{"gene":"NR2F6","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1992,"finding":"EAR-2 binds specifically to regulatory elements BA1 (-79 to -63) of ApoB and CIIIB (-87 to -63) of ApoCIII genes with dissociation constants of 1-3 nM, and represses transcription of reporter gene constructs driven by these elements in HepG2 cotransfection experiments.","method":"Gel mobility shift / EMSA, dissociation constant measurement, cotransfection reporter assay in HepG2 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding measured by EMSA with Kd determination plus functional cotransfection, single lab","pmids":["1639815"],"is_preprint":false},{"year":1997,"finding":"COUP-TFII and Ear-2 silence basal oxytocin gene promoter activity (by 54% and 75% respectively) by binding to a direct TGACC(T/C) repeat overlapping the ERE and to three proximal imperfect direct repeats (R1-R3); this represents active repression rather than simple competition with activators.","method":"Cotransfection reporter assay, 5' deletion analysis, DNase I footprinting, EMSA, site-directed mutagenesis","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EMSA, footprinting, mutagenesis, reporter assay), single lab","pmids":["9343308"],"is_preprint":false},{"year":1998,"finding":"EAR-2 directly binds to PEBP2alphaB (AML1/Runx1) and inhibits its function; overexpression of Ear-2 in 32Dc13 myeloid progenitor cells prevents G-CSF-induced granulocytic differentiation, identifying Ear-2 as a key negative regulator of this process.","method":"Co-immunoprecipitation/direct binding, overexpression in 32Dc13 cells, G-CSF differentiation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated plus functional overexpression phenotype, single lab","pmids":["9465099"],"is_preprint":false},{"year":1998,"finding":"EAR-2 binds to the CIIC hormone response element (-159 to -116) of the apoC-II promoter/HCR-1, but not to CIIB, and contributes to repression of hepatic apoC-II gene transcription in a manner requiring synergistic interaction with other elements.","method":"DNase I footprinting with nuclear extracts, EMSA, cotransfection reporter assay, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — footprinting plus mutagenesis plus reporter assay, single lab","pmids":["9461615"],"is_preprint":false},{"year":1998,"finding":"COUP-TFII and Ear-2 are expressed in oxytocin-producing uterine epithelial cells (demonstrated by Northern blot and immunocytochemistry) and antagonize estrogen receptor-mediated induction of the oxytocin promoter by binding to a direct TGACC repeat that overlaps but is distinct from the palindromic ERE.","method":"Northern blot, immunocytochemistry, cotransfection reporter assay, site-directed mutagenesis, EMSA","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization plus binding plus functional assay with mutagenesis, single lab","pmids":["9605516"],"is_preprint":false},{"year":1999,"finding":"ARP1 and Ear2 form heterodimers in solution and on directly repeated response elements with high efficiency and a specificity differing from homodimeric complexes; this interaction was confirmed in mammalian cells and the tissue distribution of Ear2 transcripts overlaps precisely with ARP1.","method":"Yeast two-hybrid, biochemical pull-down, EMSA on DR elements, mammalian cell co-expression interaction assay, Northern blot tissue distribution","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus in-solution and cell-based interaction studies, single lab","pmids":["10318855"],"is_preprint":false},{"year":2000,"finding":"Ear-2 physically interacts with thyroid hormone receptor beta1 (TRbeta1) via its ligand binding domain, inhibits TRbeta1 binding to T3 response elements, and represses both basal and T3-dependent TRbeta1-mediated transcription in a manner reversible by steroid receptor coactivator 1 (SRC-1).","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation in cells, EMSA, reporter cotransfection assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (yeast two-hybrid, GST pull-down, Co-IP, EMSA, reporter assay) establishing physical and functional interaction","pmids":["10713182"],"is_preprint":false},{"year":2001,"finding":"EAR2 and EAR3/COUP-TFI bind to a direct-repeat motif (DR) in the rat LH receptor promoter and repress rLHR gene transcription in rat granulosa cells; hCG treatment reduces EAR2 and EAR3 protein levels contributing to derepression of LHR promoter activity.","method":"EMSA, cotransfection reporter assay in granulosa cells, Western blot for protein levels","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus functional reporter assay in relevant cell type plus protein level measurement, single lab","pmids":["11682620"],"is_preprint":false},{"year":2003,"finding":"Ear2 (NR2F6) is a nuclear protein in As4.1 renin-expressing cells that binds specifically to the TGACCT direct-repeat motif in the mouse renin enhancer, dose-dependently represses basal and retinoid-induced renin promoter activity, and represses endogenous renin gene transcription; mutations abolishing Ear2 binding to TGACCT also abolish transcriptional repression.","method":"Yeast one-hybrid screen, recombinant protein purification, EMSA, subcellular fractionation/immunolocalization, cotransfection reporter assay, site-directed mutagenesis, endogenous gene repression assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including direct binding, localization, functional reporter with mutagenesis, and endogenous gene repression in a single study","pmids":["12690040"],"is_preprint":false},{"year":2005,"finding":"NR2F6/Ear2 is required for normal locus coeruleus (LC) development: in Ear2-/- embryos Phox2a/b-expressing LC progenitors are reduced ~3-fold while Mash1 expression is unaffected, placing Ear2 between Mash1 and Phox2a/b in the LC developmental cascade. >70% of LC neurons are absent in adults, cortical noradrenaline is 4-fold reduced, and the circadian Period1 expression pattern is abolished in the forebrain.","method":"Genetic knockout (Ear2-/-), in situ hybridization, immunostaining (Phox2a/b, DBH, TH), noradrenaline measurement, circadian gene expression analysis, behavioral assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — germline knockout with multiple orthogonal readouts establishing epistatic position and functional consequences","pmids":["15741322"],"is_preprint":false},{"year":2008,"finding":"NR2F6 is a PKC substrate in T lymphocytes and acts as a transcriptional repressor that directly interferes with DNA binding of the NFAT:AP-1 complex (but not NF-κB) on the IL-17A promoter, suppressing IL-2 and IL-17 cytokine gene expression; Nr2f6-deficient mice develop hyperreactive lymphocytes and are hypersusceptible to Th17-dependent EAE.","method":"PKC phosphorylation assay, EMSA/DNA-binding competition, cotransfection reporter assay, Nr2f6-/- mouse model, EAE disease model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — identified as PKC substrate, direct DNA-binding interference shown, knockout phenotype in multiple in vivo models","pmids":["18701084"],"is_preprint":false},{"year":2011,"finding":"Rasd1 physically interacts with the ligand binding domain of Ear2 (NR2F6) in vitro and in transfected COS-7 cells as well as between endogenous proteins from HEK293T cells and mouse brain; Rasd1 inhibits Ear2-mediated transcriptional repression of the renin promoter, and shRNA knockdown of Rasd1 augments Ear2-dependent renin repression while dexamethasone-induced Rasd1 counteracts it.","method":"Yeast two-hybrid, in vitro binding, co-immunoprecipitation (transfected and endogenous), luciferase reporter assay, shRNA knockdown, RT-PCR","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with endogenous proteins plus functional reporter validation, single lab","pmids":["21247419"],"is_preprint":false},{"year":2011,"finding":"EAR-2 (NR2F6) expression is greater in AML clonogenic cells; exogenous EAR-2 expression increases growth of U937 cells and prevents proliferative arrest and terminal differentiation, while EAR-2 shRNA silencing initiates terminal differentiation, demonstrating a role for EAR-2 in controlling the clonogenicity/differentiation balance in leukemia cells.","method":"Microarray analysis, retroviral overexpression, shRNA knockdown, proliferation and differentiation assays in U937 and 32Dcl3 cells","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain- and loss-of-function with matched phenotypic readouts, no direct mechanistic pathway established, single lab","pmids":["21637284"],"is_preprint":false},{"year":2011,"finding":"EAR2 knockdown reduces expression of X-linked inhibitor of apoptosis protein (XIAP) and induces apoptosis of colon cancer cells, while knockdown inhibits xenograft tumor growth in vivo.","method":"shRNA knockdown, apoptosis assays, Western blot for XIAP, xenograft tumor model","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method per readout, mechanistic link to XIAP is correlative","pmids":["21696885"],"is_preprint":false},{"year":2012,"finding":"NR2F6 directly antagonizes NFAT binding to critical regions of the Il17a gene promoter and also binds to hormone response elements (HREs) within the Il17a locus, thereby interfering with RORγt DNA access; NFAT and RORγt binding within the Il17a locus were enhanced in Nr2f6-deficient CD4+ Th17 cells and decreased in Nr2f6-overexpressing transgenic T cells.","method":"Chromatin immunoprecipitation (ChIP), EMSA, Nr2f6-/- and transgenic overexpression mouse models, Th17 differentiation assays","journal":"Journal of autoimmunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP in primary T cells plus loss- and gain-of-function genetic models plus EMSA, multiple orthogonal methods","pmids":["22921335"],"is_preprint":false},{"year":2012,"finding":"Nr2f6 negatively regulates the renin promoter through direct binding to the HRE within the renin enhancer (confirmed by ChIP); knockdown of Nr2f6 (but not Nr2f2) increased baseline endogenous renin expression 2-fold in As4.1 cells.","method":"Luciferase reporter assay, gel-shift/EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown with RT-PCR","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional knockdown, single lab, two orthogonal methods","pmids":["22278040"],"is_preprint":false},{"year":2013,"finding":"Retrovirus-mediated overexpression of Ear-2 in bone marrow HSCs causes a block in T cell development at the DN4 to DP transition accompanied by increased apoptosis, cell cycle arrest associated with upregulation of p21/p27 and Hes1/Notch3/Egr1, and decreased BclXL; this is mediated by a cell-intrinsic defect.","method":"Retroviral overexpression in BM HSCs, OP9-DL1 co-culture, BM transplantation, gene expression profiling, flow cytometry, apoptosis assays","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype with molecular correlates in gain-of-function model, single lab","pmids":["24096122"],"is_preprint":false},{"year":2015,"finding":"CD4+ and CD8+ T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the IL-2 and IFN-γ cytokine promoters; adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth.","method":"ChIP on cytokine promoters, Nr2f6-/- mouse model, TRAMP prostate cancer model, tumor rechallenge, adoptive T cell transfer","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct promoter occupancy plus adoptive transfer establishing T cell-intrinsic function in multiple tumor models","pmids":["26387951"],"is_preprint":false},{"year":2017,"finding":"NR2F6 binds to a consensus sequence at -2 kb of the Muc2 promoter and transactivates Muc2 expression in intestinal epithelial cells; loss of NR2F6 in the intestinal epithelium (not the immune compartment) increases permeability, reduces Muc2 expression and causes spontaneous late-onset colitis.","method":"ChIP on Muc2 promoter, bone marrow reconstitution experiments (separating immune vs. epithelial contribution), Nr2f6-/- mouse model, intestinal permeability assay, DSS colitis model, T cell transfer colitis","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP establishing direct promoter binding plus genetic epistasis via BM reconstitution separating tissue compartments, multiple disease models","pmids":["28779026"],"is_preprint":false},{"year":2018,"finding":"EAR-2 (NR2F6) inhibits maturation of normal bone marrow in vitro and in vivo; BM chimeras with EAR-2-transduced cells show features of MDS; EAR-2 functions through recruitment of histone deacetylases, and inhibition of differentiation in 32D cells is dependent on the DNA binding domain.","method":"Retroviral overexpression, BM transplantation/chimera experiments, shRNA knockdown, in vitro differentiation assays, HDAC co-recruitment assay","journal":"Biomarker research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo chimera model plus mechanistic HDAC recruitment and DBD dependence, single lab","pmids":["30555701"],"is_preprint":false},{"year":2018,"finding":"Genetic ablation of Nr2f6 in T cells delays tumor progression and improves survival in mouse tumor models; acute Nr2f6 silencing in both mouse and human T cells induces T cell hyper-responsiveness, establishing a non-redundant T-cell-inhibitory function; NR2F6 protein expression in tumor-infiltrating T cells in human NSCLC correlates with PD-1 and CTLA-4 expression.","method":"Germline Nr2f6-/- mouse tumor models, acute siRNA silencing in human T cells, ex vivo functional assays, IHC on human tumor samples, PD-L1 combination blockade experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mouse models plus human T cell data plus combination checkpoint blockade, replicated across two species","pmids":["29670099"],"is_preprint":false},{"year":2019,"finding":"NR2F6 sustains activated Notch3 signaling in epithelial ovarian cancer cells conferring cisplatin resistance; shown by luciferase assay, ChIP, and co-immunoprecipitation establishing NR2F6 binding to the Notch3 regulatory regions.","method":"Bioinformatics, luciferase assay, ChIP, co-immunoprecipitation, in vitro sphere/MTT/apoptosis assays, orthotopic transplantation model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus Co-IP plus in vivo model, single lab","pmids":["30895619"],"is_preprint":false},{"year":2019,"finding":"NR2F6 directly binds to the IL-21 promoter and a conserved noncoding sequence near the Il21 gene in resting CD4+ T cells; this direct DNA interaction is abolished during Tfh cell differentiation, and loss of NR2F6 causes enhanced IL-21 expression and excessive Tfh cell accumulation reversible by IL-21R blockade.","method":"ChIP in resting CD4+ T cells, Nr2f6-/- mouse model, T cell-dependent immunization, adoptive transfer, IL-21R blocking experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP establishing direct binding plus genetic loss-of-function with cytokine rescue experiment, multiple orthogonal methods","pmids":["31509749"],"is_preprint":false},{"year":2020,"finding":"NR2F6 promotes hepatic triglyceride accumulation by binding directly to the CD36 promoter in hepatocytes, increasing enrichment of nuclear receptor coactivator 1 (SRC-1) and histone acetylation at the CD36 promoter; AAV-mediated liver NR2F6 overexpression promotes TG accumulation in lean mice while hepatic-specific NR2F6 suppression improves obesity-associated steatosis.","method":"ChIP for NR2F6 binding at CD36 promoter and SRC-1/histone acetylation, AAV-mediated liver-specific overexpression and knockdown, NAFLD mouse models","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP establishing direct binding and coactivator recruitment plus bidirectional (gain and loss) in vivo genetic models","pmids":["33173745"],"is_preprint":false},{"year":2020,"finding":"NR2F6 acts as a corepressor of PDGFRB transcription by recruiting HDAC2 onto the PDGFRB promoter; BCa cells with insufficient NR2F6 expression are less responsive to docetaxel, and stable PDGFRB inhibition ameliorates NR2F6 deficiency-impaired DTX response.","method":"ChIP for HDAC2 recruitment at PDGFRB promoter, genetically engineered cell models, patient-derived xenograft models","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing HDAC2 recruitment plus rescue experiment with PDGFRB inhibition, single lab","pmids":["32203934"],"is_preprint":false},{"year":2021,"finding":"Loss of NR2F6 enhances antigen-specific CD8+ memory T cell formation following Listeria infection in a T cell-intrinsic manner; the augmented memory formation is IFN-γ mediated, as IFN-γ blocking normalizes MPEC formation in Nr2f6-deficient OT-I T cells.","method":"Germline Nr2f6-/- mouse model, adoptive transfer of OT-I Nr2f6-/- T cells, Listeria monocytogenes infection model, IFN-γ blocking antibody, flow cytometry","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adoptive transfer establishing T cell intrinsic function plus cytokine blocking to establish IFN-γ dependency, single lab","pmids":["33589606"],"is_preprint":false},{"year":2022,"finding":"Deletion of TLR4 from macrophages activates a Nr4a1/Ear2-expressing anti-inflammatory macrophage phenotype; silencing of Nr2f6 (Ear2) in TLR4-deficient BMDMs reverses their anti-inflammatory phenotype and restores LPS-stimulated M1 proinflammatory responses, placing NR2F6 as a key downstream effector of the myeloid-TLR4 negative feedback mechanism.","method":"Single-cell RNA sequencing, in vitro BMDM siRNA knockdown, LPS stimulation assays, flow cytometry","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq plus in vitro knockdown establishing functional epistasis, single lab","pmids":["35484716"],"is_preprint":false},{"year":2022,"finding":"NR2F6 physically interacts with HNRNPD (heterogeneous nuclear ribonucleoprotein D) in lung cancer cells as demonstrated by co-immunoprecipitation; both proteins positively regulate lung cancer cell proliferation.","method":"Co-immunoprecipitation, siRNA knockdown, proliferation assays","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP, single lab, no mechanistic follow-up beyond proliferation phenotype","pmids":["36119482"],"is_preprint":false},{"year":2024,"finding":"NR2F6 transcriptionally activates PPARγ expression to promote brown adipogenesis; depletion of NR2F6 in preadipocytes inhibits brown adipogenesis, causes brown adipocyte hypertrophy and impairs BAT thermogenic function without affecting white adipose tissue development, shown by ChIP-qPCR demonstrating NR2F6 binding to the PPARγ promoter.","method":"ChIP-qPCR on PPARγ promoter, Pdgfra-Cre conditional Nr2f6 knockout mice, primary and immortalized brown adipocyte differentiation assays, high-fat diet metabolic phenotyping","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-qPCR establishing direct promoter binding plus conditional in vivo knockout with multiple orthogonal metabolic readouts","pmids":["38307386"],"is_preprint":false},{"year":2024,"finding":"NR2F6 represses uncoupling protein 3 (UCP3) and PGC-1α promoter activities in skeletal muscle cells; Nr2f6 overexpression in mouse tibialis anterior causes muscle atrophy (15% reduction in mass), reduced myofibre content, impaired force production, and an inflammation-like signature; Nr2f6 knockdown increases maximal lipid oxidative capacity by 75% and upregulates myosin heavy chain genes.","method":"Promoter-reporter assays for UCP3 and PGC-1α, in vivo Nr2f6 overexpression in mouse tibialis anterior, Nr2f6 knockdown in C2C12 and primary human muscle cells, RNA-seq, ex vivo contractility experiments, histology","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter repression plus in vivo bidirectional genetic manipulation with multiple orthogonal readouts, replicated in human cells","pmids":["38682559"],"is_preprint":false},{"year":2024,"finding":"NR2F6 binds to the MAP3K5 promoter, activates the AP-1/c-Jun pathway to promote HSV-1 replication, and is itself transcriptionally repressed by c-Jun forming a negative feedback loop; NR2F6 promotes viral replication independently of the cGAS/STING pathway, and cGAS/STING represses NR2F6 through STAT3.","method":"H3K27ac ChIP-Seq, ChIP for NR2F6 at MAP3K5 promoter, reporter assay, in vitro and in vivo viral replication assays, cGAS/STING pathway analysis, STAT3 inhibitor experiments","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct promoter binding plus functional pathway dissection, single lab","pmids":["38829910"],"is_preprint":false},{"year":2024,"finding":"TLR3-NR2F6 axis drives programmed destruction of UPK3A+ umbrella cells in Hunner-type interstitial cystitis urothelium; in vitro and in vivo experiments confirmed this axis as a therapeutic target for urothelial barrier damage.","method":"Single-cell RNA sequencing, pseudotime analysis, in vitro and in vivo experiments targeting TLR3-NR2F6 axis","journal":"The Journal of pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway identification from scRNA-seq with limited mechanistic in vitro/in vivo follow-up described in abstract, single lab","pmids":["38551071"],"is_preprint":false},{"year":2025,"finding":"The NR2F6 ligand binding domain adopts an autorepressed, homodimeric conformation in the apo (unliganded) state in which helix 12 folds over the canonical coregulator binding site, generating an alternative contact surface for NSD1 binding; covalent probes targeting a cysteine near the NSD1 binding site inhibit NR2F6 coregulator recruitment.","method":"Co-crystallization of NR2F6 LBD with NSD1 coregulator peptide, X-ray crystallography (first structure of NR2F6 LBD), covalent compound screening on focused library, biochemical coregulator recruitment assay","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of LBD plus mutagenesis-informed covalent probe development with functional recruitment assay","pmids":["40931005"],"is_preprint":false},{"year":2025,"finding":"NR2F6 loss in splenic red pulp macrophages upregulates signal-regulatory protein alpha (Sirpa), impairing phagocytosis of red blood cells and Salmonella Typhimurium; blocking Sirpα restores phagocytic activity of Nr2f6-deficient macrophages to wild-type levels, partially increasing Salmonella loads in vivo.","method":"Nr2f6-/- mouse model, Salmonella Typhimurium infection model, transcriptomic analysis of red pulp macrophages, in vitro phagocytosis assays, anti-Sirpα blocking antibody in vitro and in vivo","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomics plus rescue experiment with Sirpα blockade, single lab","pmids":["40605423"],"is_preprint":false},{"year":2025,"finding":"NR2F6 represses expression of the activating NK cell receptor NKp46; loss of NR2F6 causes impaired terminal maturation of peripheral NK cells (despite normal BM development), and IL-15-dependent NK cell priming is limited in Nr2f6-deficient mice due to reduced cDC1 and macrophage populations; exogenous IL-15 complex compensates these deficits.","method":"Nr2f6-/- mouse model, flow cytometry for NK maturation stages, transcriptome analysis, in vitro and in vivo IL-15 complex treatment, B16-F10 lung metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined molecular and cellular phenotypes plus rescue experiment, single lab","pmids":["39920136"],"is_preprint":false},{"year":2025,"finding":"NR2F6 forced expression in cortical neurons doubles neurite length in culture; after pyramidotomy or complete thoracic spinal crush, NR2F6 overexpression drives robust CST axon sprouting and regeneration; mechanistically NR2F6 binds predominantly to distal enhancers, imposes a broad translational down-shift via a conserved corepressor domain, and re-packages chromatin into new topologically associating domains clustering growth genes with activated regulatory hubs.","method":"Multi-omics (RNA-seq, ATAC-seq, ChIP-seq, Hi-C), viral overexpression in cortical neurons, in vitro neurite length assay, pyramidotomy and thoracic crush in vivo models, behavioral assessment","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal omics plus in vivo functional data, but preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2026,"finding":"Palmitoylethanolamide was identified as an endogenous molecule binding NR2F6 with high affinity by mass spectrometry-based ligand screening (immunoprecipitation coupled to flow-injection high-resolution MS); NR2F6 knockdown in breast cancer cells upregulates gene networks related to cell-cell/matrix interactions and downregulates cell-cycle/proliferation networks, and NR2F6 silencing reduces directional migration of MDA-MB-231 cells.","method":"Immunoprecipitation coupled with flow-injection high-resolution mass spectrometry for ligand identification, stable shRNA knockdown, whole-genome RNA-seq, proliferation, clonogenicity, and migration assays","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based ligand identification plus transcriptome-level mechanistic characterization, single lab","pmids":["41803880"],"is_preprint":false},{"year":2014,"finding":"Snail inhibits adipogenesis by downregulating Nr2f6; NR2F6 is required for adipocyte differentiation (demonstrated by knockdown in 3T3-L1 cells), and ectopic Nr2f6 expression reverses Snail-mediated inhibition of adipogenesis; NR2F6 normally suppresses IL-17 expression, and Snail-induced IL-17 (via NR2F6 downregulation) acts as an anti-adipogenic cytokine.","method":"SILAC quantitative proteomics, Western blot, siRNA knockdown in 3T3-L1 and mMSC cells, ectopic NR2F6 expression, IL-17 blocking experiment, adipocyte differentiation assay","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional (KD and rescue) genetic manipulation in two cell types plus cytokine blocking, single lab","pmids":["25505127"],"is_preprint":false}],"current_model":"NR2F6 (EAR-2) is an orphan nuclear receptor that constitutively occupies hormone response elements (direct TGACC repeats) and cytokine gene promoters (IL-2, IL-17A, IFN-γ, IL-21) as a homodimer or heterodimer with ARP1/COUP-TFI, adopting an autorepressed LBD conformation (helix 12 blocking the canonical coregulator groove) that enables binding of non-canonical coregulators such as NSD1; it represses transcription by directly blocking NFAT:AP-1 and RORγt DNA binding in T cells, by recruiting HDAC2 to target promoters (e.g., PDGFRB), and by displacing activators from hormone response elements in hepatic and renal genes (ApoB, ApoCIII, renin, CD36); PKC-mediated phosphorylation inactivates NR2F6, relieving repression under strong TCR stimulation; in vivo, NR2F6 is essential for locus coeruleus development (positioned between Mash1 and Phox2a/b), intestinal barrier integrity (via Muc2 transactivation), brown adipogenesis (via PPARγ transactivation), and myeloid differentiation, while functioning as an intracellular immune checkpoint in effector CD4+, CD8+, Tfh, and NK cells."},"narrative":{"mechanistic_narrative":"NR2F6 (EAR-2) is an orphan nuclear receptor that functions principally as a sequence-specific transcriptional repressor, binding direct-repeat TGACC(T/C) hormone response elements and cytokine gene promoters to restrain target gene expression across immune, metabolic, and developmental programs [PMID:12690040, PMID:18701084, PMID:22921335]. It recognizes such elements with nanomolar affinity (e.g., the ApoB and ApoCIII regulatory elements) and silences target promoters either by active repression or by competing with activators for overlapping DNA elements, as shown for the oxytocin, apolipoprotein, LH receptor, and renin genes [PMID:1639815, PMID:9343308, PMID:12690040]. NR2F6 can act through several distinct molecular routes: direct physical inhibition of transcription factors such as the thyroid hormone receptor TRβ1, which it binds via its ligand-binding domain to block DNA binding in an SRC-1-reversible manner [PMID:10713182]; recruitment of histone deacetylases including HDAC2 to target promoters such as PDGFRB [PMID:32203934]; and, in T cells, direct interference with DNA binding of the NFAT:AP-1 complex and RORγt across the IL-2, IL-17A, IFN-γ, and IL-21 cytokine loci [PMID:18701084, PMID:22921335, PMID:26387951, PMID:31509749]. In the immune system NR2F6 operates as a cell-intrinsic checkpoint: it is a PKC substrate whose phosphorylation relieves repression, and its loss produces hyperreactive effector CD4+, CD8+, Tfh, and NK cells, enhanced antitumor immunity, and susceptibility to Th17-driven autoimmunity [PMID:18701084, PMID:26387951, PMID:29670099, PMID:31509749]. Beyond immunity, NR2F6 governs developmental and metabolic gene programs—it is required for locus coeruleus development by acting between Mash1 and Phox2a/b [PMID:15741322], maintains intestinal barrier integrity by transactivating Muc2 [PMID:28779026], promotes brown adipogenesis by activating PPARγ [PMID:38307386], and drives hepatic triglyceride accumulation by binding the CD36 promoter and recruiting SRC-1 [PMID:33173745]. A 2025 crystal structure resolved the apo NR2F6 ligand-binding domain in an autorepressed homodimeric conformation in which helix 12 occludes the canonical coregulator groove, generating an alternative surface for the non-canonical coregulator NSD1 [PMID:40931005].","teleology":[{"year":1992,"claim":"Established that NR2F6/EAR-2 is a high-affinity DNA-binding repressor, defining its core biochemical activity at apolipoprotein regulatory elements.","evidence":"EMSA with Kd determination and cotransfection reporter assays in HepG2 cells","pmids":["1639815"],"confidence":"Medium","gaps":["No corepressor or coactivator identified","Mechanism of repression (competition vs active) not yet distinguished"]},{"year":1997,"claim":"Showed NR2F6 mediates active repression rather than mere activator competition, refining the mechanism at the oxytocin promoter.","evidence":"DNase I footprinting, EMSA, mutagenesis and reporter assays","pmids":["9343308","9605516"],"confidence":"Medium","gaps":["Did not identify the recruited corepressor machinery","Restricted to a single promoter context"]},{"year":1998,"claim":"Extended NR2F6 function to myeloid differentiation by showing it directly binds and inhibits RUNX1, providing a protein-protein mechanism distinct from DNA element occupancy.","evidence":"Direct binding/Co-IP and G-CSF differentiation assays in 32Dc13 myeloid progenitors","pmids":["9465099","9461615"],"confidence":"Medium","gaps":["Interaction domains not mapped","Link between RUNX1 inhibition and differentiation block correlative"]},{"year":1999,"claim":"Defined NR2F6's dimerization behavior, showing it heterodimerizes with ARP1/COUP-TFI with distinct DNA specificity, expanding the combinatorial repertoire of its target recognition.","evidence":"Yeast two-hybrid, pull-down, EMSA on DR elements and tissue expression mapping","pmids":["10318855"],"confidence":"Medium","gaps":["Functional consequence of heterodimer vs homodimer on specific genes not resolved"]},{"year":2000,"claim":"Demonstrated NR2F6 represses nuclear receptor signaling by binding TRβ1 through its LBD and that coactivator SRC-1 can reverse this, revealing a tunable repression mechanism.","evidence":"Yeast two-hybrid, GST pull-down, Co-IP, EMSA and reporter assays","pmids":["10713182"],"confidence":"High","gaps":["SRC-1 competition not tested at endogenous loci","Physiological ligand for the LBD unknown"]},{"year":2003,"claim":"Confirmed NR2F6 as a direct repressor of an endogenous gene (renin), binding the TGACCT enhancer element and repressing both basal and retinoid-induced activity.","evidence":"Yeast one-hybrid, EMSA, fractionation, reporter and endogenous gene repression assays in As4.1 cells","pmids":["12690040","22278040"],"confidence":"High","gaps":["Corepressor recruited at the renin enhancer not identified in these studies"]},{"year":2005,"claim":"Placed NR2F6 in a developmental cascade, establishing it as essential for locus coeruleus neuron specification between Mash1 and Phox2a/b.","evidence":"Germline Ear2-/- knockout with in situ hybridization, noradrenaline measurement and circadian gene analysis","pmids":["15741322"],"confidence":"High","gaps":["Direct target genes downstream of NR2F6 in LC progenitors not identified","Whether activity is repressive or activating in this context unclear"]},{"year":2008,"claim":"Identified NR2F6 as a PKC-regulated intracellular immune checkpoint that directly blocks NFAT:AP-1 DNA binding to suppress IL-2 and IL-17, with knockout mice prone to autoimmunity.","evidence":"PKC phosphorylation assay, EMSA/DNA-binding competition, Nr2f6-/- mice and EAE model","pmids":["18701084"],"confidence":"High","gaps":["PKC phosphosites and their effect on DNA binding not fully mapped","Selectivity against NF-κB mechanism not detailed"]},{"year":2012,"claim":"Showed NR2F6 represses the Il17a locus by both antagonizing NFAT binding and occupying HREs that interfere with RORγt access, integrating two repressive modes at one locus.","evidence":"ChIP in primary Th17 cells, EMSA, and loss/gain-of-function genetic mouse models","pmids":["22921335"],"confidence":"High","gaps":["How NR2F6 occupancy mechanically excludes RORγt not resolved at structural level"]},{"year":2011,"claim":"Identified Rasd1 as an LBD-interacting partner that relieves NR2F6-mediated renin repression, linking NR2F6 activity to hormonal (dexamethasone) signaling.","evidence":"Yeast two-hybrid, reciprocal endogenous Co-IP, reporter assays and shRNA knockdown","pmids":["21247419"],"confidence":"Medium","gaps":["Mechanism by which Rasd1 binding inhibits repression unknown","Generalizability beyond renin not tested"]},{"year":2013,"claim":"Characterized NR2F6 gain-of-function effects in hematopoiesis, showing it blocks T cell development and leukemic differentiation, implicating it in myeloid/lymphoid malignancy.","evidence":"Retroviral overexpression, OP9-DL1 co-culture, BM transplantation and expression profiling","pmids":["24096122","21637284","21696885"],"confidence":"Medium","gaps":["Direct transcriptional targets driving the differentiation block not defined","XIAP link is correlative (Low confidence)"]},{"year":2015,"claim":"Demonstrated T-cell-intrinsic NR2F6 directly represses IL-2 and IFN-γ promoters and that its deletion enables T cells to delay tumor outgrowth, establishing therapeutic relevance.","evidence":"ChIP on cytokine promoters, Nr2f6-/- mice, TRAMP and adoptive transfer tumor models","pmids":["26387951"],"confidence":"High","gaps":["Whether repression requires the same NFAT-interference mechanism at IFN-γ as at IL-17 not directly shown"]},{"year":2017,"claim":"Revealed NR2F6 can act as a transcriptional activator, transactivating Muc2 in intestinal epithelium to maintain barrier integrity, separating an epithelial role from its immune-cell role.","evidence":"ChIP on Muc2 promoter and BM reconstitution separating epithelial vs immune compartments in colitis models","pmids":["28779026"],"confidence":"High","gaps":["Coactivators mediating Muc2 transactivation not identified","Determinants of activator vs repressor switching unknown"]},{"year":2018,"claim":"Defined NR2F6 as a non-redundant, druggable T-cell checkpoint conserved between mouse and human, correlating with PD-1/CTLA-4 in human tumor-infiltrating T cells and synergizing with PD-L1 blockade.","evidence":"Germline and acute-silencing models in mouse and human T cells, IHC on human NSCLC, combination checkpoint blockade","pmids":["29670099","30555701"],"confidence":"High","gaps":["Mechanistic basis of synergy with PD-L1 blockade not dissected","HDAC-recruitment mechanism (idx 19) shown in myeloid context, not T cells"]},{"year":2020,"claim":"Established that NR2F6 directs metabolic gene programs through both coactivator recruitment (SRC-1 at CD36 in liver) and HDAC2-mediated corepression (PDGFRB in cancer), unifying activator and repressor modes mechanistically.","evidence":"ChIP for coactivator/histone-mark enrichment and HDAC2 recruitment, AAV liver-specific manipulation and NAFLD models","pmids":["33173745","32203934"],"confidence":"High","gaps":["What dictates SRC-1 vs HDAC2 recruitment at different promoters unknown"]},{"year":2022,"claim":"Positioned NR2F6 (Ear2) as a downstream effector of myeloid TLR4 negative feedback enforcing an anti-inflammatory macrophage state.","evidence":"scRNA-seq and siRNA knockdown in TLR4-deficient BMDMs with LPS stimulation","pmids":["35484716","36119482"],"confidence":"Medium","gaps":["Direct NR2F6 targets in macrophages not mapped","HNRNPD interaction (idx 27) is a single Co-IP, Low confidence"]},{"year":2024,"claim":"Extended NR2F6's role to brown adipogenesis and skeletal muscle, showing it transactivates PPARγ for BAT thermogenesis while repressing UCP3/PGC-1α in muscle, demonstrating tissue-specific bidirectional transcriptional control.","evidence":"ChIP-qPCR, conditional and germline knockouts, promoter-reporter assays and metabolic/contractility phenotyping (human cells included)","pmids":["38307386","38682559"],"confidence":"High","gaps":["Cofactors distinguishing activation (PPARγ) from repression (UCP3) in metabolic tissues not identified"]},{"year":2025,"claim":"Solved the first NR2F6 LBD structure, revealing an autorepressed apo homodimer with helix 12 occluding the canonical groove and creating a non-canonical NSD1-binding surface that is covalently druggable.","evidence":"Co-crystallization with NSD1 peptide, X-ray crystallography and covalent probe screening with recruitment assays","pmids":["40931005"],"confidence":"High","gaps":["Whether an endogenous ligand displaces helix 12 in vivo not established here","Structural basis of DNA-bound complexes not solved"]},{"year":2025,"claim":"Expanded NR2F6's immune-checkpoint role to NK cells and red pulp macrophages, where it represses NKp46 and Sirpα respectively to license maturation and phagocytosis.","evidence":"Nr2f6-/- mice, transcriptomics, Sirpα/IL-15 rescue experiments and infection/metastasis models","pmids":["39920136","40605423"],"confidence":"Medium","gaps":["Direct promoter binding at NKp46 and Sirpa loci not shown by ChIP in these studies"]},{"year":2026,"claim":"Identified palmitoylethanolamide as a candidate endogenous NR2F6 ligand and linked NR2F6 to breast cancer migration and proliferation networks, addressing the long-standing orphan status of the receptor.","evidence":"MS-based ligand identification with shRNA knockdown and transcriptomic/migration assays","pmids":["41803880"],"confidence":"Medium","gaps":["Whether palmitoylethanolamide functionally modulates NR2F6 transcriptional activity not established","Single-lab ligand assignment requires orthogonal validation"]},{"year":null,"claim":"How NR2F6 switches between repressor (cytokines, renin, UCP3) and activator (Muc2, PPARγ, CD36) modes at different loci, and whether ligand binding to its now-structurally-defined LBD controls this switch in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified rule linking promoter context to cofactor choice (SRC-1 vs HDAC2)","Functional consequences of endogenous ligand binding in physiological tissues untested","Structures of DNA-bound and ligand-bound NR2F6 complexes lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,8,10,14,18,23,28,29]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,8,14,17,19,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,6,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[14,17,23,28]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,8,10,14,23,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,17,20,22,25,26,33,34]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[23,28,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,16,28]}],"complexes":[],"partners":["NR2F1","THRB","RUNX1","RASD1","NCOA1","HDAC2","HNRNPD","NSD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10588","full_name":"Nuclear receptor subfamily 2 group F member 6","aliases":["V-erbA-related protein 2","EAR-2"],"length_aa":404,"mass_kda":43.0,"function":"Transcription factor predominantly involved in transcriptional repression. Binds to promoter/enhancer response elements that contain the imperfect 5'-AGGTCA-3' direct or inverted repeats with various spacings which are also recognized by other nuclear hormone receptors. Involved in modulation of hormonal responses. Represses transcriptional activity of the lutropin-choriogonadotropic hormone receptor/LHCGR gene, the renin/REN gene and the oxytocin-neurophysin/OXT gene. Represses the triiodothyronine-dependent and -independent transcriptional activity of the thyroid hormone receptor gene in a cell type-specific manner. The corepressing function towards thyroid hormone receptor beta/THRB involves at least in part the inhibition of THRB binding to triiodothyronine response elements (TREs) by NR2F6. Inhibits NFATC transcription factor DNA binding and subsequently its transcriptional activity. Acts as transcriptional repressor of IL-17 expression in Th-17 differentiated CD4(+) T cells and may be involved in induction and/or maintenance of peripheral immunological tolerance and autoimmunity. Involved in development of forebrain circadian clock; is required early in the development of the locus coeruleus (LC)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P10588/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR2F6","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NR2F6","total_profiled":1310},"omim":[{"mim_id":"132880","title":"NUCLEAR RECEPTOR SUBFAMILY 2, GROUP F, MEMBER 6; NR2F6","url":"https://www.omim.org/entry/132880"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":104.3}],"url":"https://www.proteinatlas.org/search/NR2F6"},"hgnc":{"alias_symbol":["EAR-2","EAR2"],"prev_symbol":["ERBAL2"]},"alphafold":{"accession":"P10588","domains":[{"cath_id":"3.30.50.10","chopping":"64-124","consensus_level":"high","plddt":95.0184,"start":64,"end":124},{"cath_id":"1.10.565.10","chopping":"167-178_197-394","consensus_level":"high","plddt":90.958,"start":167,"end":394}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10588","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10588-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10588-F1-predicted_aligned_error_v6.png","plddt_mean":77.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR2F6","jax_strain_url":"https://www.jax.org/strain/search?query=NR2F6"},"sequence":{"accession":"P10588","fasta_url":"https://rest.uniprot.org/uniprotkb/P10588.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10588/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10588"}},"corpus_meta":[{"pmid":"1639815","id":"PMC_1639815","title":"Transcriptional 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39840064","citation_count":1,"is_preprint":false},{"pmid":"41760655","id":"PMC_41760655","title":"NR2F6 deletion revives CAR-T cell function and induces antigen-agnostic immune memory in solid tumors.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41760655","citation_count":1,"is_preprint":false},{"pmid":"40801595","id":"PMC_40801595","title":"NR2F6 as a Disease Driver and Candidate Therapeutic Target in Experimental Cerebral Malaria.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/40801595","citation_count":1,"is_preprint":false},{"pmid":"41121148","id":"PMC_41121148","title":"NR2F6 regulates Temozolomide resistance in glioma via the E2F2-PARP1 pathway.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/41121148","citation_count":1,"is_preprint":false},{"pmid":"40931005","id":"PMC_40931005","title":"Structural Elucidation and 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Tract","date":"2025-06-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.19.660319","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.26.678859","title":"Integrated Human Transcriptomics Identifies Fallopian Tube Progenitors as Plausible Precursors of High-Grade Serous Ovarian Cancer","date":"2025-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.26.678859","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.29.679070","title":"NR0B1 alters the 9-  <i>cis</i>  -retinoic acid response in Ewing Sarcoma cells","date":"2025-10-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.29.679070","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.07.647587","title":"Identifying genes underlying parallel evolution of stromal resistance to placental and cancer 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dissociation constant measurement, cotransfection reporter assay in HepG2 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding measured by EMSA with Kd determination plus functional cotransfection, single lab\",\n      \"pmids\": [\"1639815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"COUP-TFII and Ear-2 silence basal oxytocin gene promoter activity (by 54% and 75% respectively) by binding to a direct TGACC(T/C) repeat overlapping the ERE and to three proximal imperfect direct repeats (R1-R3); this represents active repression rather than simple competition with activators.\",\n      \"method\": \"Cotransfection reporter assay, 5' deletion analysis, DNase I footprinting, EMSA, site-directed mutagenesis\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EMSA, footprinting, mutagenesis, reporter assay), single lab\",\n      \"pmids\": [\"9343308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"EAR-2 directly binds to PEBP2alphaB (AML1/Runx1) and inhibits its function; overexpression of Ear-2 in 32Dc13 myeloid progenitor cells prevents G-CSF-induced granulocytic differentiation, identifying Ear-2 as a key negative regulator of this process.\",\n      \"method\": \"Co-immunoprecipitation/direct binding, overexpression in 32Dc13 cells, G-CSF differentiation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated plus functional overexpression phenotype, single lab\",\n      \"pmids\": [\"9465099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"EAR-2 binds to the CIIC hormone response element (-159 to -116) of the apoC-II promoter/HCR-1, but not to CIIB, and contributes to repression of hepatic apoC-II gene transcription in a manner requiring synergistic interaction with other elements.\",\n      \"method\": \"DNase I footprinting with nuclear extracts, EMSA, cotransfection reporter assay, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — footprinting plus mutagenesis plus reporter assay, single lab\",\n      \"pmids\": [\"9461615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"COUP-TFII and Ear-2 are expressed in oxytocin-producing uterine epithelial cells (demonstrated by Northern blot and immunocytochemistry) and antagonize estrogen receptor-mediated induction of the oxytocin promoter by binding to a direct TGACC repeat that overlaps but is distinct from the palindromic ERE.\",\n      \"method\": \"Northern blot, immunocytochemistry, cotransfection reporter assay, site-directed mutagenesis, EMSA\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization plus binding plus functional assay with mutagenesis, single lab\",\n      \"pmids\": [\"9605516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ARP1 and Ear2 form heterodimers in solution and on directly repeated response elements with high efficiency and a specificity differing from homodimeric complexes; this interaction was confirmed in mammalian cells and the tissue distribution of Ear2 transcripts overlaps precisely with ARP1.\",\n      \"method\": \"Yeast two-hybrid, biochemical pull-down, EMSA on DR elements, mammalian cell co-expression interaction assay, Northern blot tissue distribution\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus in-solution and cell-based interaction studies, single lab\",\n      \"pmids\": [\"10318855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ear-2 physically interacts with thyroid hormone receptor beta1 (TRbeta1) via its ligand binding domain, inhibits TRbeta1 binding to T3 response elements, and represses both basal and T3-dependent TRbeta1-mediated transcription in a manner reversible by steroid receptor coactivator 1 (SRC-1).\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation in cells, EMSA, reporter cotransfection assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (yeast two-hybrid, GST pull-down, Co-IP, EMSA, reporter assay) establishing physical and functional interaction\",\n      \"pmids\": [\"10713182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"EAR2 and EAR3/COUP-TFI bind to a direct-repeat motif (DR) in the rat LH receptor promoter and repress rLHR gene transcription in rat granulosa cells; hCG treatment reduces EAR2 and EAR3 protein levels contributing to derepression of LHR promoter activity.\",\n      \"method\": \"EMSA, cotransfection reporter assay in granulosa cells, Western blot for protein levels\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus functional reporter assay in relevant cell type plus protein level measurement, single lab\",\n      \"pmids\": [\"11682620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Ear2 (NR2F6) is a nuclear protein in As4.1 renin-expressing cells that binds specifically to the TGACCT direct-repeat motif in the mouse renin enhancer, dose-dependently represses basal and retinoid-induced renin promoter activity, and represses endogenous renin gene transcription; mutations abolishing Ear2 binding to TGACCT also abolish transcriptional repression.\",\n      \"method\": \"Yeast one-hybrid screen, recombinant protein purification, EMSA, subcellular fractionation/immunolocalization, cotransfection reporter assay, site-directed mutagenesis, endogenous gene repression assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including direct binding, localization, functional reporter with mutagenesis, and endogenous gene repression in a single study\",\n      \"pmids\": [\"12690040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NR2F6/Ear2 is required for normal locus coeruleus (LC) development: in Ear2-/- embryos Phox2a/b-expressing LC progenitors are reduced ~3-fold while Mash1 expression is unaffected, placing Ear2 between Mash1 and Phox2a/b in the LC developmental cascade. >70% of LC neurons are absent in adults, cortical noradrenaline is 4-fold reduced, and the circadian Period1 expression pattern is abolished in the forebrain.\",\n      \"method\": \"Genetic knockout (Ear2-/-), in situ hybridization, immunostaining (Phox2a/b, DBH, TH), noradrenaline measurement, circadian gene expression analysis, behavioral assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germline knockout with multiple orthogonal readouts establishing epistatic position and functional consequences\",\n      \"pmids\": [\"15741322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NR2F6 is a PKC substrate in T lymphocytes and acts as a transcriptional repressor that directly interferes with DNA binding of the NFAT:AP-1 complex (but not NF-κB) on the IL-17A promoter, suppressing IL-2 and IL-17 cytokine gene expression; Nr2f6-deficient mice develop hyperreactive lymphocytes and are hypersusceptible to Th17-dependent EAE.\",\n      \"method\": \"PKC phosphorylation assay, EMSA/DNA-binding competition, cotransfection reporter assay, Nr2f6-/- mouse model, EAE disease model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identified as PKC substrate, direct DNA-binding interference shown, knockout phenotype in multiple in vivo models\",\n      \"pmids\": [\"18701084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rasd1 physically interacts with the ligand binding domain of Ear2 (NR2F6) in vitro and in transfected COS-7 cells as well as between endogenous proteins from HEK293T cells and mouse brain; Rasd1 inhibits Ear2-mediated transcriptional repression of the renin promoter, and shRNA knockdown of Rasd1 augments Ear2-dependent renin repression while dexamethasone-induced Rasd1 counteracts it.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation (transfected and endogenous), luciferase reporter assay, shRNA knockdown, RT-PCR\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with endogenous proteins plus functional reporter validation, single lab\",\n      \"pmids\": [\"21247419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EAR-2 (NR2F6) expression is greater in AML clonogenic cells; exogenous EAR-2 expression increases growth of U937 cells and prevents proliferative arrest and terminal differentiation, while EAR-2 shRNA silencing initiates terminal differentiation, demonstrating a role for EAR-2 in controlling the clonogenicity/differentiation balance in leukemia cells.\",\n      \"method\": \"Microarray analysis, retroviral overexpression, shRNA knockdown, proliferation and differentiation assays in U937 and 32Dcl3 cells\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain- and loss-of-function with matched phenotypic readouts, no direct mechanistic pathway established, single lab\",\n      \"pmids\": [\"21637284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EAR2 knockdown reduces expression of X-linked inhibitor of apoptosis protein (XIAP) and induces apoptosis of colon cancer cells, while knockdown inhibits xenograft tumor growth in vivo.\",\n      \"method\": \"shRNA knockdown, apoptosis assays, Western blot for XIAP, xenograft tumor model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method per readout, mechanistic link to XIAP is correlative\",\n      \"pmids\": [\"21696885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NR2F6 directly antagonizes NFAT binding to critical regions of the Il17a gene promoter and also binds to hormone response elements (HREs) within the Il17a locus, thereby interfering with RORγt DNA access; NFAT and RORγt binding within the Il17a locus were enhanced in Nr2f6-deficient CD4+ Th17 cells and decreased in Nr2f6-overexpressing transgenic T cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), EMSA, Nr2f6-/- and transgenic overexpression mouse models, Th17 differentiation assays\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP in primary T cells plus loss- and gain-of-function genetic models plus EMSA, multiple orthogonal methods\",\n      \"pmids\": [\"22921335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nr2f6 negatively regulates the renin promoter through direct binding to the HRE within the renin enhancer (confirmed by ChIP); knockdown of Nr2f6 (but not Nr2f2) increased baseline endogenous renin expression 2-fold in As4.1 cells.\",\n      \"method\": \"Luciferase reporter assay, gel-shift/EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown with RT-PCR\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"22278040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Retrovirus-mediated overexpression of Ear-2 in bone marrow HSCs causes a block in T cell development at the DN4 to DP transition accompanied by increased apoptosis, cell cycle arrest associated with upregulation of p21/p27 and Hes1/Notch3/Egr1, and decreased BclXL; this is mediated by a cell-intrinsic defect.\",\n      \"method\": \"Retroviral overexpression in BM HSCs, OP9-DL1 co-culture, BM transplantation, gene expression profiling, flow cytometry, apoptosis assays\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype with molecular correlates in gain-of-function model, single lab\",\n      \"pmids\": [\"24096122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD4+ and CD8+ T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the IL-2 and IFN-γ cytokine promoters; adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth.\",\n      \"method\": \"ChIP on cytokine promoters, Nr2f6-/- mouse model, TRAMP prostate cancer model, tumor rechallenge, adoptive T cell transfer\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct promoter occupancy plus adoptive transfer establishing T cell-intrinsic function in multiple tumor models\",\n      \"pmids\": [\"26387951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NR2F6 binds to a consensus sequence at -2 kb of the Muc2 promoter and transactivates Muc2 expression in intestinal epithelial cells; loss of NR2F6 in the intestinal epithelium (not the immune compartment) increases permeability, reduces Muc2 expression and causes spontaneous late-onset colitis.\",\n      \"method\": \"ChIP on Muc2 promoter, bone marrow reconstitution experiments (separating immune vs. epithelial contribution), Nr2f6-/- mouse model, intestinal permeability assay, DSS colitis model, T cell transfer colitis\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP establishing direct promoter binding plus genetic epistasis via BM reconstitution separating tissue compartments, multiple disease models\",\n      \"pmids\": [\"28779026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EAR-2 (NR2F6) inhibits maturation of normal bone marrow in vitro and in vivo; BM chimeras with EAR-2-transduced cells show features of MDS; EAR-2 functions through recruitment of histone deacetylases, and inhibition of differentiation in 32D cells is dependent on the DNA binding domain.\",\n      \"method\": \"Retroviral overexpression, BM transplantation/chimera experiments, shRNA knockdown, in vitro differentiation assays, HDAC co-recruitment assay\",\n      \"journal\": \"Biomarker research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo chimera model plus mechanistic HDAC recruitment and DBD dependence, single lab\",\n      \"pmids\": [\"30555701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Genetic ablation of Nr2f6 in T cells delays tumor progression and improves survival in mouse tumor models; acute Nr2f6 silencing in both mouse and human T cells induces T cell hyper-responsiveness, establishing a non-redundant T-cell-inhibitory function; NR2F6 protein expression in tumor-infiltrating T cells in human NSCLC correlates with PD-1 and CTLA-4 expression.\",\n      \"method\": \"Germline Nr2f6-/- mouse tumor models, acute siRNA silencing in human T cells, ex vivo functional assays, IHC on human tumor samples, PD-L1 combination blockade experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mouse models plus human T cell data plus combination checkpoint blockade, replicated across two species\",\n      \"pmids\": [\"29670099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NR2F6 sustains activated Notch3 signaling in epithelial ovarian cancer cells conferring cisplatin resistance; shown by luciferase assay, ChIP, and co-immunoprecipitation establishing NR2F6 binding to the Notch3 regulatory regions.\",\n      \"method\": \"Bioinformatics, luciferase assay, ChIP, co-immunoprecipitation, in vitro sphere/MTT/apoptosis assays, orthotopic transplantation model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus Co-IP plus in vivo model, single lab\",\n      \"pmids\": [\"30895619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NR2F6 directly binds to the IL-21 promoter and a conserved noncoding sequence near the Il21 gene in resting CD4+ T cells; this direct DNA interaction is abolished during Tfh cell differentiation, and loss of NR2F6 causes enhanced IL-21 expression and excessive Tfh cell accumulation reversible by IL-21R blockade.\",\n      \"method\": \"ChIP in resting CD4+ T cells, Nr2f6-/- mouse model, T cell-dependent immunization, adoptive transfer, IL-21R blocking experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP establishing direct binding plus genetic loss-of-function with cytokine rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"31509749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NR2F6 promotes hepatic triglyceride accumulation by binding directly to the CD36 promoter in hepatocytes, increasing enrichment of nuclear receptor coactivator 1 (SRC-1) and histone acetylation at the CD36 promoter; AAV-mediated liver NR2F6 overexpression promotes TG accumulation in lean mice while hepatic-specific NR2F6 suppression improves obesity-associated steatosis.\",\n      \"method\": \"ChIP for NR2F6 binding at CD36 promoter and SRC-1/histone acetylation, AAV-mediated liver-specific overexpression and knockdown, NAFLD mouse models\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP establishing direct binding and coactivator recruitment plus bidirectional (gain and loss) in vivo genetic models\",\n      \"pmids\": [\"33173745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NR2F6 acts as a corepressor of PDGFRB transcription by recruiting HDAC2 onto the PDGFRB promoter; BCa cells with insufficient NR2F6 expression are less responsive to docetaxel, and stable PDGFRB inhibition ameliorates NR2F6 deficiency-impaired DTX response.\",\n      \"method\": \"ChIP for HDAC2 recruitment at PDGFRB promoter, genetically engineered cell models, patient-derived xenograft models\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing HDAC2 recruitment plus rescue experiment with PDGFRB inhibition, single lab\",\n      \"pmids\": [\"32203934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of NR2F6 enhances antigen-specific CD8+ memory T cell formation following Listeria infection in a T cell-intrinsic manner; the augmented memory formation is IFN-γ mediated, as IFN-γ blocking normalizes MPEC formation in Nr2f6-deficient OT-I T cells.\",\n      \"method\": \"Germline Nr2f6-/- mouse model, adoptive transfer of OT-I Nr2f6-/- T cells, Listeria monocytogenes infection model, IFN-γ blocking antibody, flow cytometry\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adoptive transfer establishing T cell intrinsic function plus cytokine blocking to establish IFN-γ dependency, single lab\",\n      \"pmids\": [\"33589606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Deletion of TLR4 from macrophages activates a Nr4a1/Ear2-expressing anti-inflammatory macrophage phenotype; silencing of Nr2f6 (Ear2) in TLR4-deficient BMDMs reverses their anti-inflammatory phenotype and restores LPS-stimulated M1 proinflammatory responses, placing NR2F6 as a key downstream effector of the myeloid-TLR4 negative feedback mechanism.\",\n      \"method\": \"Single-cell RNA sequencing, in vitro BMDM siRNA knockdown, LPS stimulation assays, flow cytometry\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq plus in vitro knockdown establishing functional epistasis, single lab\",\n      \"pmids\": [\"35484716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR2F6 physically interacts with HNRNPD (heterogeneous nuclear ribonucleoprotein D) in lung cancer cells as demonstrated by co-immunoprecipitation; both proteins positively regulate lung cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, proliferation assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP, single lab, no mechanistic follow-up beyond proliferation phenotype\",\n      \"pmids\": [\"36119482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR2F6 transcriptionally activates PPARγ expression to promote brown adipogenesis; depletion of NR2F6 in preadipocytes inhibits brown adipogenesis, causes brown adipocyte hypertrophy and impairs BAT thermogenic function without affecting white adipose tissue development, shown by ChIP-qPCR demonstrating NR2F6 binding to the PPARγ promoter.\",\n      \"method\": \"ChIP-qPCR on PPARγ promoter, Pdgfra-Cre conditional Nr2f6 knockout mice, primary and immortalized brown adipocyte differentiation assays, high-fat diet metabolic phenotyping\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-qPCR establishing direct promoter binding plus conditional in vivo knockout with multiple orthogonal metabolic readouts\",\n      \"pmids\": [\"38307386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR2F6 represses uncoupling protein 3 (UCP3) and PGC-1α promoter activities in skeletal muscle cells; Nr2f6 overexpression in mouse tibialis anterior causes muscle atrophy (15% reduction in mass), reduced myofibre content, impaired force production, and an inflammation-like signature; Nr2f6 knockdown increases maximal lipid oxidative capacity by 75% and upregulates myosin heavy chain genes.\",\n      \"method\": \"Promoter-reporter assays for UCP3 and PGC-1α, in vivo Nr2f6 overexpression in mouse tibialis anterior, Nr2f6 knockdown in C2C12 and primary human muscle cells, RNA-seq, ex vivo contractility experiments, histology\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter repression plus in vivo bidirectional genetic manipulation with multiple orthogonal readouts, replicated in human cells\",\n      \"pmids\": [\"38682559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR2F6 binds to the MAP3K5 promoter, activates the AP-1/c-Jun pathway to promote HSV-1 replication, and is itself transcriptionally repressed by c-Jun forming a negative feedback loop; NR2F6 promotes viral replication independently of the cGAS/STING pathway, and cGAS/STING represses NR2F6 through STAT3.\",\n      \"method\": \"H3K27ac ChIP-Seq, ChIP for NR2F6 at MAP3K5 promoter, reporter assay, in vitro and in vivo viral replication assays, cGAS/STING pathway analysis, STAT3 inhibitor experiments\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct promoter binding plus functional pathway dissection, single lab\",\n      \"pmids\": [\"38829910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TLR3-NR2F6 axis drives programmed destruction of UPK3A+ umbrella cells in Hunner-type interstitial cystitis urothelium; in vitro and in vivo experiments confirmed this axis as a therapeutic target for urothelial barrier damage.\",\n      \"method\": \"Single-cell RNA sequencing, pseudotime analysis, in vitro and in vivo experiments targeting TLR3-NR2F6 axis\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway identification from scRNA-seq with limited mechanistic in vitro/in vivo follow-up described in abstract, single lab\",\n      \"pmids\": [\"38551071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The NR2F6 ligand binding domain adopts an autorepressed, homodimeric conformation in the apo (unliganded) state in which helix 12 folds over the canonical coregulator binding site, generating an alternative contact surface for NSD1 binding; covalent probes targeting a cysteine near the NSD1 binding site inhibit NR2F6 coregulator recruitment.\",\n      \"method\": \"Co-crystallization of NR2F6 LBD with NSD1 coregulator peptide, X-ray crystallography (first structure of NR2F6 LBD), covalent compound screening on focused library, biochemical coregulator recruitment assay\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of LBD plus mutagenesis-informed covalent probe development with functional recruitment assay\",\n      \"pmids\": [\"40931005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NR2F6 loss in splenic red pulp macrophages upregulates signal-regulatory protein alpha (Sirpa), impairing phagocytosis of red blood cells and Salmonella Typhimurium; blocking Sirpα restores phagocytic activity of Nr2f6-deficient macrophages to wild-type levels, partially increasing Salmonella loads in vivo.\",\n      \"method\": \"Nr2f6-/- mouse model, Salmonella Typhimurium infection model, transcriptomic analysis of red pulp macrophages, in vitro phagocytosis assays, anti-Sirpα blocking antibody in vitro and in vivo\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomics plus rescue experiment with Sirpα blockade, single lab\",\n      \"pmids\": [\"40605423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NR2F6 represses expression of the activating NK cell receptor NKp46; loss of NR2F6 causes impaired terminal maturation of peripheral NK cells (despite normal BM development), and IL-15-dependent NK cell priming is limited in Nr2f6-deficient mice due to reduced cDC1 and macrophage populations; exogenous IL-15 complex compensates these deficits.\",\n      \"method\": \"Nr2f6-/- mouse model, flow cytometry for NK maturation stages, transcriptome analysis, in vitro and in vivo IL-15 complex treatment, B16-F10 lung metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined molecular and cellular phenotypes plus rescue experiment, single lab\",\n      \"pmids\": [\"39920136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NR2F6 forced expression in cortical neurons doubles neurite length in culture; after pyramidotomy or complete thoracic spinal crush, NR2F6 overexpression drives robust CST axon sprouting and regeneration; mechanistically NR2F6 binds predominantly to distal enhancers, imposes a broad translational down-shift via a conserved corepressor domain, and re-packages chromatin into new topologically associating domains clustering growth genes with activated regulatory hubs.\",\n      \"method\": \"Multi-omics (RNA-seq, ATAC-seq, ChIP-seq, Hi-C), viral overexpression in cortical neurons, in vitro neurite length assay, pyramidotomy and thoracic crush in vivo models, behavioral assessment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal omics plus in vivo functional data, but preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Palmitoylethanolamide was identified as an endogenous molecule binding NR2F6 with high affinity by mass spectrometry-based ligand screening (immunoprecipitation coupled to flow-injection high-resolution MS); NR2F6 knockdown in breast cancer cells upregulates gene networks related to cell-cell/matrix interactions and downregulates cell-cycle/proliferation networks, and NR2F6 silencing reduces directional migration of MDA-MB-231 cells.\",\n      \"method\": \"Immunoprecipitation coupled with flow-injection high-resolution mass spectrometry for ligand identification, stable shRNA knockdown, whole-genome RNA-seq, proliferation, clonogenicity, and migration assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based ligand identification plus transcriptome-level mechanistic characterization, single lab\",\n      \"pmids\": [\"41803880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Snail inhibits adipogenesis by downregulating Nr2f6; NR2F6 is required for adipocyte differentiation (demonstrated by knockdown in 3T3-L1 cells), and ectopic Nr2f6 expression reverses Snail-mediated inhibition of adipogenesis; NR2F6 normally suppresses IL-17 expression, and Snail-induced IL-17 (via NR2F6 downregulation) acts as an anti-adipogenic cytokine.\",\n      \"method\": \"SILAC quantitative proteomics, Western blot, siRNA knockdown in 3T3-L1 and mMSC cells, ectopic NR2F6 expression, IL-17 blocking experiment, adipocyte differentiation assay\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional (KD and rescue) genetic manipulation in two cell types plus cytokine blocking, single lab\",\n      \"pmids\": [\"25505127\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR2F6 (EAR-2) is an orphan nuclear receptor that constitutively occupies hormone response elements (direct TGACC repeats) and cytokine gene promoters (IL-2, IL-17A, IFN-γ, IL-21) as a homodimer or heterodimer with ARP1/COUP-TFI, adopting an autorepressed LBD conformation (helix 12 blocking the canonical coregulator groove) that enables binding of non-canonical coregulators such as NSD1; it represses transcription by directly blocking NFAT:AP-1 and RORγt DNA binding in T cells, by recruiting HDAC2 to target promoters (e.g., PDGFRB), and by displacing activators from hormone response elements in hepatic and renal genes (ApoB, ApoCIII, renin, CD36); PKC-mediated phosphorylation inactivates NR2F6, relieving repression under strong TCR stimulation; in vivo, NR2F6 is essential for locus coeruleus development (positioned between Mash1 and Phox2a/b), intestinal barrier integrity (via Muc2 transactivation), brown adipogenesis (via PPARγ transactivation), and myeloid differentiation, while functioning as an intracellular immune checkpoint in effector CD4+, CD8+, Tfh, and NK cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR2F6 (EAR-2) is an orphan nuclear receptor that functions principally as a sequence-specific transcriptional repressor, binding direct-repeat TGACC(T/C) hormone response elements and cytokine gene promoters to restrain target gene expression across immune, metabolic, and developmental programs [#8, #10, #14]. It recognizes such elements with nanomolar affinity (e.g., the ApoB and ApoCIII regulatory elements) and silences target promoters either by active repression or by competing with activators for overlapping DNA elements, as shown for the oxytocin, apolipoprotein, LH receptor, and renin genes [#0, #1, #8]. NR2F6 can act through several distinct molecular routes: direct physical inhibition of transcription factors such as the thyroid hormone receptor TRβ1, which it binds via its ligand-binding domain to block DNA binding in an SRC-1-reversible manner [#6]; recruitment of histone deacetylases including HDAC2 to target promoters such as PDGFRB [#24]; and, in T cells, direct interference with DNA binding of the NFAT:AP-1 complex and RORγt across the IL-2, IL-17A, IFN-γ, and IL-21 cytokine loci [#10, #14, #17, #22]. In the immune system NR2F6 operates as a cell-intrinsic checkpoint: it is a PKC substrate whose phosphorylation relieves repression, and its loss produces hyperreactive effector CD4+, CD8+, Tfh, and NK cells, enhanced antitumor immunity, and susceptibility to Th17-driven autoimmunity [#10, #17, #20, #22]. Beyond immunity, NR2F6 governs developmental and metabolic gene programs—it is required for locus coeruleus development by acting between Mash1 and Phox2a/b [#9], maintains intestinal barrier integrity by transactivating Muc2 [#18], promotes brown adipogenesis by activating PPARγ [#28], and drives hepatic triglyceride accumulation by binding the CD36 promoter and recruiting SRC-1 [#23]. A 2025 crystal structure resolved the apo NR2F6 ligand-binding domain in an autorepressed homodimeric conformation in which helix 12 occludes the canonical coregulator groove, generating an alternative surface for the non-canonical coregulator NSD1 [#32].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that NR2F6/EAR-2 is a high-affinity DNA-binding repressor, defining its core biochemical activity at apolipoprotein regulatory elements.\",\n      \"evidence\": \"EMSA with Kd determination and cotransfection reporter assays in HepG2 cells\",\n      \"pmids\": [\"1639815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No corepressor or coactivator identified\", \"Mechanism of repression (competition vs active) not yet distinguished\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed NR2F6 mediates active repression rather than mere activator competition, refining the mechanism at the oxytocin promoter.\",\n      \"evidence\": \"DNase I footprinting, EMSA, mutagenesis and reporter assays\",\n      \"pmids\": [\"9343308\", \"9605516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the recruited corepressor machinery\", \"Restricted to a single promoter context\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Extended NR2F6 function to myeloid differentiation by showing it directly binds and inhibits RUNX1, providing a protein-protein mechanism distinct from DNA element occupancy.\",\n      \"evidence\": \"Direct binding/Co-IP and G-CSF differentiation assays in 32Dc13 myeloid progenitors\",\n      \"pmids\": [\"9465099\", \"9461615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction domains not mapped\", \"Link between RUNX1 inhibition and differentiation block correlative\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined NR2F6's dimerization behavior, showing it heterodimerizes with ARP1/COUP-TFI with distinct DNA specificity, expanding the combinatorial repertoire of its target recognition.\",\n      \"evidence\": \"Yeast two-hybrid, pull-down, EMSA on DR elements and tissue expression mapping\",\n      \"pmids\": [\"10318855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of heterodimer vs homodimer on specific genes not resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated NR2F6 represses nuclear receptor signaling by binding TRβ1 through its LBD and that coactivator SRC-1 can reverse this, revealing a tunable repression mechanism.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, Co-IP, EMSA and reporter assays\",\n      \"pmids\": [\"10713182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SRC-1 competition not tested at endogenous loci\", \"Physiological ligand for the LBD unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Confirmed NR2F6 as a direct repressor of an endogenous gene (renin), binding the TGACCT enhancer element and repressing both basal and retinoid-induced activity.\",\n      \"evidence\": \"Yeast one-hybrid, EMSA, fractionation, reporter and endogenous gene repression assays in As4.1 cells\",\n      \"pmids\": [\"12690040\", \"22278040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Corepressor recruited at the renin enhancer not identified in these studies\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed NR2F6 in a developmental cascade, establishing it as essential for locus coeruleus neuron specification between Mash1 and Phox2a/b.\",\n      \"evidence\": \"Germline Ear2-/- knockout with in situ hybridization, noradrenaline measurement and circadian gene analysis\",\n      \"pmids\": [\"15741322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes downstream of NR2F6 in LC progenitors not identified\", \"Whether activity is repressive or activating in this context unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified NR2F6 as a PKC-regulated intracellular immune checkpoint that directly blocks NFAT:AP-1 DNA binding to suppress IL-2 and IL-17, with knockout mice prone to autoimmunity.\",\n      \"evidence\": \"PKC phosphorylation assay, EMSA/DNA-binding competition, Nr2f6-/- mice and EAE model\",\n      \"pmids\": [\"18701084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKC phosphosites and their effect on DNA binding not fully mapped\", \"Selectivity against NF-κB mechanism not detailed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed NR2F6 represses the Il17a locus by both antagonizing NFAT binding and occupying HREs that interfere with RORγt access, integrating two repressive modes at one locus.\",\n      \"evidence\": \"ChIP in primary Th17 cells, EMSA, and loss/gain-of-function genetic mouse models\",\n      \"pmids\": [\"22921335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NR2F6 occupancy mechanically excludes RORγt not resolved at structural level\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified Rasd1 as an LBD-interacting partner that relieves NR2F6-mediated renin repression, linking NR2F6 activity to hormonal (dexamethasone) signaling.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal endogenous Co-IP, reporter assays and shRNA knockdown\",\n      \"pmids\": [\"21247419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Rasd1 binding inhibits repression unknown\", \"Generalizability beyond renin not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterized NR2F6 gain-of-function effects in hematopoiesis, showing it blocks T cell development and leukemic differentiation, implicating it in myeloid/lymphoid malignancy.\",\n      \"evidence\": \"Retroviral overexpression, OP9-DL1 co-culture, BM transplantation and expression profiling\",\n      \"pmids\": [\"24096122\", \"21637284\", \"21696885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets driving the differentiation block not defined\", \"XIAP link is correlative (Low confidence)\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated T-cell-intrinsic NR2F6 directly represses IL-2 and IFN-γ promoters and that its deletion enables T cells to delay tumor outgrowth, establishing therapeutic relevance.\",\n      \"evidence\": \"ChIP on cytokine promoters, Nr2f6-/- mice, TRAMP and adoptive transfer tumor models\",\n      \"pmids\": [\"26387951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether repression requires the same NFAT-interference mechanism at IFN-γ as at IL-17 not directly shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed NR2F6 can act as a transcriptional activator, transactivating Muc2 in intestinal epithelium to maintain barrier integrity, separating an epithelial role from its immune-cell role.\",\n      \"evidence\": \"ChIP on Muc2 promoter and BM reconstitution separating epithelial vs immune compartments in colitis models\",\n      \"pmids\": [\"28779026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coactivators mediating Muc2 transactivation not identified\", \"Determinants of activator vs repressor switching unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined NR2F6 as a non-redundant, druggable T-cell checkpoint conserved between mouse and human, correlating with PD-1/CTLA-4 in human tumor-infiltrating T cells and synergizing with PD-L1 blockade.\",\n      \"evidence\": \"Germline and acute-silencing models in mouse and human T cells, IHC on human NSCLC, combination checkpoint blockade\",\n      \"pmids\": [\"29670099\", \"30555701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis of synergy with PD-L1 blockade not dissected\", \"HDAC-recruitment mechanism (idx 19) shown in myeloid context, not T cells\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that NR2F6 directs metabolic gene programs through both coactivator recruitment (SRC-1 at CD36 in liver) and HDAC2-mediated corepression (PDGFRB in cancer), unifying activator and repressor modes mechanistically.\",\n      \"evidence\": \"ChIP for coactivator/histone-mark enrichment and HDAC2 recruitment, AAV liver-specific manipulation and NAFLD models\",\n      \"pmids\": [\"33173745\", \"32203934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What dictates SRC-1 vs HDAC2 recruitment at different promoters unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned NR2F6 (Ear2) as a downstream effector of myeloid TLR4 negative feedback enforcing an anti-inflammatory macrophage state.\",\n      \"evidence\": \"scRNA-seq and siRNA knockdown in TLR4-deficient BMDMs with LPS stimulation\",\n      \"pmids\": [\"35484716\", \"36119482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NR2F6 targets in macrophages not mapped\", \"HNRNPD interaction (idx 27) is a single Co-IP, Low confidence\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended NR2F6's role to brown adipogenesis and skeletal muscle, showing it transactivates PPARγ for BAT thermogenesis while repressing UCP3/PGC-1α in muscle, demonstrating tissue-specific bidirectional transcriptional control.\",\n      \"evidence\": \"ChIP-qPCR, conditional and germline knockouts, promoter-reporter assays and metabolic/contractility phenotyping (human cells included)\",\n      \"pmids\": [\"38307386\", \"38682559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors distinguishing activation (PPARγ) from repression (UCP3) in metabolic tissues not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Solved the first NR2F6 LBD structure, revealing an autorepressed apo homodimer with helix 12 occluding the canonical groove and creating a non-canonical NSD1-binding surface that is covalently druggable.\",\n      \"evidence\": \"Co-crystallization with NSD1 peptide, X-ray crystallography and covalent probe screening with recruitment assays\",\n      \"pmids\": [\"40931005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether an endogenous ligand displaces helix 12 in vivo not established here\", \"Structural basis of DNA-bound complexes not solved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded NR2F6's immune-checkpoint role to NK cells and red pulp macrophages, where it represses NKp46 and Sirpα respectively to license maturation and phagocytosis.\",\n      \"evidence\": \"Nr2f6-/- mice, transcriptomics, Sirpα/IL-15 rescue experiments and infection/metastasis models\",\n      \"pmids\": [\"39920136\", \"40605423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding at NKp46 and Sirpa loci not shown by ChIP in these studies\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified palmitoylethanolamide as a candidate endogenous NR2F6 ligand and linked NR2F6 to breast cancer migration and proliferation networks, addressing the long-standing orphan status of the receptor.\",\n      \"evidence\": \"MS-based ligand identification with shRNA knockdown and transcriptomic/migration assays\",\n      \"pmids\": [\"41803880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether palmitoylethanolamide functionally modulates NR2F6 transcriptional activity not established\", \"Single-lab ligand assignment requires orthogonal validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NR2F6 switches between repressor (cytokines, renin, UCP3) and activator (Muc2, PPARγ, CD36) modes at different loci, and whether ligand binding to its now-structurally-defined LBD controls this switch in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified rule linking promoter context to cofactor choice (SRC-1 vs HDAC2)\", \"Functional consequences of endogenous ligand binding in physiological tissues untested\", \"Structures of DNA-bound and ligand-bound NR2F6 complexes lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 8, 10, 14, 18, 23, 28, 29]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 8, 14, 17, 19, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 6, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [14, 17, 23, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 8, 10, 14, 23, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 17, 20, 22, 25, 26, 33, 34]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [23, 28, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 16, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NR2F1\", \"THRB\", \"RUNX1\", \"RASD1\", \"NCOA1\", \"HDAC2\", \"HNRNPD\", \"NSD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}