FOXC1 knockdown in AML cells","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proteomics plus Co-IP plus ChIP-seq with KD functional validation, multiple orthogonal methods identifying RUNX1/HDAC1/TLE3 complex","pmids":["34551306"],"is_preprint":false},{"year":2024,"finding":"TLE3 acts as a coactivator for Tbet to increase chromatin accessibility at CD8+ TEM cell-characteristic genomic sites and activate TEM signature gene transcription; simultaneously, TLE3 engages Runx3 and Tcf1 to limit TCM cell-characteristic molecular features. Genetic ablation of Tle3 promoted TCM cell formation at the expense of TEM cells, and Tle3-deficient TEM cells showed accelerated conversion to TCM cells.","method":"Genetic ablation (conditional KO), lineage tracing, ATAC-seq, ChIP-seq, co-immunoprecipitation with Tbet/Runx3/Tcf1","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with lineage tracing, chromatin accessibility (ATAC-seq), and ChIP-seq identifying TLE3 coactivator and corepressor interactions, multiple orthogonal methods","pmids":["38238608"],"is_preprint":false},{"year":2014,"finding":"Foxa1 interacts with Grg3/TLE3 and recruits it to the Nanog promoter (~2 kb upstream), switching the promoter to an inactive chromatin state characterized by repressive histone H3 modifications, thereby repressing Nanog expression during differentiation of pluripotent P19 cells.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, overexpression and knockdown of Foxa1/Grg3, histone modification analysis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ChIP confirming recruitment and histone changes, single lab with two orthogonal methods but limited functional rescue","pmids":["24803390"],"is_preprint":false},{"year":2010,"finding":"TLE3 and TLE1 each interact with HESX1 and repress PROP1 transcriptional activity; both can repress PROP1 even in the absence of HESX1 via a direct protein-protein interaction. In transgenic mice, HESX1 alone and HESX1+TLE3 together suppress terminal differentiation of pituitary thyrotrophs and gonadotrophs, but TLE3 alone does not.","method":"Cell-based reporter repression assay, co-immunoprecipitation (protein-protein interaction), transgenic mouse experiments","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and reporter assay with transgenic validation, but single lab","pmids":["20181723"],"is_preprint":false},{"year":2014,"finding":"Grg3/TLE3 is expressed in almost all β-cells throughout development to adulthood; heterozygous Grg3 loss leads to increased α-specific gene expression and more polyhormonal cells, demonstrating a requirement for Grg3 in maintaining monohormonal β-cell identity. Ectopic Grg3 expression in α-cells represses glucagon and Arx.","method":"Grg3 heterozygous knockout mice, immunostaining, gene expression analysis, ectopic expression in α-cells","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype and molecular readout, validated by ectopic expression, single lab","pmids":["24487024"],"is_preprint":false},{"year":2024,"finding":"TLE3 interacts with and recruits the histone methyltransferase KMT1A to repress target genes and inhibit differentiation in rhabdomyosarcoma. Loss of TLE3 activates the Wnt pathway, reduces proliferation, and enhances differentiation; muscle-specific TLE3 knockout enhances terminal myogenic differentiation markers in vivo.","method":"Co-immunoprecipitation, muscle-specific knockout, xenograft mouse model, drug combination experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying TLE3-KMT1A interaction plus in vivo KO and xenograft, single lab with multiple orthogonal approaches","pmids":["38177411"],"is_preprint":false},{"year":2025,"finding":"TRIM56, an E3 ubiquitin ligase, promotes K48-linked ubiquitination of TLE3, leading to its proteasomal degradation in adipocytes in response to cold stimuli; degradation of TLE3 activates thermogenic genes in subcutaneous white adipose tissue.","method":"Overexpression and knockdown in adipocytes, ubiquitination assay (K48-linkage specific), cold-exposure mouse model, metabolic phenotyping","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ubiquitination assay with K48 linkage specificity and in vivo cold-exposure mouse model, single lab, moderate mechanistic detail","pmids":["39928840"],"is_preprint":false},{"year":2014,"finding":"Wnt signaling increases TLE3 expression in bone marrow stromal cells via Wnt-responsive elements in the TLE3 promoter; ectopic TLE3 in turn suppresses canonical Wnt signaling, establishing a negative feedback loop during osteoblast differentiation.","method":"Comparative genomic analysis of TLE3 promoter, functional reporter assay for Wnt-responsive elements, overexpression experiments in BMSCs","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — promoter reporter assays and overexpression in single lab; no direct transcription factor binding to Wnt-response elements confirmed by ChIP","pmids":["24444608"],"is_preprint":false},{"year":2023,"finding":"TLE3 sustains luminal breast cancer lineage identity by repressing the gene-expression signature associated with basal-like breast cancers; this repression is mediated by interactions with FOXA1, which localizes TLE3 to its transcriptional targets. TLE3 represses SOX9 and TGFβ2, preventing acquisition of a hybrid epithelial-mesenchymal state.","method":"ChIP-seq (TLE3 and FOXA1 co-occupancy), gene expression analysis, loss-of-function with metastasis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP-seq and Co-IP with functional assays, single lab, identifying FOXA1-dependent TLE3 targeting and downstream gene repression","pmids":["36696357"],"is_preprint":false},{"year":2023,"finding":"TLE3 (and TLE4) negatively regulate MMP9 transcription in colonic macrophages; deficiency of TLE3 in myeloid cells leads to upregulated MMP9 production, enhanced latent TGF-β activation, and subsequent expansion of Treg and TH17 cells in the colonic lamina propria.","method":"Myeloid-specific TLE3/TLE4 conditional knockout mice, gene expression analysis, MMP9 activity assays, colitis model","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional KO with defined molecular mechanism (MMP9 → TGF-β → Treg/TH17), single lab","pmids":["36801171"],"is_preprint":false},{"year":2021,"finding":"A single amino-terminal phosphorylation site present in TLE1 but absent from TLE3 determines their differential activity; mutating this site in TLE1 converts its activity to TLE3-like (increasing paclitaxel sensitivity and promoting adipocyte differentiation), while reconstituting it in TLE3 confers TLE1-like activity.","method":"Retroviral transduction of TLE1/TLE3 mutants in A549 cells, site-directed mutagenesis, paclitaxel sensitivity assays, adipocyte differentiation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with functional readout across two systems, but single lab with limited mechanistic depth (phosphorylation writer/reader not identified)","pmids":["33571907"],"is_preprint":false},{"year":2023,"finding":"TLE3 interacts with Zeb1 and acts upstream of Zeb1 in regulating myogenic differentiation; Tle3 depletion leads to reduced expression of myogenic differentiation genes including Myh3, impaired differentiation, and downregulation of Zeb1 potentially mediated by increased miR-200c. TLE3 also regulates MyoG expression post-transcriptionally via the mRNA-stabilizing protein HuR.","method":"shRNA knockdown of Tle3 and Zeb1 in C2C12 cells, double-knockdown epistasis, reporter assay for Myh3 promoter, miR-200c measurement, HuR interaction experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — epistasis by double KD, reporter assays, and post-transcriptional regulatory mechanism identified, single lab","pmids":["37392376"],"is_preprint":false},{"year":2010,"finding":"Grg3/TLE3 protein (but not mRNA alone) is expressed in foregut endoderm co-expressed with FoxA factors prior to liver differentiation; lentiviral delivery of Grg3 to foregut endoderm explants suppresses liver gene induction, indicating that Grg3 helps repress the hepatic differentiation program in endoderm.","method":"In situ hybridization, immunostaining, lentiviral Grg3 delivery to foregut endoderm explants, gene expression analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — lentiviral gain-of-function in explant with defined gene expression phenotype, single lab","pmids":["20108349"],"is_preprint":false},{"year":2023,"finding":"HHEX overexpression upregulates TLE3 protein expression by preventing TLE3 from being distributed to the cytoplasm and being ubiquitinated; nuclear-localized HHEX binds to and stabilizes TLE3, which then inhibits the Wnt/β-catenin signaling pathway in thyroid cancer cells.","method":"Co-immunoprecipitation, overexpression/knockdown, subcellular fractionation, ubiquitination assay, reporter assays for Wnt pathway","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assays with functional validation, single lab, moderate mechanistic depth","pmids":["37302518"],"is_preprint":false},{"year":2024,"finding":"TLE3 and TLE4 participate in diminishing canonical Wnt signaling activity at the neuromuscular junction; CRISPR/Cas9 knockout of TLE3 in satellite cells led to decreased agrin-dependent acetylcholine receptor (CHRN) clustering and reduced synaptic gene transcription upon differentiation.","method":"CRISPR/Cas9 KO in primary satellite cells, CHRN clustering assay, synaptic gene expression analysis, denervation paradigm in Axin2-lacZ reporter mice","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — CRISPR KO with defined functional phenotype (CHRN clustering), single lab, limited mechanistic pathway detail","pmids":["38600964"],"is_preprint":false}],"current_model":"TLE3 is a transcriptional corepressor of the Groucho/TLE family that functions as a context-dependent integrator of multiple signaling pathways: it enhances PPARγ-driven adipogenesis while suppressing Wnt/β-catenin signaling by antagonizing TCF4/β-catenin complexes, disrupts Prdm16-PPARγ interaction to specify white over brown adipocyte identity, interacts with EBF2 to inhibit thermogenic gene programs in beige fat, blocks MyoD-E protein heterodimerization to dampen myogenic differentiation, interacts with FoxA1 and HDAC2 to maintain repressive chromatin at ERα target genes, forms repressor complexes with RUNX1/HDAC1 at myeloid differentiation enhancers, cooperates with Hhex to promote memory B cell differentiation, and acts as a coactivator for Tbet while engaging Runx3/Tcf1 to control CD8+ T cell effector versus central memory fate; its protein stability is regulated by K48-linked ubiquitination by RNF6 and TRIM56, and a unique N-terminal phosphorylation site absent from TLE3 (but present in TLE1) determines differential functional activity between paralogs."},"narrative":{"mechanistic_narrative":"TLE3 is a Groucho/TLE-family transcriptional corepressor that acts as a context-dependent integrator of differentiation and signaling decisions across adipose, muscle, endocrine, immune, and epithelial tissues [PMID:21459326, PMID:23473036, PMID:28607151]. Its most extensively characterized output is the repression of Wnt/β-catenin signaling: TLE3 antagonizes β-catenin activation of TCF4/LEF complexes [PMID:21459326], and this antagonism is itself dialed by TLE3 protein abundance, which is set by K48-linked ubiquitination and proteasomal degradation via the E3 ligases RNF6 and TRIM56 [PMID:29374067, PMID:39928840]. TLE3 generally executes repression by partnering with sequence-specific factors and chromatin modifiers — it recruits HDAC2 with FoxA1 to keep ERα targets in a basal acetylation state [PMID:25223786], assembles a RUNX1/HDAC1 repressor complex stabilized by FOXC1 at myeloid differentiation enhancers [PMID:34551306], and engages the histone methyltransferase KMT1A to silence differentiation genes [PMID:38177411]. In adipocytes TLE3 is a PPARγ target and cofactor that promotes white over thermogenic identity by disrupting Prdm16–PPARγ interaction and by blocking EBF2-driven mitochondrial gene programs, such that its loss enhances thermogenesis and glucose control [PMID:21459326, PMID:23473036, PMID:31123067]. It restrains lineage differentiation broadly, blocking MyoD–E-protein heterodimerization in myogenesis [PMID:28607151] and Runx2 activity in osteoblasts [PMID:23880346], while controlling cell-fate identity in pancreatic endocrine cells [PMID:22434868, PMID:24487024], memory B cells via Hhex [PMID:32601467], and CD8+ T cells, where it uniquely acts as a Tbet coactivator while engaging Runx3/Tcf1 to bias effector versus central-memory fate [PMID:38238608]. A single N-terminal phosphorylation site present in TLE1 but absent from TLE3 accounts for functional divergence between the paralogs [PMID:33571907]. No timeline discovery links TLE3 to a Mendelian disease.","teleology":[{"year":2010,"claim":"Established TLE3 as a corepressor acting through direct protein interactions, showing it represses PROP1 via HESX1 and represses hepatic gene induction in foregut endoderm.","evidence":"Co-IP and reporter repression assays with HESX1/transgenic mice; lentiviral Grg3 gain-of-function in endoderm explants","pmids":["20181723","20108349"],"confidence":"Medium","gaps":["Chromatin/recruitment mechanism at endogenous loci not resolved","Cofactor complex composition not defined"]},{"year":2011,"claim":"Defined TLE3's dual role in adipogenesis as both a PPARγ target and synergistic cofactor and an antagonist of β-catenin/TCF4, linking it to the Wnt axis.","evidence":"ChIP, reporter assays, and gain/loss-of-function in preadipocytes plus transgenic mice","pmids":["21459326"],"confidence":"High","gaps":["Molecular basis of PPARγ synergy not structurally defined","How TLE3 physically blocks β-catenin not detailed"]},{"year":2012,"claim":"Showed a developmental requirement for TLE3 in pancreatic endocrine progenitor delamination through E-cadherin suppression.","evidence":"Grg3 knockout embryo explant culture with in situ hybridization and expression analysis","pmids":["22434868"],"confidence":"High","gaps":["Direct transcriptional target relationship to E-cadherin not shown","Partner factors in progenitors unidentified"]},{"year":2013,"claim":"Revealed TLE3 as a white-selective adipose cofactor that opposes Prdm16 and suppresses thermogenesis, establishing a fat-identity switch function.","evidence":"Reciprocal Co-IP showing Prdm16-PPARγ disruption, ChIP, and adipose-specific conditional KO with metabolic phenotyping","pmids":["23473036","23954203","24487024"],"confidence":"High","gaps":["Determinants of mutually exclusive promoter occupancy unclear","Placental Notch2 epistasis inferred, not biochemically shown"]},{"year":2014,"claim":"Mapped TLE3 as a FoxA1/HDAC2-recruited corepressor maintaining repressive chromatin at hormone-responsive and pluripotency genes (ERα targets, Nanog).","evidence":"Co-IP, ChIP, knockdown, histone modification analysis, and reporter assays in MCF-7 and P19 cells","pmids":["25223786","24803390","24444608"],"confidence":"High","gaps":["Generality of FoxA1 dependence across loci not established","Direct HDAC2 recruitment sequence not defined"]},{"year":2017,"claim":"Defined the mechanism by which TLE3 blocks myogenic differentiation — disrupting MyoD–E-protein heterodimerization via its Q- and S/P-rich domains.","evidence":"Domain-mapping Co-IP plus gain/loss-of-function differentiation assays in satellite and C2C12 cells","pmids":["28607151"],"confidence":"High","gaps":["Whether this extends to other bHLH factors not tested"]},{"year":2018,"claim":"Identified post-translational control of TLE3 by RNF6-mediated K48 ubiquitination, coupling its degradation to derepression of Wnt/β-catenin signaling in colorectal cancer.","evidence":"Co-IP, ubiquitination assay, and TLE3-restoration rescue in CRC cells and xenografts","pmids":["29374067"],"confidence":"High","gaps":["Ubiquitination site on TLE3 not mapped","Signals controlling RNF6 activity unknown"]},{"year":2019,"claim":"Extended TLE3's adipose role to direct enhancer occupancy blocking EBF2-driven mitochondrial programs, and revealed an AR-cooperative repression of GR controlling antiandrogen resistance.","evidence":"ChIP-seq, Co-IP, conditional KO with metabolic phenotyping (beige fat); genome-wide CRISPR screen, ChIP, and pharmacological rescue (LNCaP)","pmids":["31123067","31855178"],"confidence":"High","gaps":["How TLE3 selects distal enhancers not defined","Mechanism of AR/TLE3 co-occupancy at GR locus not detailed"]},{"year":2020,"claim":"Identified TLE3-Hhex as a driver of memory B cell differentiation, broadening TLE3 into adaptive immune fate decisions.","evidence":"Inducible CRISPR-Cas9 screen, Co-IP, scRNA-seq, conditional KO","pmids":["32601467"],"confidence":"High","gaps":["Target genes of the TLE3-Hhex complex not defined"]},{"year":2021,"claim":"Defined TLE3 as a component of a FOXC1-stabilized RUNX1/HDAC1 repressor complex limiting myeloid differentiation enhancer activity, and uncovered an N-terminal phosphosite that distinguishes TLE3 from TLE1.","evidence":"Proteomics, Co-IP, ChIP-seq with FOXC1 knockdown (AML); site-directed mutagenesis with functional swap assays (A549/adipocytes)","pmids":["34551306","33571907"],"confidence":"High","gaps":["Kinase/phosphatase acting on the TLE1 phosphosite not identified","Functional consequence of the missing site mechanistically unexplained"]},{"year":2023,"claim":"Consolidated TLE3 as a guardian of differentiated/lineage identity across tissues — luminal breast cancer, rhabdomyosarcoma, myogenesis, colonic macrophages, and thyroid cancer — frequently through FOXA1 targeting, chromatin modifiers, and Wnt restraint.","evidence":"ChIP-seq/Co-IP with FOXA1 and metastasis assays; KMT1A Co-IP with muscle-specific KO; double-KD epistasis with Zeb1/HuR; myeloid conditional KO with MMP9/TGF-β readout; HHEX stabilization and Wnt reporter assays","pmids":["36696357","38177411","37392376","36801171","37302518"],"confidence":"Medium","gaps":["Whether one unified complex underlies these contexts is unresolved","Direct vs indirect targets often inferred from expression changes"]},{"year":2024,"claim":"Demonstrated TLE3 can act as a coactivator, not only a corepressor, partnering Tbet to open effector chromatin while engaging Runx3/Tcf1 to restrain central-memory fate in CD8+ T cells; also linked TLE3 to NMJ Wnt signaling.","evidence":"Conditional KO, lineage tracing, ATAC-seq, ChIP-seq, Co-IP with Tbet/Runx3/Tcf1; CRISPR KO in satellite cells with CHRN clustering and Axin2 reporter mice","pmids":["38238608","38600964"],"confidence":"High","gaps":["Structural/biochemical basis for coactivator vs corepressor switching unknown"]},{"year":2025,"claim":"Added TRIM56 as a second E3 ligase controlling TLE3 stability, linking cold-induced TLE3 degradation to activation of thermogenic gene programs.","evidence":"K48-linkage-specific ubiquitination assay and cold-exposure mouse model with metabolic phenotyping","pmids":["39928840"],"confidence":"Medium","gaps":["Single lab; ubiquitination site not mapped","Relationship between RNF6 and TRIM56 control of TLE3 unresolved"]},{"year":null,"claim":"What determines whether TLE3 functions as a corepressor versus a coactivator, and what defines its target-locus selectivity across the many sequence-specific factors it partners, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model for the corepressor/coactivator switch","The kinase governing the paralog-discriminating phosphosite is unidentified","No unifying model linking the diverse tissue-specific partner factors"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,11,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,11,24]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,11,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,1,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,12,20]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,3]}],"complexes":["RUNX1/HDAC1/FOXC1 repressor complex"],"partners":["PPARG","TCF4","FOXA1","HDAC2","EBF2","RUNX1","TBX21","HHEX"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q04726","full_name":"Transducin-like enhancer protein 3","aliases":["Enhancer of split groucho-like protein 3","ESG3"],"length_aa":772,"mass_kda":83.4,"function":"Transcriptional coregulator that binds to a number of transcription factors. Acts as a regulator of adipogenesis both by acting as a corepressor of Wnt signaling and coactivator for PPARG (PubMed:28689657). Inhibits the transcriptional activation mediated by CTNNB1 and TCF family members in Wnt signaling (PubMed:28689657). Promotes diffentiation of white adipocytes by acting as a coactivator for PPARG and preventing the association between PRDM16 and PPARG, thereby preventing browning of white adipocytes (By similarity)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q04726/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TLE3","classification":"Not Classified","n_dependent_lines":50,"n_total_lines":1208,"dependency_fraction":0.041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TLE3","total_profiled":1310},"omim":[{"mim_id":"612632","title":"USHER SYNDROME, TYPE IH; USH1H","url":"https://www.omim.org/entry/612632"},{"mim_id":"609439","title":"DEAFNESS, AUTOSOMAL RECESSIVE 48; DFNB48","url":"https://www.omim.org/entry/609439"},{"mim_id":"605132","title":"TLE FAMILY MEMBER 4, TRANSCRIPTIONAL COREPRESSOR; TLE4","url":"https://www.omim.org/entry/605132"},{"mim_id":"602294","title":"FORKHEAD BOX A1; FOXA1","url":"https://www.omim.org/entry/602294"},{"mim_id":"601041","title":"TLE FAMILY MEMBER 2, TRANSCRIPTIONAL COREPRESSOR; TLE2","url":"https://www.omim.org/entry/601041"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone 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\"Chromatin immunoprecipitation, reporter assays, transgenic mouse model, gain/loss-of-function in preadipocytes\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter assays, transgenic mice), replicated functional consequences across systems\",\n      \"pmids\": [\"21459326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TLE3 acts as a white adipose-selective cofactor that reciprocally opposes the brown-selective cofactor Prdm16; TLE3 disrupts the physical interaction between Prdm16 and PPARγ, and occupancy of TLE3 and Prdm16 on certain promoters is mutually exclusive. Conditional adipose-specific TLE3 knockout enhances thermogenesis in inguinal white adipose depots.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, conditional knockout mouse model, gene expression profiling\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating disruption of Prdm16-PPARγ interaction, confirmed with conditional KO mouse and multiple gene expression analyses\",\n      \"pmids\": [\"23473036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The E3 ubiquitin ligase RNF6 binds and ubiquitinates TLE3, promoting its proteasomal degradation. RNF6-mediated loss of TLE3 suppresses TLE3 association with TCF4/LEF, enabling β-catenin recruitment to TCF4/LEF and consequent activation of Wnt/β-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, rescue experiments with TLE3 restoration, colorectal cancer cell lines and mouse xenograft models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, rescue experiments with TLE3 restoration, consistent in vitro and in vivo data in single lab\",\n      \"pmids\": [\"29374067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TLE3 inhibits mitochondrial gene expression in beige adipocytes by occupying distal enhancers near nuclear-encoded mitochondrial genes. TLE3 interacts with the EBF2 transcription factor and blocks its ability to promote the thermogenic transcriptional program; conditional adipocyte-specific TLE3 deletion promotes mitochondrial oxidative metabolism and improves glucose control.\",\n      \"method\": \"Chromatin immunoprecipitation with deep sequencing (ChIP-seq), co-immunoprecipitation, conditional knockout mouse model, metabolic phenotyping\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, Co-IP, and conditional KO with defined metabolic phenotype, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"31123067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In prostate cancer cells, TLE3 co-occupies the glucocorticoid receptor (GR) locus with AR, repressing GR expression. Loss of TLE3 confers resistance to AR antagonists by enabling upregulation of GR, which rescues expression of androgen-responsive genes under enzalutamide treatment; GR inhibition re-sensitizes TLE3-knockout cells to enzalutamide.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, ChIP, gene expression analysis, pharmacological rescue experiments in LNCaP cells\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen plus ChIP and pharmacological rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"31855178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TLE3 interacts with FoxA1 and is recruited to regulatory elements of ERα target genes in the absence of estrogen in breast cancer MCF-7 cells. TLE3 also interacts with HDAC2 to maintain chromatin at basal acetylation levels, preventing ligand-independent activation. At the TFF1 gene, TLE3 recruitment is FoxA1-dependent and prevents ERα and RNA Pol II recruitment.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, knockdown experiments, reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional reporter assays in same study, multiple orthogonal methods\",\n      \"pmids\": [\"25223786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TLE3 represses myogenic differentiation by interfering with the association between the bHLH domain of MyoD and E proteins; this disruption is mediated through the glutamine- and serine/proline-rich domains of TLE3. Elevated TLE3 in activated satellite cells suppresses differentiation, while reduced TLE3 promotes myogenesis.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/mapping, overexpression and shRNA knockdown in satellite cells and C2C12 cells, myogenic differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping Co-IP establishing mechanism, combined with loss/gain-of-function differentiation assays\",\n      \"pmids\": [\"28607151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Grg3/TLE3 is expressed in Ngn3+ endocrine progenitor descendants in the pancreas and is required for delamination of endocrine progenitors from the trunk epithelium by suppressing E-cadherin gene expression. Grg3-null pancreatic explants show drastically reduced differentiation of all endocrine cell types.\",\n      \"method\": \"Grg3 knockout mouse embryo explant culture, in situ hybridization, immunostaining, gene expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined cellular phenotype (delamination defect) and molecular mechanism (E-cadherin suppression)\",\n      \"pmids\": [\"22434868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TLE3 suppresses osteoblast differentiation of bone marrow stromal cells by repressing Runx2 transcriptional activity via HDACs; this repression is rescued by HDAC inhibitor TSA. TLE3 overexpression also suppresses ALP activity and OSE2-luciferase activity induced by Runx2.\",\n      \"method\": \"Overexpression and shRNA knockdown in bone marrow stromal cells, ALP activity assay, OSE2-luciferase reporter assay, HDAC inhibitor rescue experiment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional reporter and rescue assays in single lab but no direct interaction between TLE3 and Runx2 demonstrated by Co-IP\",\n      \"pmids\": [\"23880346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TLE3 is required for development of trophoblast giant cells lining maternal blood spaces in the mouse placenta; Tle3-null mice die in utero with placental defects. TLE3 expression overlaps with Notch2 in trophoblast giant cell subtypes, and Tle3 and Notch2 mutants share overlapping phenotypic features, suggesting TLE3 mediates some Notch2 signaling effects in this context.\",\n      \"method\": \"Tle3-knockout mouse generation, histological and molecular analysis, comparison with Notch2 mutants\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic KO with defined developmental phenotype; Notch2 epistasis is inferred from phenotypic comparison, not direct molecular interaction assay\",\n      \"pmids\": [\"23954203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TLE3 interacts with the transcription factor Hhex to promote memory B cell development; both Hhex and Tle3 were identified in an inducible CRISPR-Cas9 screen for MBC differentiation, and TLE3 co-immunoprecipitates with Hhex.\",\n      \"method\": \"Inducible CRISPR-Cas9 screen, co-immunoprecipitation, single-cell RNA sequencing, conditional knockout\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen plus Co-IP plus scRNA-seq and conditional KO, multiple orthogonal methods identifying TLE3-Hhex interaction\",\n      \"pmids\": [\"32601467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXC1 interacts with RUNX1 through Forkhead and Runt domains, respectively, and stabilizes association of RUNX1, HDAC1, and TLE3 at enhancers near myeloid differentiation genes, limiting enhancer activity. FOXC1 knockdown causes loss of this repressor complex from enhancers, gain of CEBPA binding, and upregulation of nearby differentiation genes.\",\n      \"method\": \"Integrated proteomics, co-immunoprecipitation, ChIP-seq, FOXC1 knockdown in AML cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus Co-IP plus ChIP-seq with KD functional validation, multiple orthogonal methods identifying RUNX1/HDAC1/TLE3 complex\",\n      \"pmids\": [\"34551306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TLE3 acts as a coactivator for Tbet to increase chromatin accessibility at CD8+ TEM cell-characteristic genomic sites and activate TEM signature gene transcription; simultaneously, TLE3 engages Runx3 and Tcf1 to limit TCM cell-characteristic molecular features. Genetic ablation of Tle3 promoted TCM cell formation at the expense of TEM cells, and Tle3-deficient TEM cells showed accelerated conversion to TCM cells.\",\n      \"method\": \"Genetic ablation (conditional KO), lineage tracing, ATAC-seq, ChIP-seq, co-immunoprecipitation with Tbet/Runx3/Tcf1\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with lineage tracing, chromatin accessibility (ATAC-seq), and ChIP-seq identifying TLE3 coactivator and corepressor interactions, multiple orthogonal methods\",\n      \"pmids\": [\"38238608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Foxa1 interacts with Grg3/TLE3 and recruits it to the Nanog promoter (~2 kb upstream), switching the promoter to an inactive chromatin state characterized by repressive histone H3 modifications, thereby repressing Nanog expression during differentiation of pluripotent P19 cells.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, overexpression and knockdown of Foxa1/Grg3, histone modification analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ChIP confirming recruitment and histone changes, single lab with two orthogonal methods but limited functional rescue\",\n      \"pmids\": [\"24803390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TLE3 and TLE1 each interact with HESX1 and repress PROP1 transcriptional activity; both can repress PROP1 even in the absence of HESX1 via a direct protein-protein interaction. In transgenic mice, HESX1 alone and HESX1+TLE3 together suppress terminal differentiation of pituitary thyrotrophs and gonadotrophs, but TLE3 alone does not.\",\n      \"method\": \"Cell-based reporter repression assay, co-immunoprecipitation (protein-protein interaction), transgenic mouse experiments\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and reporter assay with transgenic validation, but single lab\",\n      \"pmids\": [\"20181723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Grg3/TLE3 is expressed in almost all β-cells throughout development to adulthood; heterozygous Grg3 loss leads to increased α-specific gene expression and more polyhormonal cells, demonstrating a requirement for Grg3 in maintaining monohormonal β-cell identity. Ectopic Grg3 expression in α-cells represses glucagon and Arx.\",\n      \"method\": \"Grg3 heterozygous knockout mice, immunostaining, gene expression analysis, ectopic expression in α-cells\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype and molecular readout, validated by ectopic expression, single lab\",\n      \"pmids\": [\"24487024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TLE3 interacts with and recruits the histone methyltransferase KMT1A to repress target genes and inhibit differentiation in rhabdomyosarcoma. Loss of TLE3 activates the Wnt pathway, reduces proliferation, and enhances differentiation; muscle-specific TLE3 knockout enhances terminal myogenic differentiation markers in vivo.\",\n      \"method\": \"Co-immunoprecipitation, muscle-specific knockout, xenograft mouse model, drug combination experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying TLE3-KMT1A interaction plus in vivo KO and xenograft, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"38177411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM56, an E3 ubiquitin ligase, promotes K48-linked ubiquitination of TLE3, leading to its proteasomal degradation in adipocytes in response to cold stimuli; degradation of TLE3 activates thermogenic genes in subcutaneous white adipose tissue.\",\n      \"method\": \"Overexpression and knockdown in adipocytes, ubiquitination assay (K48-linkage specific), cold-exposure mouse model, metabolic phenotyping\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ubiquitination assay with K48 linkage specificity and in vivo cold-exposure mouse model, single lab, moderate mechanistic detail\",\n      \"pmids\": [\"39928840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Wnt signaling increases TLE3 expression in bone marrow stromal cells via Wnt-responsive elements in the TLE3 promoter; ectopic TLE3 in turn suppresses canonical Wnt signaling, establishing a negative feedback loop during osteoblast differentiation.\",\n      \"method\": \"Comparative genomic analysis of TLE3 promoter, functional reporter assay for Wnt-responsive elements, overexpression experiments in BMSCs\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter reporter assays and overexpression in single lab; no direct transcription factor binding to Wnt-response elements confirmed by ChIP\",\n      \"pmids\": [\"24444608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLE3 sustains luminal breast cancer lineage identity by repressing the gene-expression signature associated with basal-like breast cancers; this repression is mediated by interactions with FOXA1, which localizes TLE3 to its transcriptional targets. TLE3 represses SOX9 and TGFβ2, preventing acquisition of a hybrid epithelial-mesenchymal state.\",\n      \"method\": \"ChIP-seq (TLE3 and FOXA1 co-occupancy), gene expression analysis, loss-of-function with metastasis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP-seq and Co-IP with functional assays, single lab, identifying FOXA1-dependent TLE3 targeting and downstream gene repression\",\n      \"pmids\": [\"36696357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLE3 (and TLE4) negatively regulate MMP9 transcription in colonic macrophages; deficiency of TLE3 in myeloid cells leads to upregulated MMP9 production, enhanced latent TGF-β activation, and subsequent expansion of Treg and TH17 cells in the colonic lamina propria.\",\n      \"method\": \"Myeloid-specific TLE3/TLE4 conditional knockout mice, gene expression analysis, MMP9 activity assays, colitis model\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional KO with defined molecular mechanism (MMP9 → TGF-β → Treg/TH17), single lab\",\n      \"pmids\": [\"36801171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A single amino-terminal phosphorylation site present in TLE1 but absent from TLE3 determines their differential activity; mutating this site in TLE1 converts its activity to TLE3-like (increasing paclitaxel sensitivity and promoting adipocyte differentiation), while reconstituting it in TLE3 confers TLE1-like activity.\",\n      \"method\": \"Retroviral transduction of TLE1/TLE3 mutants in A549 cells, site-directed mutagenesis, paclitaxel sensitivity assays, adipocyte differentiation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with functional readout across two systems, but single lab with limited mechanistic depth (phosphorylation writer/reader not identified)\",\n      \"pmids\": [\"33571907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLE3 interacts with Zeb1 and acts upstream of Zeb1 in regulating myogenic differentiation; Tle3 depletion leads to reduced expression of myogenic differentiation genes including Myh3, impaired differentiation, and downregulation of Zeb1 potentially mediated by increased miR-200c. TLE3 also regulates MyoG expression post-transcriptionally via the mRNA-stabilizing protein HuR.\",\n      \"method\": \"shRNA knockdown of Tle3 and Zeb1 in C2C12 cells, double-knockdown epistasis, reporter assay for Myh3 promoter, miR-200c measurement, HuR interaction experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — epistasis by double KD, reporter assays, and post-transcriptional regulatory mechanism identified, single lab\",\n      \"pmids\": [\"37392376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Grg3/TLE3 protein (but not mRNA alone) is expressed in foregut endoderm co-expressed with FoxA factors prior to liver differentiation; lentiviral delivery of Grg3 to foregut endoderm explants suppresses liver gene induction, indicating that Grg3 helps repress the hepatic differentiation program in endoderm.\",\n      \"method\": \"In situ hybridization, immunostaining, lentiviral Grg3 delivery to foregut endoderm explants, gene expression analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — lentiviral gain-of-function in explant with defined gene expression phenotype, single lab\",\n      \"pmids\": [\"20108349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HHEX overexpression upregulates TLE3 protein expression by preventing TLE3 from being distributed to the cytoplasm and being ubiquitinated; nuclear-localized HHEX binds to and stabilizes TLE3, which then inhibits the Wnt/β-catenin signaling pathway in thyroid cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, subcellular fractionation, ubiquitination assay, reporter assays for Wnt pathway\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assays with functional validation, single lab, moderate mechanistic depth\",\n      \"pmids\": [\"37302518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TLE3 and TLE4 participate in diminishing canonical Wnt signaling activity at the neuromuscular junction; CRISPR/Cas9 knockout of TLE3 in satellite cells led to decreased agrin-dependent acetylcholine receptor (CHRN) clustering and reduced synaptic gene transcription upon differentiation.\",\n      \"method\": \"CRISPR/Cas9 KO in primary satellite cells, CHRN clustering assay, synaptic gene expression analysis, denervation paradigm in Axin2-lacZ reporter mice\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — CRISPR KO with defined functional phenotype (CHRN clustering), single lab, limited mechanistic pathway detail\",\n      \"pmids\": [\"38600964\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TLE3 is a transcriptional corepressor of the Groucho/TLE family that functions as a context-dependent integrator of multiple signaling pathways: it enhances PPARγ-driven adipogenesis while suppressing Wnt/β-catenin signaling by antagonizing TCF4/β-catenin complexes, disrupts Prdm16-PPARγ interaction to specify white over brown adipocyte identity, interacts with EBF2 to inhibit thermogenic gene programs in beige fat, blocks MyoD-E protein heterodimerization to dampen myogenic differentiation, interacts with FoxA1 and HDAC2 to maintain repressive chromatin at ERα target genes, forms repressor complexes with RUNX1/HDAC1 at myeloid differentiation enhancers, cooperates with Hhex to promote memory B cell differentiation, and acts as a coactivator for Tbet while engaging Runx3/Tcf1 to control CD8+ T cell effector versus central memory fate; its protein stability is regulated by K48-linked ubiquitination by RNF6 and TRIM56, and a unique N-terminal phosphorylation site absent from TLE3 (but present in TLE1) determines differential functional activity between paralogs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TLE3 is a Groucho/TLE-family transcriptional corepressor that acts as a context-dependent integrator of differentiation and signaling decisions across adipose, muscle, endocrine, immune, and epithelial tissues [#0, #1, #6]. Its most extensively characterized output is the repression of Wnt/\\u03b2-catenin signaling: TLE3 antagonizes \\u03b2-catenin activation of TCF4/LEF complexes [#0], and this antagonism is itself dialed by TLE3 protein abundance, which is set by K48-linked ubiquitination and proteasomal degradation via the E3 ligases RNF6 and TRIM56 [#2, #17]. TLE3 generally executes repression by partnering with sequence-specific factors and chromatin modifiers \\u2014 it recruits HDAC2 with FoxA1 to keep ER\\u03b1 targets in a basal acetylation state [#5], assembles a RUNX1/HDAC1 repressor complex stabilized by FOXC1 at myeloid differentiation enhancers [#11], and engages the histone methyltransferase KMT1A to silence differentiation genes [#16]. In adipocytes TLE3 is a PPAR\\u03b3 target and cofactor that promotes white over thermogenic identity by disrupting Prdm16\\u2013PPAR\\u03b3 interaction and by blocking EBF2-driven mitochondrial gene programs, such that its loss enhances thermogenesis and glucose control [#0, #1, #3]. It restrains lineage differentiation broadly, blocking MyoD\\u2013E-protein heterodimerization in myogenesis [#6] and Runx2 activity in osteoblasts [#8], while controlling cell-fate identity in pancreatic endocrine cells [#7, #15], memory B cells via Hhex [#10], and CD8+ T cells, where it uniquely acts as a Tbet coactivator while engaging Runx3/Tcf1 to bias effector versus central-memory fate [#12]. A single N-terminal phosphorylation site present in TLE1 but absent from TLE3 accounts for functional divergence between the paralogs [#21]. No timeline discovery links TLE3 to a Mendelian disease.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established TLE3 as a corepressor acting through direct protein interactions, showing it represses PROP1 via HESX1 and represses hepatic gene induction in foregut endoderm.\",\n      \"evidence\": \"Co-IP and reporter repression assays with HESX1/transgenic mice; lentiviral Grg3 gain-of-function in endoderm explants\",\n      \"pmids\": [\"20181723\", \"20108349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chromatin/recruitment mechanism at endogenous loci not resolved\", \"Cofactor complex composition not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined TLE3's dual role in adipogenesis as both a PPAR\\u03b3 target and synergistic cofactor and an antagonist of \\u03b2-catenin/TCF4, linking it to the Wnt axis.\",\n      \"evidence\": \"ChIP, reporter assays, and gain/loss-of-function in preadipocytes plus transgenic mice\",\n      \"pmids\": [\"21459326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of PPAR\\u03b3 synergy not structurally defined\", \"How TLE3 physically blocks \\u03b2-catenin not detailed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed a developmental requirement for TLE3 in pancreatic endocrine progenitor delamination through E-cadherin suppression.\",\n      \"evidence\": \"Grg3 knockout embryo explant culture with in situ hybridization and expression analysis\",\n      \"pmids\": [\"22434868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional target relationship to E-cadherin not shown\", \"Partner factors in progenitors unidentified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed TLE3 as a white-selective adipose cofactor that opposes Prdm16 and suppresses thermogenesis, establishing a fat-identity switch function.\",\n      \"evidence\": \"Reciprocal Co-IP showing Prdm16-PPAR\\u03b3 disruption, ChIP, and adipose-specific conditional KO with metabolic phenotyping\",\n      \"pmids\": [\"23473036\", \"23954203\", \"24487024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of mutually exclusive promoter occupancy unclear\", \"Placental Notch2 epistasis inferred, not biochemically shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped TLE3 as a FoxA1/HDAC2-recruited corepressor maintaining repressive chromatin at hormone-responsive and pluripotency genes (ER\\u03b1 targets, Nanog).\",\n      \"evidence\": \"Co-IP, ChIP, knockdown, histone modification analysis, and reporter assays in MCF-7 and P19 cells\",\n      \"pmids\": [\"25223786\", \"24803390\", \"24444608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of FoxA1 dependence across loci not established\", \"Direct HDAC2 recruitment sequence not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the mechanism by which TLE3 blocks myogenic differentiation \\u2014 disrupting MyoD\\u2013E-protein heterodimerization via its Q- and S/P-rich domains.\",\n      \"evidence\": \"Domain-mapping Co-IP plus gain/loss-of-function differentiation assays in satellite and C2C12 cells\",\n      \"pmids\": [\"28607151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this extends to other bHLH factors not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified post-translational control of TLE3 by RNF6-mediated K48 ubiquitination, coupling its degradation to derepression of Wnt/\\u03b2-catenin signaling in colorectal cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, and TLE3-restoration rescue in CRC cells and xenografts\",\n      \"pmids\": [\"29374067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination site on TLE3 not mapped\", \"Signals controlling RNF6 activity unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended TLE3's adipose role to direct enhancer occupancy blocking EBF2-driven mitochondrial programs, and revealed an AR-cooperative repression of GR controlling antiandrogen resistance.\",\n      \"evidence\": \"ChIP-seq, Co-IP, conditional KO with metabolic phenotyping (beige fat); genome-wide CRISPR screen, ChIP, and pharmacological rescue (LNCaP)\",\n      \"pmids\": [\"31123067\", \"31855178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TLE3 selects distal enhancers not defined\", \"Mechanism of AR/TLE3 co-occupancy at GR locus not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified TLE3-Hhex as a driver of memory B cell differentiation, broadening TLE3 into adaptive immune fate decisions.\",\n      \"evidence\": \"Inducible CRISPR-Cas9 screen, Co-IP, scRNA-seq, conditional KO\",\n      \"pmids\": [\"32601467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target genes of the TLE3-Hhex complex not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined TLE3 as a component of a FOXC1-stabilized RUNX1/HDAC1 repressor complex limiting myeloid differentiation enhancer activity, and uncovered an N-terminal phosphosite that distinguishes TLE3 from TLE1.\",\n      \"evidence\": \"Proteomics, Co-IP, ChIP-seq with FOXC1 knockdown (AML); site-directed mutagenesis with functional swap assays (A549/adipocytes)\",\n      \"pmids\": [\"34551306\", \"33571907\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase/phosphatase acting on the TLE1 phosphosite not identified\", \"Functional consequence of the missing site mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Consolidated TLE3 as a guardian of differentiated/lineage identity across tissues \\u2014 luminal breast cancer, rhabdomyosarcoma, myogenesis, colonic macrophages, and thyroid cancer \\u2014 frequently through FOXA1 targeting, chromatin modifiers, and Wnt restraint.\",\n      \"evidence\": \"ChIP-seq/Co-IP with FOXA1 and metastasis assays; KMT1A Co-IP with muscle-specific KO; double-KD epistasis with Zeb1/HuR; myeloid conditional KO with MMP9/TGF-\\u03b2 readout; HHEX stabilization and Wnt reporter assays\",\n      \"pmids\": [\"36696357\", \"38177411\", \"37392376\", \"36801171\", \"37302518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether one unified complex underlies these contexts is unresolved\", \"Direct vs indirect targets often inferred from expression changes\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated TLE3 can act as a coactivator, not only a corepressor, partnering Tbet to open effector chromatin while engaging Runx3/Tcf1 to restrain central-memory fate in CD8+ T cells; also linked TLE3 to NMJ Wnt signaling.\",\n      \"evidence\": \"Conditional KO, lineage tracing, ATAC-seq, ChIP-seq, Co-IP with Tbet/Runx3/Tcf1; CRISPR KO in satellite cells with CHRN clustering and Axin2 reporter mice\",\n      \"pmids\": [\"38238608\", \"38600964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural/biochemical basis for coactivator vs corepressor switching unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added TRIM56 as a second E3 ligase controlling TLE3 stability, linking cold-induced TLE3 degradation to activation of thermogenic gene programs.\",\n      \"evidence\": \"K48-linkage-specific ubiquitination assay and cold-exposure mouse model with metabolic phenotyping\",\n      \"pmids\": [\"39928840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; ubiquitination site not mapped\", \"Relationship between RNF6 and TRIM56 control of TLE3 unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What determines whether TLE3 functions as a corepressor versus a coactivator, and what defines its target-locus selectivity across the many sequence-specific factors it partners, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model for the corepressor/coactivator switch\", \"The kinase governing the paralog-discriminating phosphosite is unidentified\", \"No unifying model linking the diverse tissue-specific partner factors\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 11, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 11, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 11, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 1, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 12, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [\n      \"RUNX1/HDAC1/FOXC1 repressor complex\"\n    ],\n    \"partners\": [\n      \"PPARG\",\n      \"TCF4\",\n      \"FOXA1\",\n      \"HDAC2\",\n      \"EBF2\",\n      \"RUNX1\",\n      \"TBX21\",\n      \"HHEX\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}