{"gene":"NR2F2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2005,"finding":"COUP-TFII (NR2F2) is specifically expressed in venous but not arterial endothelium; endothelial-specific ablation enables veins to acquire arterial characteristics including NP-1 and Notch signaling molecule expression, while ectopic expression causes vein-artery fusion. COUP-TFII represses Notch signaling to maintain vein identity.","method":"Conditional knockout and transgenic overexpression in mouse endothelial cells; arterial/venous marker analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function in vivo, replicated across multiple transgenic lines, clear molecular pathway placement (Notch suppression)","pmids":["15875024"],"is_preprint":false},{"year":1999,"finding":"COUP-TFII is required for angiogenesis and heart development; null mice fail to remodel the primitive capillary plexus, and atria/sinus venosus do not develop past the primitive tube stage. Angiopoietin-1 expression is down-regulated in COUP-TFII mutant hearts, suggesting COUP-TFII controls mesenchymal-endothelial signaling through Angiopoietin-1.","method":"Targeted gene deletion in mice; in situ hybridization and expression analysis of Angiopoietin-1","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined developmental phenotype, downstream target (Ang-1) identified, replicated across multiple labs","pmids":["10215630"],"is_preprint":false},{"year":2008,"finding":"Crystal structure of human COUP-TFII ligand-binding domain at 1.48 Å reveals an autorepressed conformation where helix α10 is bent into the ligand-binding pocket and the AF-2 helix is folded into the cofactor binding site, preventing coactivator recruitment. Retinoic acids can promote COUP-TFII to recruit coactivators and activate transcription by releasing the receptor from this autorepressed conformation. Mutations disrupting cofactor binding, dimerization, or ligand binding substantially reduce transcriptional activity.","method":"X-ray crystallography (1.48 Å); cell-based transcription assays; site-directed mutagenesis; coactivator recruitment assays","journal":"PLoS Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional transcription assays in multiple cell lines","pmids":["18798693"],"is_preprint":false},{"year":2008,"finding":"COUP-TFII physically interacts with Prox1 to form a stable complex in lymphatic endothelial cells (LECs) and multiple other cell types. This COUP-TFII/Prox1 complex functions as a co-regulator to control lineage-specific genes including VEGFR-3, FGFR-3, and neuropilin-1, and is required along with Prox1 to maintain LEC phenotype.","method":"Co-immunoprecipitation; stable complex formation assays; gene expression analysis with knockdown","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating physical interaction, functional validation with downstream target gene regulation","pmids":["18815287"],"is_preprint":false},{"year":2013,"finding":"COUP-TFII homodimers inhibit arterial differentiation in venous ECs through direct binding to promoter regions of Notch target genes HEY1 and HEY2, whereas NR2F2/PROX1 heterodimers lack this inhibitory effect on HEY1/2, resulting in non-canonical HEY1/2 expression in LECs. NR2F2/PROX1 heterodimers actively induce LEC-specific gene expression.","method":"Chromatin immunoprecipitation; promoter binding assays; gain- and loss-of-function in endothelial cells; gene expression profiling","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP showing direct promoter binding, functional distinction between homodimer and heterodimer activity, multiple orthogonal methods","pmids":["23345397"],"is_preprint":false},{"year":2012,"finding":"COUP-TFII inhibits SMAD4-dependent transcription to override the TGF-β-dependent growth checkpoint in PTEN-null prostate tumors. Conditional overexpression of COUP-TFII in mouse prostate cooperates with PTEN deletion to drive metastatic progression; conditional loss of SMAD4 diminishes the inhibitory effects of COUP-TFII ablation, establishing functional counteraction between COUP-TFII and SMAD4.","method":"Genetically engineered mouse models (conditional overexpression and knockout); epistasis analysis of COUP-TFII and SMAD4 double mutants; transcriptional reporter assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double-mutant mouse models, replicated with patient sample correlation, clear pathway placement","pmids":["23201680"],"is_preprint":false},{"year":2007,"finding":"Stromal COUP-TFII mediates progesterone control of uterine implantation by suppressing epithelial estrogen receptor (ERα) activity. Conditional knockout of uterine COUP-TFII leads to implantation failure and impaired decidualization; BMP2 lies downstream of COUP-TFII in a pathway regulated by the progesterone-Indian hedgehog-Patched-COUP-TFII-BMP2 axis.","method":"Conditional COUP-TFII knockout mouse; ERα antagonist rescue experiments; pathway analysis in vivo","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with specific phenotype, pharmacological rescue experiment defining ERα as the downstream effector, genetic pathway established","pmids":["17590085"],"is_preprint":false},{"year":2010,"finding":"Stromal COUP-TFII suppresses ERα activity in the uterine luminal epithelium during the periimplantation period; pharmacological inhibition of ERα with ICI 182,780 rescues embryo attachment and decidualization (including Wnt4 and BMP2 expression) in COUP-TFII knockout uteri, demonstrating that COUP-TFII regulates implantation through controlling ERα activity.","method":"Conditional knockout mouse; ERα antagonist (ICI 182,780) rescue; gene expression analysis of ERα target genes","journal":"Molecular Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis experiment definitively placing ERα downstream of COUP-TFII, supported by gene expression readouts","pmids":["20219888"],"is_preprint":false},{"year":1997,"finding":"A Sonic hedgehog (Shh) response element in the COUP-TFII promoter binds a factor distinct from Gli. Shh-N signaling can be mimicked by protein phosphatase treatment to activate this binding activity, and Shh-N-induced activation of COUP-TFII is blocked by phosphatase inhibitors, indicating that Shh-N signaling activates COUP-TFII expression through dephosphorylation of a target transcription factor.","method":"Promoter binding assays; pharmacological phosphatase inhibitor experiments; Shh-N stimulation in P19 cells","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of signaling pathway, single lab, supported by two orthogonal approaches (Shh stimulation and phosphatase treatment)","pmids":["9395397"],"is_preprint":false},{"year":2013,"finding":"Cardiomyocyte-specific COUP-TFII ablation produces ventricularized atria with ventricle-like action potentials, larger cardiomyocyte size, and T-tubule development. ChIP assays identify Tbx5, Hey2, Irx4, MLC2v, MLC2a, and MLC1a as direct COUP-TFII target genes in atria, demonstrating that COUP-TFII directly binds and regulates atrial identity genes.","method":"Cardiomyocyte-specific conditional knockout; electrophysiology; chromatin immunoprecipitation with E13.5 atrial tissue; genome-wide gene expression profiling","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with functional electrophysiology phenotype, in vivo ChIP identifying direct targets, multiple orthogonal methods","pmids":["23725765"],"is_preprint":false},{"year":2010,"finding":"COUP-TFII in pericytes directly regulates transcription of Angiopoietin-1 to enhance tumor neoangiogenesis; provision of exogenous Angiopoietin-1 partially rescues angiogenic defects in COUP-TFII-deficient mice, demonstrating COUP-TFII controls Angiopoietin-1/Tie2 signaling.","method":"Conditional adult COUP-TFII knockout; xenograft tumor models; Angiopoietin-1 rescue experiment; transcriptional regulation assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional knockout with rescue experiment placing Ang-1 directly downstream, functional angiogenesis readout","pmids":["20133706"],"is_preprint":false},{"year":2010,"finding":"COUP-TFII suppresses VEGFR-1 transcription in endothelial cells to regulate VEGF/VEGFR-2 signaling balance during tumor angiogenesis; COUP-TFII plays a cell-autonomous role in endothelial cell proliferation and migration.","method":"Conditional COUP-TFII knockout in tumor microenvironment; RIP-Tag pancreatic islet tumor model; transcriptional repression assays for VEGFR-1","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout in defined model system, transcriptional mechanism identified for VEGFR-1, single lab","pmids":["20978203"],"is_preprint":false},{"year":2009,"finding":"COUP-TFII plays a pivotal role in white adipocyte development; COUP-TFII heterozygous mice have less white adipose tissue and decreased expression of key WAT regulators. ChIP analysis reveals Wnt10b is a direct transcriptional target of COUP-TFII, and knockdown of COUP-TFII in 3T3-L1 cells increases Wnt10b expression.","method":"Heterozygous knockout mice; 3T3-L1 knockdown; chromatin immunoprecipitation; gene expression analysis","journal":"Cell Metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockout phenotype combined with in vitro ChIP demonstrating direct target binding, two orthogonal methods","pmids":["19117548"],"is_preprint":false},{"year":2011,"finding":"COUP-TFII inactivation in mesenchymal progenitors shifts lineage fate toward osteoblast and myoblast development while impairing adipogenic and chondrogenic programs. COUP-TFII directs mesenchymal progenitor plasticity through combined modulation of Wnt signaling, Runx2 activity, and PPARγ and Sox9 expression.","method":"Conditional knockout in mesenchymal progenitors; in vivo bone density, muscle mass, and fat/cartilage quantification; pathway analysis","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with multiple tissue phenotypes and pathway placement, single lab","pmids":["21873211"],"is_preprint":false},{"year":2012,"finding":"COUP-TFII directly regulates E2F1 transcription by tethering to Sp1 binding sites in the E2F1 promoter (demonstrated by ChIP) to modulate cell proliferation. COUP-TFII also directly regulates Foxc1, Np-1, and Hey2 (Notch pathway genes) as shown by ChIP in HUVECs.","method":"Microarray in COUP-TFII-depleted HUVECs; chromatin immunoprecipitation; gene expression analysis","journal":"Molecular Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding for E2F1 and Notch targets, single lab","pmids":["22734039"],"is_preprint":false},{"year":2013,"finding":"BRG1 chromatin-remodeling enzyme promotes COUP-TFII expression in venous endothelial cells by binding conserved regulatory elements in the COUP-TFII promoter and remodeling chromatin accessibility; conditional deletion of Brg1 from vascular endothelium downregulates COUP-TFII and causes aberrant arterial marker expression on veins.","method":"Conditional endothelial Brg1 knockout; chromatin accessibility assays; ChIP for BRG1 binding to COUP-TFII promoter","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout placing BRG1 upstream of COUP-TFII, ChIP demonstrating direct promoter binding, single lab","pmids":["23406903"],"is_preprint":false},{"year":2016,"finding":"Tie2 signaling maintains COUP-TFII protein levels in venous endothelial cells via Akt-mediated stabilization; Ang-1 stimulation increases COUP-TFII protein, while Tie2 knockdown or PI3K/Akt pathway blockade reduces COUP-TFII levels, an effect reversed by proteasome inhibition.","method":"Tie2/Tek conditional knockout mice; Ang-1 stimulation assays; Tie2 knockdown in cultured ECs; PI3K/Akt inhibition; proteasome inhibitor rescue","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic approaches in vitro and in vivo, proteasome inhibitor rescue supporting post-translational regulation, single lab","pmids":["28005008"],"is_preprint":false},{"year":2008,"finding":"COUP-TFII is required for Leydig cell differentiation; ablation prior to puberty arrests Leydig cell differentiation at the progenitor stage, causing testosterone deficiency and spermatogenetic arrest. Testosterone administration rescues most but not all defects, while Leydig cell maturation failure persists, establishing COUP-TFII as intrinsically required for Leydig cell differentiation but not maintenance.","method":"Tamoxifen-inducible conditional knockout at different developmental stages; testosterone rescue experiment; histological analysis of Leydig cell differentiation","journal":"PLoS ONE","confidence":"High","confidence_rationale":"Tier 2 / Strong — stage-specific conditional knockout with hormonal rescue experiment dissecting differentiation vs maintenance functions","pmids":["18818749"],"is_preprint":false},{"year":2014,"finding":"COUP-TFII (NR2F2) directly activates Star (steroidogenic acute regulatory protein) gene transcription in Leydig cells by binding to a DR1-like element between -131 and -95 bp of the Star promoter; mutation of the DR1-like element that prevents COUP-TFII binding blunts promoter activation. COUP-TFII also cooperates with SF1 via protein-protein interactions to further enhance INSL3 and Star transcription.","method":"siRNA knockdown in MA-10/MLTC-1 cells; promoter deletion analysis; ChIP; electrophoretic mobility shift assay; site-directed mutagenesis; cotransfection with SF1","journal":"Biology of Reproduction","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis of binding site combined with ChIP and EMSA establishing direct binding, functional steroidogenesis readout","pmids":["24899578"],"is_preprint":false},{"year":2014,"finding":"COUP-TFII directly binds a DR0-like element in the INSL3 promoter (-186 to -79 bp) to activate Insl3 transcription in Leydig cells; mutation of the DR0-like element prevents COUP-TFII binding. COUP-TFII also acts through protein-protein interactions with SF1 bound at the Insl3 promoter to further activate transcription.","method":"siRNA knockdown; promoter deletion assays; ChIP; DNA precipitation assay; DR0-like element mutagenesis; cotransfection with SF1","journal":"Journal of Molecular Endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding confirmed by EMSA/ChIP plus mutagenesis of binding site, protein-protein interaction with SF1 demonstrated functionally","pmids":["24780841"],"is_preprint":false},{"year":2015,"finding":"Increased COUP-TFII in adult cardiomyocytes causes heart failure by repressing genes critical for mitochondrial electron transport chain activity, oxidative stress detoxification, and mitochondrial dynamics, resulting in increased ROS and reduced oxygen consumption. COUP-TFII also suppresses the PGC-1 network and decreases glucose and lipid utilization gene expression. COUP-TFII haploinsufficiency attenuates dilated cardiomyopathy in a calcineurin transgenic model.","method":"Cardiac-specific COUP-TFII overexpression transgenic mice; cardiac-specific heterozygous knockout; mitochondrial respiration assays; ROS measurement; gene expression profiling","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — both gain- and loss-of-function in vivo, direct functional measurement of mitochondrial respiration and ROS, pathway placement via PGC-1 network","pmids":["26356605"],"is_preprint":false},{"year":2021,"finding":"COUP-TFII enhances glycolysis and suppresses fatty acid oxidation in myofibroblasts to drive kidney fibrosis; COUP-TFII binds the PGC1α promoter (ChIP-qPCR) and reduces PGC1α expression, thereby suppressing mitochondrial metabolism. Overexpression of COUP-TFII induces αSMA and collagen 1 production; knockout decreases glycolysis and collagen 1 levels.","method":"Conditional knockout in mice; fibroblast overexpression; ChIP-qPCR for PGC1α promoter; unbiased proteomics; glycolysis and FAO metabolic assays","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockout, ChIP-qPCR for direct target, proteomic pathway analysis, multiple orthogonal methods in single study","pmids":["34031962"],"is_preprint":false},{"year":2016,"finding":"COUP-TFII regulates satellite cell function in skeletal muscle; ectopic COUP-TFII expression in satellite cells causes Duchenne-like dystrophy through deficient SC proliferation and impaired myoblast fusion. Mechanistically, COUP-TFII represses expression of Npnt, Itgb1D, and Cav3 (genes important for cell-cell fusion) and reduces activation of focal adhesion kinase (FAK).","method":"Satellite cell-specific COUP-TFII overexpression transgenic mice; mdx dystrophic model; satellite cell functional assays; gene expression analysis; FAK activation assays","journal":"Journal of Clinical Investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with specific cellular phenotype, downstream target identification, FAK pathway placement, single lab","pmids":["27617862"],"is_preprint":false},{"year":2017,"finding":"COUP-TFII represses myoblast fusion during skeletal muscle development by transcriptionally repressing Npnt, Itgb1D, and Cav3, and reducing focal adhesion kinase (FAK) activation; maintaining COUP-TFII expression in myogenic precursors (via ectopic expression) causes inefficient skeletal muscle development in mice.","method":"Myogenic precursor-specific COUP-TFII overexpression mouse model; myoblast fusion assays; FAK activation measurement; gene expression analysis","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with specific fusion phenotype, downstream target and signaling pathway identified, single lab","pmids":["28600496"],"is_preprint":false},{"year":2012,"finding":"COUP-TFII is required for metanephric mesenchyme specification; deletion at E7.5 results in absence of Eya1, Six2, Pax2, and Gdnf in the metanephric mesenchyme. COUP-TFII directly regulates Eya1 and Wt1 expression in the metanephric mesenchyme.","method":"Conditional knockout at E7.5; ChIP; gene expression analysis of developmental regulators","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with specific developmental phenotype, ChIP supporting direct target regulation, single lab","pmids":["22669823"],"is_preprint":false},{"year":2012,"finding":"COUP-TFII controls amygdala development by directly regulating Nrp1 and Nrp2 (semaphorin receptors controlling neuronal migration) in CGE-derived cells; ChIP assays in telencephalon confirm Nrp1 and Nrp2 as direct COUP-TFII targets, and CGE-specific conditional knockout causes failure of Pax6+ cell migration into the BMA nucleus.","method":"Rx-Cre conditional knockout mice; in vivo ChIP in telencephalon for Nrp1/Nrp2 promoters; cell migration analysis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo ChIP identifying direct targets, conditional knockout with specific migration phenotype, single lab","pmids":["22492355"],"is_preprint":false},{"year":2008,"finding":"COUP-TFII is preferentially expressed in caudal ganglionic eminence (CGE) neurons; transplantation of COUP-TFII-expressing MGE cells into CGE redirects their migration caudally, and knockdown of COUP-TFII inhibits caudal migration of CGE cells, demonstrating COUP-TFII is both necessary and sufficient for CGE-specific caudal migratory behavior.","method":"Transcriptome comparison of CGE/MGE/LGE; transplantation experiments; siRNA knockdown; migration assays","journal":"Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function (transplantation) and loss-of-function (knockdown) both demonstrate sufficiency and necessity for directional migration","pmids":["19074032"],"is_preprint":false},{"year":2015,"finding":"COUP-TFII-induced expression of Neuropilin-2 (Nrp2) controls the destination of POa-derived GABAergic neurons; suppression of COUP-TFII/Nrp2 redirects cells to the neocortex, while overexpression causes cells to end up in the medial amygdala, establishing COUP-TFII/Nrp2 as a molecular switch for migration pathway selection.","method":"In utero electroporation for gain- and loss-of-function; live cell migration tracking; Nrp2 expression analysis","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function establishing sufficiency and necessity, clear downstream effector (Nrp2) identified","pmids":["26305926"],"is_preprint":false},{"year":2010,"finding":"OCT4 and OCT4-induced miR-302 directly repress NR2F2 transcription and translation in undifferentiated hESCs; conversely, NR2F2 directly inhibits OCT4 during differentiation, forming a mutual repression loop. NR2F2 is among the earliest neural markers detected during hESC differentiation.","method":"Reporter assays; siRNA knockdown; miR-302 overexpression; chromatin-based transcription analysis in hESCs","journal":"EMBO Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal regulatory experiments demonstrating mutual repression, multiple reporter assay validations, single lab","pmids":["21151097"],"is_preprint":false},{"year":2013,"finding":"miR-302 directly targets NR2F2 mRNA (confirmed by luciferase reporter assay); NR2F2 directly inhibits OCT4 promoter activity. shRNA knockdown of NR2F2 mimics miR-302 overexpression by enhancing iPSC reprogramming efficiency.","method":"Luciferase reporter assay with NR2F2 3'UTR; OCT4 promoter activity assay; shRNA knockdown; reprogramming efficiency quantification","journal":"Stem Cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assay validating direct miRNA targeting, functional reprogramming phenotype, partially corroborates PMID:21151097","pmids":["23136034"],"is_preprint":false},{"year":1995,"finding":"ARP-1/COUP-TFII represses Oct-3/4 promoter activity through the RAREoct site in embryonal carcinoma cells in a dose-dependent manner; the C-terminal domain harbors the silencing region. COUP-TFII competes with and displaces RAR:RXR heterodimers from the RAREoct site due to higher binding affinity, thereby silencing Oct-3/4.","method":"Promoter-reporter assays; electrophoretic mobility shift assay (EMSA) for competitive binding; domain deletion analysis; P19 EC cell differentiation model","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA demonstrating competitive displacement of RAR:RXR, domain mapping, functional reporter assays, single lab","pmids":["7823919"],"is_preprint":false},{"year":1997,"finding":"The C-terminal domain of ARP-1/COUP-TFII (residues 210-414, encompassing helices 3-12) confers active repressor activity when fused to a heterologous DBD. The domains required for transrepression include the DBD and residues 193-399. Transrepression (not active repression) is the predominant mechanism, likely involving interaction with coactivator proteins used by liver-enriched transactivators (HNF-3, C/EBP, HNF-4) but not Sp1 or ATF.","method":"GAL4-fusion domain deletion analysis; transcription assays; Flu-tagged mutant series; co-transfection with liver-enriched and ubiquitous transactivators","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain mapping with multiple deletion constructs and heterologous DBD fusions, functional distinction between active repression and transrepression","pmids":["9271371"],"is_preprint":false},{"year":2000,"finding":"COUP-TFII synergistically activates CYP7A1 (cholesterol 7α-hydroxylase) transcription together with HNF4; in vitro-translated COUP-TFII binds DR0 and DR4 elements in the CYP7A1 promoter. The synergistic effect of HNF4 and COUP-TFII results from protein-protein interactions facilitated by juxtaposition of their binding elements rather than absolute requirement for the COUP-TFII binding sites.","method":"Cotransfection reporter assays; EMSA with in vitro-translated COUP-TFII; promoter mutagenesis","journal":"Journal of Lipid Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA with in vitro-translated protein, mutagenesis of binding sites, functional reporter assays demonstrating protein-protein interaction mechanism","pmids":["10627496"],"is_preprint":false},{"year":2004,"finding":"Glucocorticoid receptor (GR) physically interacts with COUP-TFII; GR stimulates COUP-TFII-induced transactivation via its AF-1 domain, while COUP-TFII represses GR-governed transcriptional activity by tethering corepressors SMRT and NCoR via its C-terminal domain.","method":"Co-immunoprecipitation; domain mapping; transcriptional assays with AF-1 mutants; corepressor recruitment assays","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP demonstrating physical interaction, domain-level mechanism proposed and partially validated, single lab","pmids":["15265774"],"is_preprint":false},{"year":2016,"finding":"COUP-TFII directly binds the miR-21 promoter (demonstrated by ChIP and luciferase assay) to transcriptionally activate miR-21 expression in CRC cells; miR-21 then targets Smad7, allowing COUP-TFII to promote TGF-β-induced EMT indirectly through this NR2F2→miR-21→Smad7 axis.","method":"ChIP; luciferase reporter assay; siRNA knockdown; EMT marker analysis","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assay demonstrating direct promoter binding, functional validation of downstream pathway, single lab","pmids":["28192117"],"is_preprint":false},{"year":2016,"finding":"COUP-TFII directly binds the COX-2 promoter to inhibit its transcription (demonstrated by ChIP and reporter assays); proinflammatory cytokines (IL-1β, TNF-α, TGF-β1) reduce COUP-TFII expression via microRNA-302a (which targets COUP-TFII 3'UTR), leading to de-repression of COX-2 in endometriosis.","method":"ChIP; luciferase reporter assay; miR-302a overexpression; COUP-TFII knockout mouse endometriosis transplantation model; primary human endometrial stromal cells","journal":"Journal of Clinical Endocrinology and Metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct COX-2 promoter binding, in vivo mouse model, mechanism validated in human primary cells","pmids":["24423359"],"is_preprint":false},{"year":2018,"finding":"COUP-TFII binds the ANG (angiogenin) promoter to suppress its transcription (demonstrated by ChIP and promoter activity assays); hypoxia reduces COUP-TFII levels leading to de-repression of ANG and enhanced angiogenesis in endometriosis.","method":"ChIP; luciferase promoter activity assay; siRNA knockdown and overexpression; HUVEC tube formation assay","journal":"Human Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, functional angiogenesis readout, reciprocal gain/loss-of-function experiments, single lab","pmids":["29982401"],"is_preprint":false},{"year":2014,"finding":"COUP-TFII directly targets the Snail1 promoter to regulate Snail1 transcription and expression in colorectal cancer cells; COUP-TFII together with Snail1 inhibits E-cadherin, ZO-1, and β-catenin expression to promote cell migration and metastasis.","method":"ChIP; promoter reporter assay; COUP-TFII overexpression/knockdown; tamoxifen-inducible knockout mice; cell migration and invasion assays","journal":"British Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct Snail1 promoter binding, in vivo knockout model for metastasis, single lab","pmids":["25032732"],"is_preprint":false},{"year":2019,"finding":"KRAS/MEK signaling upregulates COUP-TFII, which increases LDHA (lactate dehydrogenase A) expression leading to lactate production; lactate then inhibits TSC2-Rheb interaction to activate mTORC1, connecting KRAS signaling to glycolysis and mTORC1 activation via COUP-TFII.","method":"COUP-TFII overexpression and knockdown; LDHA expression analysis; TSC2-Rheb interaction assays; mTORC1 activity measurements; MEK inhibition","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic dissection of KRAS→COUP-TFII→LDHA→lactate→mTORC1 pathway, mechanistic biochemical assays, single lab","pmids":["30988000"],"is_preprint":false},{"year":2020,"finding":"A small-molecule COUP-TFII inhibitor (identified by high-throughput screening) directly binds the COUP-TFII ligand-binding domain and disrupts COUP-TFII interaction with FOXA1 and other transcription regulators, thereby repressing COUP-TFII transcriptional activity on target genes and exerting antitumor effects in prostate cancer models.","method":"High-throughput screening; ligand-binding domain binding assay; Co-IP for FOXA1-COUP-TFII interaction disruption; target gene expression; xenograft and patient-derived xenograft mouse models","journal":"Science Advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct LBD binding assay, protein-protein interaction disruption demonstrated, in vivo efficacy in multiple tumor models, multiple orthogonal methods","pmids":["32494682"],"is_preprint":false},{"year":2019,"finding":"NR2F2 functions as a co-factor with pioneer factors FOXA1 and GATA3 to promote ERα-dependent transcription in breast cancer; NR2F2 binds to most ERα binding sites independently of estrogen. Perturbation of NR2F2 decreases ERα DNA binding, chromatin accessibility, and estrogen-dependent cell growth.","method":"ChIP-seq (40 transcription factors in ENCODE); ATAC-seq; RNA-seq; NR2F2 perturbation experiments; ERα binding analysis","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq combined with functional NR2F2 perturbation and ERα binding readout, single lab","pmids":["31588232"],"is_preprint":false},{"year":2015,"finding":"COUP-TFII haploinsufficiency is regulated by insulin and glucose: insulin represses COUP-TFII in pancreatic β-cells through Foxo1 signaling, and high glucose represses COUP-TFII in hepatocytes through both Foxo1 and ChREBP. Ex vivo, COUP-TFII reduces insulin production and secretion; pancreatic COUP-TFII expression is activated by TCF7L2 (Wnt signaling), creating a feedback loop.","method":"Pancreatic-specific conditional knockout mice; Foxo1 signaling inhibition; ChREBP knockdown in hepatocytes; islet isolation ex vivo experiments; TCF7L2 reporter assays","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological approaches establishing regulatory pathway, ex vivo functional assay for insulin secretion, single lab","pmids":["18765640"],"is_preprint":false},{"year":2012,"finding":"COUP-TFII induces β-catenin gene expression and its target genes (cyclin D1, axin 2) in pancreatic β-cells; GLP-1 activation of the β-catenin pathway is impaired in COUP-TFII-deficient islets. COUP-TFII expression is activated by TCF7L2 in human islets and rat β-cells, forming a feedback loop. COUP-TFII is required for GLP-1-mediated β-catenin signaling and neonatal β-cell mass determination.","method":"Pancreatic conditional knockout (pdx1-Cre); islet isolation; gain- and loss-of-function in cultured β-cells; GLP-1 stimulation assays; gene expression analysis","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with ex vivo islet functional assays, GLP-1 pathway rescue experiments, TCF7L2 feedback validated in human islets","pmids":["22292058"],"is_preprint":false},{"year":2016,"finding":"miR-101 and miR-27a negatively regulate COUP-TFII expression; loss of miR-101 increases COUP-TFII, which in turn activates FOXM1 and CENPF expression to promote prostate cancer metastasis. COUP-TFII is a critical intermediate in the miRNA→COUP-TFII→FOXM1→CENPF metastatic cascade and also contributes to enzalutamide resistance.","method":"miRNA overexpression and inhibition; COUP-TFII knockdown/overexpression; downstream FOXM1/CENPF expression analysis; clinical PCa dataset correlation","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established through sequential knockdown/overexpression, correlation with clinical data, single lab","pmids":["27108958"],"is_preprint":false},{"year":2015,"finding":"A 5 amino acid deletion in the hinge region of NR2F2 (from zinc-finger nuclease gene editing) reduces interaction between wild-type NR2F2 and Fog2 (Friend of Gata2); the mutant NR2F2 protein has greater interaction with Fog2, and Nr2f2-mutant rats have significantly lower systolic and diastolic blood pressure, establishing the hinge region-Fog2 interaction as critical for blood pressure regulation.","method":"Zinc-finger nuclease-generated Nr2f2 mutant rat; protein-protein interaction assays (co-IP); blood pressure measurement","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene-edited animal model with specific hinge-region deletion, protein-protein interaction assay linking Fog2 binding to BP phenotype, single lab","pmids":["25687237"],"is_preprint":false},{"year":2010,"finding":"NR2F2 directly activates TFAP2A (AP-2α) promoter activity to promote human villous cytotrophoblast differentiation to syncytiotrophoblast; siRNA silencing of NR2F2 blocks induction of TFAP2A mRNA and STB marker genes (hPL, PSG1, CRH). NR2F2-mediated TFAP2A induction is potentiated by RAR-α and RXR-α.","method":"TFAP2A promoter reporter assays; siRNA knockdown in primary CTB cells and JEG-3 cells; cotransfection with RARA and RXRA","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — promoter reporter assay and siRNA knockdown in primary human cells, cooperativity with other nuclear receptors demonstrated, single lab","pmids":["20195529"],"is_preprint":false},{"year":2021,"finding":"COUP-TFII overexpression in fibroblasts induces αSMA and collagen 1 production; COUP-TFII binds the PGC1α promoter (by ChIP-qPCR) and represses PGC1α expression to suppress fatty acid oxidation and enhance glycolysis, driving myofibroblast activation and organ fibrosis. Knockout of COUP-TFII in mice attenuates injury-induced kidney fibrosis.","method":"Conditional fibroblast-specific knockout mice; unbiased proteomics; ChIP-qPCR; glycolysis/FAO metabolic assays; αSMA and collagen 1 quantification","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockout phenotype, direct promoter binding by ChIP, proteomic pathway validation, multiple orthogonal methods","pmids":["34031962"],"is_preprint":false},{"year":2023,"finding":"An alternative NR2F2 isoform (NR2F2-Iso2), transcribed from an alternative TSS and lacking the N-terminal DNA-binding domain, is regulated by DNA methylation during melanocyte differentiation. NR2F2-Iso2 re-expression during metastatic melanoma progression drives EMT and neural crest cell-like features by modulating the activity of full-length NR2F2 (Iso1) on EMT- and NCC-associated target genes.","method":"DNA methylation profiling; alternative TSS identification; functional gain- and loss-of-function; EMT and NCC target gene expression analysis","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic regulation of isoform-specific expression combined with functional studies in melanoma, mechanism of Iso2 modulating full-length NR2F2 activity established","pmids":["37015919"],"is_preprint":false},{"year":2021,"finding":"Fbxo21 (an F-box E3 ubiquitin ligase) ubiquitinates NR2F2 protein and targets it for proteasomal degradation in gastric cancer cells; Fbxo21 expression is negatively correlated with NR2F2 protein levels, and NR2F2 re-expression rescues EMT inhibition caused by Fbxo21 overexpression.","method":"Co-immunoprecipitation; ubiquitination assay; proteasome inhibitor treatment; gain- and loss-of-function; EMT marker analysis","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay identifying Fbxo21 as E3 ligase for NR2F2, proteasomal degradation mechanism established, single lab","pmids":["33531987"],"is_preprint":false},{"year":2020,"finding":"Elevated COUP-TFII in dopaminergic (DA) neurons represses cytosolic aldehyde dehydrogenase gene expression (epigenetic mechanism), leading to DOPAL accumulation, enhanced oxidative stress, and mitochondrial dysfunction with reduced cristae. Overexpression of COUP-TFII in DA neurons accelerates PD progression in MitoPark mice; underexpression of COUP-TFII slows motor deterioration.","method":"DA neuron-specific COUP-TFII overexpression and underexpression in mice; MitoPark PD model; mitochondrial morphology (EM); aldehyde dehydrogenase gene expression; epigenetic analysis","journal":"PLoS Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain and loss-of-function in DA neurons, mitochondrial morphology and pathway analysis, mechanistic link to DOPAL via ALDH repression","pmids":["32579581"],"is_preprint":false},{"year":2014,"finding":"COUP-TFII regulates gene expression in human endometrial stromal cells involved in cell adhesion, angiogenesis, and inflammation, including inflammatory cytokines; ChIP-seq identifies direct COUP-TFII binding sites across the endometrial stromal transcriptome.","method":"siRNA knockdown in primary human endometrial stromal cells; microarray; ChIP followed by deep sequencing (ChIP-seq)","journal":"Molecular Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq identifying genome-wide direct binding combined with gene expression profiling after knockdown, single lab in primary human cells","pmids":["24176914"],"is_preprint":false},{"year":2013,"finding":"NR2F2 (COUP-TFII) inhibits NFκB activation in breast cancer cells; COUP-TFII co-immunoprecipitates with NFκB subunits RelB and NFκB1 in MCF-7 cells; COUP-TFII inhibits NFκB-DNA binding in vitro and impairs coactivator-induced NFκB transactivation.","method":"Co-immunoprecipitation; EMSA for NFκB-DNA binding; NFκB reporter assays; COUP-TFII overexpression in LCC9 cells","journal":"Molecular and Cellular Endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP demonstrating physical interaction with NFκB subunits, EMSA for DNA binding inhibition, functional reporter validation, single lab","pmids":["24141032"],"is_preprint":false}],"current_model":"NR2F2 (COUP-TFII) is an orphan nuclear receptor that functions as a context-dependent transcriptional activator or repressor; its ligand-binding domain adopts an autorepressed conformation that is relieved by ligand (including retinoic acid) to allow coactivator recruitment. NR2F2 operates at the top of the venous endothelial identity pathway by directly repressing Notch target genes (HEY1/2) as a homodimer to suppress arterial fate, while forming heterodimers with PROX1 to specify lymphatic endothelial identity; Tie2/Akt signaling stabilizes COUP-TFII protein against proteasomal degradation, and BRG1 chromatin remodeling promotes its expression in veins. Beyond vascular biology, NR2F2 directly regulates target gene promoters (Angiopoietin-1, VEGFR-1, E2F1, COX-2, Snail1, LDHA, PGC1α, STAR, INSL3, Nrp1/2, Wnt10b, and others) through DNA binding or by tethering to other transcription factors; it interacts physically with partners including Prox1, HNF4, GR, SF1, FOXA1, GATA3, and NFκB subunits to co-regulate transcription. NR2F2 controls cell fate decisions in multiple lineages—including venous vs. arterial, adipogenic vs. osteogenic/myogenic, atrial vs. ventricular cardiomyocyte, and Leydig cell differentiation—and its dysregulation drives pathological states including heart failure (via mitochondrial dysfunction and PGC-1 network suppression), fibrosis (via glycolysis enhancement through PGC1α repression), Parkinson's disease progression (via ALDH repression and DOPAL accumulation), and multiple cancers (via TGF-β/SMAD4 pathway antagonism, EMT promotion, and KRAS/MEK/LDHA/mTORC1 axis)."},"narrative":{"mechanistic_narrative":"NR2F2 (COUP-TFII) is an orphan nuclear receptor that acts as a context-dependent transcriptional regulator governing cell-fate decisions across vascular, cardiac, reproductive, neural, metabolic, and mesenchymal lineages [PMID:15875024, PMID:23725765, PMID:21873211, PMID:18818749]. Its ligand-binding domain adopts an autorepressed conformation in which helix α10 occupies the ligand pocket and the AF-2 helix folds into the cofactor groove; retinoic acid relieves this state to permit coactivator recruitment, and mutations disrupting cofactor binding, dimerization, or ligand binding abolish activity [PMID:18798693]. NR2F2 can bind DNA directly at DR-type elements (e.g. the Star DR1-like and INSL3 DR0-like promoter sites) or operate by tethering to other transcription factors and by competitive displacement, as when it outcompetes RAR:RXR at the Oct-3/4 RAREoct site [PMID:24899578, PMID:24780841, PMID:7823919]. In the vasculature it establishes venous identity by binding HEY1/HEY2 promoters as a homodimer to repress Notch-driven arterial differentiation, while heterodimerization with PROX1 abolishes this repression and instead activates lymphatic endothelial genes (VEGFR-3, FGFR-3, neuropilin-1) — a dimer-state switch that partitions venous versus lymphatic fate [PMID:15875024, PMID:18815287, PMID:23345397]. Its abundance and activity are tuned at multiple levels: BRG1 remodels its venous promoter, Tie2/Akt signaling stabilizes the protein against proteasomal turnover, the Fbxo21 E3 ligase targets it for degradation, and miR-302/miR-101/miR-27a repress its expression [PMID:23406903, PMID:28005008, PMID:33531987, PMID:23136034, PMID:27108958]. Through this regulatory logic NR2F2 directs atrial versus ventricular cardiomyocyte identity, adipogenic versus osteo-/myogenic mesenchymal fate, Leydig cell differentiation and steroidogenesis, and GABAergic neuron migration via neuropilin induction [PMID:23725765, PMID:21873211, PMID:18818749, PMID:26305926]. Dysregulation drives disease: cardiac overexpression causes heart failure by repressing the PGC-1/mitochondrial network, fibroblast COUP-TFII enhances glycolysis and represses PGC1α to drive organ fibrosis, and in cancer it antagonizes SMAD4-dependent TGF-β checkpoints, promotes EMT and metastasis, and couples KRAS/MEK signaling to LDHA-driven glycolysis and mTORC1 activation [PMID:26356605, PMID:34031962, PMID:23201680, PMID:25032732, PMID:30988000].","teleology":[{"year":1995,"claim":"Established the first molecular mechanism of COUP-TFII repression: it silences a target promoter by outcompeting an activating nuclear-receptor heterodimer rather than by a passive mechanism.","evidence":"Promoter-reporter assays, EMSA competition, and domain deletion in embryonal carcinoma cells showing displacement of RAR:RXR from the Oct-3/4 RAREoct site","pmids":["7823919"],"confidence":"Medium","gaps":["Did not resolve whether displacement operates at endogenous loci genome-wide","C-terminal silencing domain partners not identified"]},{"year":1997,"claim":"Mapped the repression machinery, distinguishing active repression from transrepression and implicating shared coactivator squelching with liver-enriched factors.","evidence":"GAL4-fusion domain deletion series and co-transfection with HNF-3/C/EBP/HNF-4 transactivators","pmids":["9271371","9395397"],"confidence":"Medium","gaps":["Specific coactivators competed for were inferred, not biochemically isolated","The Shh-responsive transcription factor activated by dephosphorylation was not identified"]},{"year":1999,"claim":"Defined COUP-TFII as essential for cardiovascular morphogenesis and identified Angiopoietin-1 as a downstream effector linking it to mesenchymal-endothelial signaling.","evidence":"Targeted gene deletion in mice with in situ analysis of Ang-1","pmids":["10215630"],"confidence":"High","gaps":["Direct promoter binding to Ang-1 not shown in this study","Did not separate angiogenic from cardiac roles"]},{"year":2005,"claim":"Placed COUP-TFII at the top of venous identity by showing it represses Notch signaling to prevent arterial fate, resolving how veins are molecularly specified.","evidence":"Endothelial conditional knockout and transgenic overexpression with arterial/venous marker analysis in mice","pmids":["15875024"],"confidence":"High","gaps":["Direct Notch-target promoter binding not yet demonstrated","Did not address lymphatic fate"]},{"year":2008,"claim":"Provided the structural basis for ligand-dependent regulation and defined the PROX1 partnership that switches COUP-TFII output toward lymphatic identity.","evidence":"1.48 Å crystal structure with mutagenesis and coactivator assays; reciprocal Co-IP and target-gene analysis for the COUP-TFII/Prox1 complex; stage-specific Leydig knockout with testosterone rescue","pmids":["18798693","18815287","18818749"],"confidence":"High","gaps":["Endogenous physiological ligand remains unidentified","Stoichiometry and DNA-binding mode of the COUP-TFII/Prox1 complex not structurally resolved"]},{"year":2013,"claim":"Unified vascular biology into a dimer-state model: homodimers repress HEY1/HEY2 to block arterial fate while NR2F2/PROX1 heterodimers relieve this and drive lymphatic genes; concurrently established direct atrial-identity target binding and an upstream BRG1 input.","evidence":"ChIP and promoter binding distinguishing homodimer vs heterodimer activity in ECs; cardiomyocyte conditional knockout with ChIP and electrophysiology; endothelial Brg1 knockout with ChIP on the COUP-TFII promoter","pmids":["23345397","23725765","23406903"],"confidence":"High","gaps":["How dimer choice is biochemically controlled in vivo not defined","BRG1 study correlative for chromatin remodeling causality"]},{"year":2010,"claim":"Demonstrated COUP-TFII bidirectionally tunes the angiogenic program — activating Angiopoietin-1 in pericytes while repressing VEGFR-1 in endothelium — and defined a mutual repression loop with OCT4 governing pluripotency exit.","evidence":"Conditional knockouts in tumor and RIP-Tag models with Ang-1 rescue and VEGFR-1 repression assays; reporter and knockdown experiments mapping the OCT4/miR-302/NR2F2 loop in hESCs","pmids":["20133706","20978203","21151097"],"confidence":"High","gaps":["Cell-type basis for activation vs repression of angiogenic targets not mechanistically explained","Direct OCT4 promoter occupancy partly inferred"]},{"year":2012,"claim":"Generalized COUP-TFII as a master fate selector by showing direct, lineage-specific target regulation in adipose, mesenchymal, renal, neural, and proliferative contexts.","evidence":"ChIP-validated direct targets (Wnt10b, Eya1/Wt1, Nrp1/Nrp2, E2F1 via Sp1 tethering) across knockout and knockdown systems; SMAD4 antagonism by genetic epistasis in PTEN-null prostate tumors","pmids":["19117548","21873211","22669823","22492355","22734039","23201680"],"confidence":"High","gaps":["Whether a single biochemical mode explains both DNA-direct and tethered regulation unresolved","Lineage specificity of cofactor selection not defined"]},{"year":2014,"claim":"Resolved direct DNA-binding mechanisms at steroidogenic promoters and showed cooperation with SF1, while extending the repertoire to EMT and inflammatory targets.","evidence":"ChIP, EMSA, and DR-element mutagenesis at Star and INSL3 promoters with SF1 cotransfection; ChIP and reporter assays on Snail1, COX-2, and endometrial ChIP-seq","pmids":["24899578","24780841","25032732","24423359","24176914"],"confidence":"High","gaps":["Structural basis of the SF1 interaction not determined","Genome-wide binding only mapped in select cell types"]},{"year":2016,"claim":"Established post-translational control of COUP-TFII abundance and connected it to oncogenic metabolic rewiring and inflammatory signaling.","evidence":"Tie2/Akt stabilization with proteasome-inhibitor rescue; ChIP/luciferase for the miR-21/Smad7 axis; miR-101/27a regulation of the FOXM1/CENPF cascade; Co-IP and EMSA showing NFκB inhibition","pmids":["28005008","28192117","27108958","24141032"],"confidence":"Medium","gaps":["The stabilizing E3/deubiquitinase machinery downstream of Akt not identified here","NFκB interaction shown by single-lab Co-IP without reciprocal in vivo validation"]},{"year":2019,"claim":"Integrated COUP-TFII into KRAS-driven glycolysis and cofactor networks with pioneer factors, defining actionable mechanisms.","evidence":"Genetic/pharmacological dissection of KRAS→COUP-TFII→LDHA→lactate→mTORC1; ChIP-seq/ATAC-seq showing NR2F2 cofactor activity with FOXA1/GATA3 at ERα sites","pmids":["30988000","31588232"],"confidence":"Medium","gaps":["Direct LDHA promoter occupancy by COUP-TFII not fully resolved","FOXA1/GATA3 cooperativity from single-lab genomic dataset"]},{"year":2020,"claim":"Defined COUP-TFII as a druggable driver and disease node in heart failure, fibrosis, and Parkinson's via mitochondrial/metabolic gene repression.","evidence":"Small-molecule LBD binder disrupting FOXA1 interaction with in vivo antitumor efficacy; cardiac and fibroblast knockout/overexpression with ChIP on PGC1α; DA-neuron gain/loss-of-function repressing ALDH in MitoPark mice","pmids":["32494682","26356605","34031962","32579581"],"confidence":"High","gaps":["Whether inhibitor selectivity extends beyond FOXA1-dependent complexes unknown","Epigenetic mechanism of ALDH repression only partially characterized"]},{"year":2023,"claim":"Revealed isoform-level and species-specific regulation expanding the mechanistic model: a DBD-lacking isoform modulates full-length activity, and a hinge-region/Fog2 interaction controls blood pressure.","evidence":"DNA-methylation-regulated alternative-TSS isoform with EMT/NCC functional assays in melanoma; zinc-finger-nuclease hinge-deletion rat with Co-IP and blood-pressure phenotyping","pmids":["37015919","25687237"],"confidence":"Medium","gaps":["Mechanism by which Iso2 modulates full-length NR2F2 not biochemically defined","Fog2 interaction effect on transcriptional targets not mapped"]},{"year":null,"claim":"The endogenous physiological ligand and the rules that select between DNA-direct binding, factor tethering, homodimer repression, and heterodimer activation in a given cell type remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No native ligand identified despite retinoic-acid responsiveness","No unifying model for dimer-partner and cofactor selection across lineages","Structural basis of most protein-protein tethering interactions unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,9,18,19,30,37]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,18,19,30,50]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,32,33,40,51]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4,18,30]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,9,13,17,26]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,18,19,30,37]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,16,38,42]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[20,38,46]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,20,37,38,46,49]}],"complexes":["NR2F2/PROX1 lymphatic co-regulator complex"],"partners":["PROX1","SF1","HNF4","GR","FOXA1","GATA3","FOG2","RELB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P24468","full_name":"COUP transcription factor 2","aliases":["Apolipoprotein A-I regulatory protein 1","ARP-1","COUP transcription factor II","COUP-TF II","Nuclear receptor subfamily 2 group F member 2"],"length_aa":414,"mass_kda":45.6,"function":"Ligand-activated transcription factor. Activated by high concentrations of 9-cis-retinoic acid and all-trans-retinoic acid, but not by dexamethasone, cortisol or progesterone (in vitro). Regulation of the apolipoprotein A-I gene transcription. Binds to DNA site A. May be required to establish ovary identity during early gonad development (PubMed:29478779)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P24468/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR2F2","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NR2F2","total_profiled":1310},"omim":[{"mim_id":"621058","title":"NK1 HOMEOBOX 2; NKX1-2","url":"https://www.omim.org/entry/621058"},{"mim_id":"618901","title":"46,XX SEX REVERSAL 5; SRXX5","url":"https://www.omim.org/entry/618901"},{"mim_id":"617962","title":"ZINC FINGER PROTEIN 827; ZNF827","url":"https://www.omim.org/entry/617962"},{"mim_id":"616297","title":"MULTIPLE C2 DOMAINS-CONTAINING TRANSMEMBRANE PROTEIN 2; MCTP2","url":"https://www.omim.org/entry/616297"},{"mim_id":"615779","title":"CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 4; CHTD4","url":"https://www.omim.org/entry/615779"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NR2F2"},"hgnc":{"alias_symbol":["COUP-TFII","COUPTFB","SVP40","NF-E3","COUPTF2"],"prev_symbol":["ARP1","TFCOUP2"]},"alphafold":{"accession":"P24468","domains":[{"cath_id":"3.30.50.10","chopping":"87-147","consensus_level":"high","plddt":95.2893,"start":87,"end":147},{"cath_id":"1.10.565.10","chopping":"172-190_208-401","consensus_level":"high","plddt":89.5022,"start":172,"end":401}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P24468","model_url":"https://alphafold.ebi.ac.uk/files/AF-P24468-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P24468-F1-predicted_aligned_error_v6.png","plddt_mean":76.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR2F2","jax_strain_url":"https://www.jax.org/strain/search?query=NR2F2"},"sequence":{"accession":"P24468","fasta_url":"https://rest.uniprot.org/uniprotkb/P24468.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P24468/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P24468"}},"corpus_meta":[{"pmid":"15875024","id":"PMC_15875024","title":"Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15875024","citation_count":522,"is_preprint":false},{"pmid":"10215630","id":"PMC_10215630","title":"The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development.","date":"1999","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10215630","citation_count":437,"is_preprint":false},{"pmid":"17590085","id":"PMC_17590085","title":"COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity.","date":"2007","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17590085","citation_count":178,"is_preprint":false},{"pmid":"18798693","id":"PMC_18798693","title":"Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor.","date":"2008","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/18798693","citation_count":172,"is_preprint":false},{"pmid":"21151097","id":"PMC_21151097","title":"A regulatory circuitry comprised of miR-302 and the transcription factors OCT4 and NR2F2 regulates human embryonic stem cell differentiation.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21151097","citation_count":161,"is_preprint":false},{"pmid":"23201680","id":"PMC_23201680","title":"COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23201680","citation_count":158,"is_preprint":false},{"pmid":"24702954","id":"PMC_24702954","title":"Rare variants in NR2F2 cause congenital heart defects in humans.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24702954","citation_count":139,"is_preprint":false},{"pmid":"7823919","id":"PMC_7823919","title":"A dynamic balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and retinoic acid receptor:retinoid X receptor heterodimers regulates Oct-3/4 expression in embryonal carcinoma cells.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7823919","citation_count":138,"is_preprint":false},{"pmid":"18815287","id":"PMC_18815287","title":"Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18815287","citation_count":136,"is_preprint":false},{"pmid":"9395397","id":"PMC_9395397","title":"Mediation of Sonic hedgehog-induced expression of COUP-TFII by a protein phosphatase.","date":"1997","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9395397","citation_count":130,"is_preprint":false},{"pmid":"19074032","id":"PMC_19074032","title":"COUP-TFII is preferentially expressed in the caudal ganglionic eminence and is involved in the caudal migratory stream.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19074032","citation_count":125,"is_preprint":false},{"pmid":"19117548","id":"PMC_19117548","title":"The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism.","date":"2009","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/19117548","citation_count":119,"is_preprint":false},{"pmid":"23725765","id":"PMC_23725765","title":"Atrial identity is determined by a COUP-TFII regulatory network.","date":"2013","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/23725765","citation_count":114,"is_preprint":false},{"pmid":"23136034","id":"PMC_23136034","title":"MicroRNA-302 increases reprogramming efficiency via repression of NR2F2.","date":"2013","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/23136034","citation_count":111,"is_preprint":false},{"pmid":"10627496","id":"PMC_10627496","title":"HNF4 and COUP-TFII interact to modulate transcription of the cholesterol 7alpha-hydroxylase gene (CYP7A1).","date":"2000","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/10627496","citation_count":110,"is_preprint":false},{"pmid":"15829524","id":"PMC_15829524","title":"COUP-TFII is essential for radial and anteroposterior patterning of the stomach.","date":"2005","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15829524","citation_count":108,"is_preprint":false},{"pmid":"20133706","id":"PMC_20133706","title":"COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20133706","citation_count":102,"is_preprint":false},{"pmid":"27108958","id":"PMC_27108958","title":"Dysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27108958","citation_count":98,"is_preprint":false},{"pmid":"18818749","id":"PMC_18818749","title":"Essential roles of COUP-TFII in Leydig cell differentiation and male fertility.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18818749","citation_count":97,"is_preprint":false},{"pmid":"20130170","id":"PMC_20130170","title":"Expression of COUP-TFII nuclear receptor in restricted GABAergic neuronal populations in the adult rat hippocampus.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20130170","citation_count":94,"is_preprint":false},{"pmid":"25412310","id":"PMC_25412310","title":"MicroRNA-194 reciprocally stimulates osteogenesis and inhibits adipogenesis via regulating COUP-TFII expression.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/25412310","citation_count":90,"is_preprint":false},{"pmid":"29478779","id":"PMC_29478779","title":"Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29478779","citation_count":71,"is_preprint":false},{"pmid":"8622679","id":"PMC_8622679","title":"Positive regulation of the vHNF1 promoter by the orphan receptors COUP-TF1/Ear3 and COUP-TFII/Arp1.","date":"1996","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8622679","citation_count":71,"is_preprint":false},{"pmid":"22734039","id":"PMC_22734039","title":"COUP-TFII is a major regulator of cell cycle and Notch signaling pathways.","date":"2012","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/22734039","citation_count":70,"is_preprint":false},{"pmid":"17404209","id":"PMC_17404209","title":"Deletion of the orphan nuclear receptor COUP-TFII in uterus leads to placental deficiency.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17404209","citation_count":70,"is_preprint":false},{"pmid":"23345397","id":"PMC_23345397","title":"COUP-TFII orchestrates venous and lymphatic endothelial identity by homo- or hetero-dimerisation with PROX1.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23345397","citation_count":68,"is_preprint":false},{"pmid":"20219888","id":"PMC_20219888","title":"Suppression of ERalpha activity by COUP-TFII is essential for successful implantation and decidualization.","date":"2010","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/20219888","citation_count":68,"is_preprint":false},{"pmid":"30592135","id":"PMC_30592135","title":"LncRNA NR2F2-AS1 promotes tumourigenesis through modulating BMI1 expression by targeting miR-320b in non-small cell lung cancer.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30592135","citation_count":65,"is_preprint":false},{"pmid":"15572686","id":"PMC_15572686","title":"The nuclear orphan receptor COUP-TFII is required for limb and skeletal muscle development.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15572686","citation_count":63,"is_preprint":false},{"pmid":"28005008","id":"PMC_28005008","title":"Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28005008","citation_count":62,"is_preprint":false},{"pmid":"31906104","id":"PMC_31906104","title":"COUP-TFII in Health and Disease.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31906104","citation_count":60,"is_preprint":false},{"pmid":"21873211","id":"PMC_21873211","title":"Nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) modulates mesenchymal cell commitment and differentiation.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21873211","citation_count":60,"is_preprint":false},{"pmid":"23406903","id":"PMC_23406903","title":"BRG1 promotes COUP-TFII expression and venous specification during embryonic vascular development.","date":"2013","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23406903","citation_count":59,"is_preprint":false},{"pmid":"26356605","id":"PMC_26356605","title":"Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26356605","citation_count":59,"is_preprint":false},{"pmid":"22492355","id":"PMC_22492355","title":"COUP-TFII controls amygdala patterning by regulating neuropilin expression.","date":"2012","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22492355","citation_count":57,"is_preprint":false},{"pmid":"20978203","id":"PMC_20978203","title":"Nuclear receptor COUP-TFII controls pancreatic islet tumor angiogenesis by regulating vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20978203","citation_count":57,"is_preprint":false},{"pmid":"28192117","id":"PMC_28192117","title":"NR2F2 inhibits Smad7 expression and promotes TGF-β-dependent epithelial-mesenchymal transition of CRC via transactivation of miR-21.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28192117","citation_count":51,"is_preprint":false},{"pmid":"24899578","id":"PMC_24899578","title":"The nuclear receptor NR2F2 activates star expression and steroidogenesis in mouse MA-10 and MLTC-1 Leydig cells.","date":"2014","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/24899578","citation_count":51,"is_preprint":false},{"pmid":"28922831","id":"PMC_28922831","title":"The Transcription Factors COUP-TFI and COUP-TFII have Distinct Roles in Arealisation and GABAergic Interneuron Specification in the Early Human Fetal Telencephalon.","date":"2017","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/28922831","citation_count":51,"is_preprint":false},{"pmid":"28694260","id":"PMC_28694260","title":"Coup-TF1 and Coup-TF2 control subtype and laminar identity of MGE-derived neocortical interneurons.","date":"2017","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28694260","citation_count":50,"is_preprint":false},{"pmid":"25800782","id":"PMC_25800782","title":"miR-30-HNF4γ and miR-194-NR2F2 regulatory networks contribute to the upregulation of metaplasia markers in the stomach.","date":"2015","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/25800782","citation_count":50,"is_preprint":false},{"pmid":"9271371","id":"PMC_9271371","title":"Functional domains of the human orphan receptor ARP-1/COUP-TFII involved in active repression and transrepression.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9271371","citation_count":50,"is_preprint":false},{"pmid":"27844448","id":"PMC_27844448","title":"miR-27b inhibits gastric cancer metastasis by targeting NR2F2.","date":"2016","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/27844448","citation_count":47,"is_preprint":false},{"pmid":"24176914","id":"PMC_24176914","title":"COUP-TFII regulates human endometrial stromal genes involved in inflammation.","date":"2013","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/24176914","citation_count":45,"is_preprint":false},{"pmid":"26537113","id":"PMC_26537113","title":"Venous Endothelial Marker COUP-TFII Regulates the Distinct Pathologic Potentials of Adult Arteries and Veins.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26537113","citation_count":45,"is_preprint":false},{"pmid":"29173897","id":"PMC_29173897","title":"A COUP-TFII Human Embryonic Stem Cell Reporter Line to Identify and Select Atrial Cardiomyocytes.","date":"2017","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29173897","citation_count":43,"is_preprint":false},{"pmid":"8652410","id":"PMC_8652410","title":"Developmental expression and differential regulation by retinoic acid of Xenopus COUP-TF-A and COUP-TF-B.","date":"1996","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/8652410","citation_count":43,"is_preprint":false},{"pmid":"25215426","id":"PMC_25215426","title":"MicroRNA-302a stimulates osteoblastic differentiation by repressing COUP-TFII expression.","date":"2015","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25215426","citation_count":42,"is_preprint":false},{"pmid":"21641336","id":"PMC_21641336","title":"Transcription factor COUP-TFII is indispensable for venous and lymphatic development in zebrafish and Xenopus laevis.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21641336","citation_count":41,"is_preprint":false},{"pmid":"23690307","id":"PMC_23690307","title":"Expression and functional pathway analysis of nuclear receptor NR2F2 in ovarian cancer.","date":"2013","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23690307","citation_count":40,"is_preprint":false},{"pmid":"22966133","id":"PMC_22966133","title":"Multiple roles of COUP-TFII in cancer initiation and progression.","date":"2012","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22966133","citation_count":40,"is_preprint":false},{"pmid":"24423359","id":"PMC_24423359","title":"Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis.","date":"2014","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24423359","citation_count":40,"is_preprint":false},{"pmid":"23378030","id":"PMC_23378030","title":"Sonic hedgehog (Shh) regulates the expression of angiogenic growth factors in oxygen-glucose-deprived astrocytes by mediating the nuclear receptor NR2F2.","date":"2013","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/23378030","citation_count":40,"is_preprint":false},{"pmid":"12385758","id":"PMC_12385758","title":"Expression of COUP-TFII in metabolic tissues during development.","date":"2002","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/12385758","citation_count":39,"is_preprint":false},{"pmid":"22669823","id":"PMC_22669823","title":"COUP-TFII is essential for metanephric mesenchyme formation and kidney precursor cell survival.","date":"2012","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22669823","citation_count":39,"is_preprint":false},{"pmid":"25283503","id":"PMC_25283503","title":"The role of the orphan nuclear receptor COUP-TFII in tumorigenesis.","date":"2014","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/25283503","citation_count":38,"is_preprint":false},{"pmid":"27748848","id":"PMC_27748848","title":"MicroRNA-382 inhibits prostate cancer cell proliferation and metastasis through targeting COUP-TFII.","date":"2016","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/27748848","citation_count":38,"is_preprint":false},{"pmid":"22178710","id":"PMC_22178710","title":"COUP-TFII expressing interneurons in human fetal forebrain.","date":"2011","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/22178710","citation_count":38,"is_preprint":false},{"pmid":"35122061","id":"PMC_35122061","title":"NR2F2 controls malignant squamous cell carcinoma state by promoting stemness and invasion and repressing differentiation.","date":"2021","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35122061","citation_count":37,"is_preprint":false},{"pmid":"26800338","id":"PMC_26800338","title":"MiR-382 inhibits cell growth and invasion by targeting NR2F2 in colorectal cancer.","date":"2016","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/26800338","citation_count":37,"is_preprint":false},{"pmid":"26305926","id":"PMC_26305926","title":"The COUP-TFII/Neuropilin-2 is a molecular switch steering diencephalon-derived GABAergic neurons in the developing mouse brain.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26305926","citation_count":37,"is_preprint":false},{"pmid":"24780841","id":"PMC_24780841","title":"The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells.","date":"2014","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24780841","citation_count":36,"is_preprint":false},{"pmid":"18765640","id":"PMC_18765640","title":"The transcription factor COUP-TFII is negatively regulated by insulin and glucose via Foxo1- and ChREBP-controlled pathways.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18765640","citation_count":36,"is_preprint":false},{"pmid":"27363585","id":"PMC_27363585","title":"De novo frameshift mutation in COUP-TFII (NR2F2) in human congenital diaphragmatic hernia.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/27363585","citation_count":34,"is_preprint":false},{"pmid":"36081650","id":"PMC_36081650","title":"Nr2f2 Overexpression Aggravates Ferroptosis and Mitochondrial Dysfunction by Regulating the PGC-1α Signaling in Diabetes-Induced Heart Failure Mice.","date":"2022","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/36081650","citation_count":33,"is_preprint":false},{"pmid":"24122412","id":"PMC_24122412","title":"COUP-TFII in pancreatic adenocarcinoma: clinical implication for patient survival and tumor progression.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24122412","citation_count":33,"is_preprint":false},{"pmid":"30988000","id":"PMC_30988000","title":"Oncogenic KRAS signaling activates mTORC1 through COUP-TFII-mediated lactate production.","date":"2019","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/30988000","citation_count":32,"is_preprint":false},{"pmid":"31588232","id":"PMC_31588232","title":"Cooperativity of co-factor NR2F2 with Pioneer Factors GATA3, FOXA1 in promoting ERα function.","date":"2019","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/31588232","citation_count":32,"is_preprint":false},{"pmid":"25032732","id":"PMC_25032732","title":"COUP-TFII regulates metastasis of colorectal adenocarcinoma cells by modulating Snail1.","date":"2014","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25032732","citation_count":32,"is_preprint":false},{"pmid":"20195529","id":"PMC_20195529","title":"Involvement of transcription factor NR2F2 in human trophoblast differentiation.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20195529","citation_count":32,"is_preprint":false},{"pmid":"25328664","id":"PMC_25328664","title":"The critical roles of COUP-TFII in tumor progression and metastasis.","date":"2014","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/25328664","citation_count":30,"is_preprint":false},{"pmid":"34031962","id":"PMC_34031962","title":"Orphan nuclear receptor COUP-TFII enhances myofibroblast glycolysis leading to kidney fibrosis.","date":"2021","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/34031962","citation_count":30,"is_preprint":false},{"pmid":"32631390","id":"PMC_32631390","title":"NR2F2 plays a major role in insulin-induced epithelial-mesenchymal transition in breast cancer cells.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32631390","citation_count":30,"is_preprint":false},{"pmid":"32494682","id":"PMC_32494682","title":"Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32494682","citation_count":30,"is_preprint":false},{"pmid":"29222010","id":"PMC_29222010","title":"A novel NR2F2 loss-of-function mutation predisposes to congenital heart defect.","date":"2017","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29222010","citation_count":30,"is_preprint":false},{"pmid":"15265774","id":"PMC_15265774","title":"Interaction of the glucocorticoid receptor and the chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII): implications for the actions of glucocorticoids on glucose, lipoprotein, and xenobiotic metabolism.","date":"2004","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/15265774","citation_count":30,"is_preprint":false},{"pmid":"11168401","id":"PMC_11168401","title":"COUP-TFI and COUP-TFII regulate expression of the NHE through a nuclear hormone responsive element with enhancer activity.","date":"2001","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11168401","citation_count":26,"is_preprint":false},{"pmid":"25129343","id":"PMC_25129343","title":"High NR2F2 transcript level is associated with increased survival and its expression inhibits TGF-β-dependent epithelial-mesenchymal transition in breast cancer.","date":"2014","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/25129343","citation_count":25,"is_preprint":false},{"pmid":"25922524","id":"PMC_25922524","title":"Transcription factors COUP-TFI and COUP-TFII are required for the production of granule cells in the mouse olfactory bulb.","date":"2015","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25922524","citation_count":24,"is_preprint":false},{"pmid":"27617862","id":"PMC_27617862","title":"COUP-TFII regulates satellite cell function and muscular dystrophy.","date":"2016","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/27617862","citation_count":24,"is_preprint":false},{"pmid":"27345768","id":"PMC_27345768","title":"NR2F2 regulates chondrogenesis of human mesenchymal stem cells in bioprinted cartilage.","date":"2016","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/27345768","citation_count":24,"is_preprint":false},{"pmid":"28600496","id":"PMC_28600496","title":"Dysregulation of nuclear receptor COUP-TFII impairs skeletal muscle development.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28600496","citation_count":23,"is_preprint":false},{"pmid":"22292058","id":"PMC_22292058","title":"COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22292058","citation_count":23,"is_preprint":false},{"pmid":"30481528","id":"PMC_30481528","title":"COUP-TFII revisited: Its role in metabolic gene regulation.","date":"2018","source":"Steroids","url":"https://pubmed.ncbi.nlm.nih.gov/30481528","citation_count":22,"is_preprint":false},{"pmid":"27866920","id":"PMC_27866920","title":"The orphan nuclear receptor COUP-TFII coordinates hypoxia-independent proangiogenic responses in hepatic stellate cells.","date":"2016","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/27866920","citation_count":22,"is_preprint":false},{"pmid":"30720060","id":"PMC_30720060","title":"NR2F2 loss‑of‑function mutation is responsible for congenital bicuspid aortic valve.","date":"2019","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30720060","citation_count":21,"is_preprint":false},{"pmid":"15907456","id":"PMC_15907456","title":"Dynamic expression of COUP-TFI and COUP-TFII during development and functional maturation of the mouse inner ear.","date":"2005","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/15907456","citation_count":21,"is_preprint":false},{"pmid":"33531987","id":"PMC_33531987","title":"Fbxo21 regulates the epithelial-to-mesenchymal transition through ubiquitination of Nr2f2 in gastric cancer.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33531987","citation_count":21,"is_preprint":false},{"pmid":"37015919","id":"PMC_37015919","title":"An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37015919","citation_count":20,"is_preprint":false},{"pmid":"23704310","id":"PMC_23704310","title":"Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids.","date":"2013","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23704310","citation_count":20,"is_preprint":false},{"pmid":"29982401","id":"PMC_29982401","title":"Suppression of COUP-TFII upregulates angiogenin and promotes angiogenesis in endometriosis.","date":"2018","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29982401","citation_count":20,"is_preprint":false},{"pmid":"24141032","id":"PMC_24141032","title":"COUP-TFII inhibits NFkappaB activation in endocrine-resistant breast cancer cells.","date":"2013","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24141032","citation_count":20,"is_preprint":false},{"pmid":"26658017","id":"PMC_26658017","title":"Choose your destiny: Make a cell fate decision with COUP-TFII.","date":"2015","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26658017","citation_count":19,"is_preprint":false},{"pmid":"32469064","id":"PMC_32469064","title":"NR2F2-AS1 accelerates cell proliferation through regulating miR-4429/MBD1 axis in cervical cancer.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32469064","citation_count":18,"is_preprint":false},{"pmid":"32579581","id":"PMC_32579581","title":"Elevated COUP-TFII expression in dopaminergic neurons accelerates the progression of Parkinson's disease through mitochondrial dysfunction.","date":"2020","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32579581","citation_count":18,"is_preprint":false},{"pmid":"25687237","id":"PMC_25687237","title":"Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25687237","citation_count":18,"is_preprint":false},{"pmid":"32210626","id":"PMC_32210626","title":"LncRNA NR2F2-AS1 Silencing Induces Cell Cycle Arrest in G0/G1 Phase via Downregulating Cyclin D1 in Colorectal Cancer.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32210626","citation_count":18,"is_preprint":false},{"pmid":"28059499","id":"PMC_28059499","title":"Inactivation of the Nuclear Orphan Receptor COUP-TFII by Small Chemicals.","date":"2017","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/28059499","citation_count":17,"is_preprint":false},{"pmid":"37500725","id":"PMC_37500725","title":"Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays.","date":"2023","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/37500725","citation_count":17,"is_preprint":false},{"pmid":"27193872","id":"PMC_27193872","title":"Knockdown of COUP-TFII inhibits cell proliferation and induces apoptosis through upregulating BRCA1 in renal cell carcinoma cells.","date":"2016","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27193872","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50583,"output_tokens":13451,"usd":0.176757,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":25559,"output_tokens":5179,"usd":0.128635,"stage2_stop_reason":"end_turn"},"total_usd":0.305392,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"COUP-TFII (NR2F2) is specifically expressed in venous but not arterial endothelium; endothelial-specific ablation enables veins to acquire arterial characteristics including NP-1 and Notch signaling molecule expression, while ectopic expression causes vein-artery fusion. COUP-TFII represses Notch signaling to maintain vein identity.\",\n      \"method\": \"Conditional knockout and transgenic overexpression in mouse endothelial cells; arterial/venous marker analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function in vivo, replicated across multiple transgenic lines, clear molecular pathway placement (Notch suppression)\",\n      \"pmids\": [\"15875024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"COUP-TFII is required for angiogenesis and heart development; null mice fail to remodel the primitive capillary plexus, and atria/sinus venosus do not develop past the primitive tube stage. Angiopoietin-1 expression is down-regulated in COUP-TFII mutant hearts, suggesting COUP-TFII controls mesenchymal-endothelial signaling through Angiopoietin-1.\",\n      \"method\": \"Targeted gene deletion in mice; in situ hybridization and expression analysis of Angiopoietin-1\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined developmental phenotype, downstream target (Ang-1) identified, replicated across multiple labs\",\n      \"pmids\": [\"10215630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of human COUP-TFII ligand-binding domain at 1.48 Å reveals an autorepressed conformation where helix α10 is bent into the ligand-binding pocket and the AF-2 helix is folded into the cofactor binding site, preventing coactivator recruitment. Retinoic acids can promote COUP-TFII to recruit coactivators and activate transcription by releasing the receptor from this autorepressed conformation. Mutations disrupting cofactor binding, dimerization, or ligand binding substantially reduce transcriptional activity.\",\n      \"method\": \"X-ray crystallography (1.48 Å); cell-based transcription assays; site-directed mutagenesis; coactivator recruitment assays\",\n      \"journal\": \"PLoS Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional transcription assays in multiple cell lines\",\n      \"pmids\": [\"18798693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"COUP-TFII physically interacts with Prox1 to form a stable complex in lymphatic endothelial cells (LECs) and multiple other cell types. This COUP-TFII/Prox1 complex functions as a co-regulator to control lineage-specific genes including VEGFR-3, FGFR-3, and neuropilin-1, and is required along with Prox1 to maintain LEC phenotype.\",\n      \"method\": \"Co-immunoprecipitation; stable complex formation assays; gene expression analysis with knockdown\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating physical interaction, functional validation with downstream target gene regulation\",\n      \"pmids\": [\"18815287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COUP-TFII homodimers inhibit arterial differentiation in venous ECs through direct binding to promoter regions of Notch target genes HEY1 and HEY2, whereas NR2F2/PROX1 heterodimers lack this inhibitory effect on HEY1/2, resulting in non-canonical HEY1/2 expression in LECs. NR2F2/PROX1 heterodimers actively induce LEC-specific gene expression.\",\n      \"method\": \"Chromatin immunoprecipitation; promoter binding assays; gain- and loss-of-function in endothelial cells; gene expression profiling\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing direct promoter binding, functional distinction between homodimer and heterodimer activity, multiple orthogonal methods\",\n      \"pmids\": [\"23345397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"COUP-TFII inhibits SMAD4-dependent transcription to override the TGF-β-dependent growth checkpoint in PTEN-null prostate tumors. Conditional overexpression of COUP-TFII in mouse prostate cooperates with PTEN deletion to drive metastatic progression; conditional loss of SMAD4 diminishes the inhibitory effects of COUP-TFII ablation, establishing functional counteraction between COUP-TFII and SMAD4.\",\n      \"method\": \"Genetically engineered mouse models (conditional overexpression and knockout); epistasis analysis of COUP-TFII and SMAD4 double mutants; transcriptional reporter assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double-mutant mouse models, replicated with patient sample correlation, clear pathway placement\",\n      \"pmids\": [\"23201680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Stromal COUP-TFII mediates progesterone control of uterine implantation by suppressing epithelial estrogen receptor (ERα) activity. Conditional knockout of uterine COUP-TFII leads to implantation failure and impaired decidualization; BMP2 lies downstream of COUP-TFII in a pathway regulated by the progesterone-Indian hedgehog-Patched-COUP-TFII-BMP2 axis.\",\n      \"method\": \"Conditional COUP-TFII knockout mouse; ERα antagonist rescue experiments; pathway analysis in vivo\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with specific phenotype, pharmacological rescue experiment defining ERα as the downstream effector, genetic pathway established\",\n      \"pmids\": [\"17590085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Stromal COUP-TFII suppresses ERα activity in the uterine luminal epithelium during the periimplantation period; pharmacological inhibition of ERα with ICI 182,780 rescues embryo attachment and decidualization (including Wnt4 and BMP2 expression) in COUP-TFII knockout uteri, demonstrating that COUP-TFII regulates implantation through controlling ERα activity.\",\n      \"method\": \"Conditional knockout mouse; ERα antagonist (ICI 182,780) rescue; gene expression analysis of ERα target genes\",\n      \"journal\": \"Molecular Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis experiment definitively placing ERα downstream of COUP-TFII, supported by gene expression readouts\",\n      \"pmids\": [\"20219888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A Sonic hedgehog (Shh) response element in the COUP-TFII promoter binds a factor distinct from Gli. Shh-N signaling can be mimicked by protein phosphatase treatment to activate this binding activity, and Shh-N-induced activation of COUP-TFII is blocked by phosphatase inhibitors, indicating that Shh-N signaling activates COUP-TFII expression through dephosphorylation of a target transcription factor.\",\n      \"method\": \"Promoter binding assays; pharmacological phosphatase inhibitor experiments; Shh-N stimulation in P19 cells\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of signaling pathway, single lab, supported by two orthogonal approaches (Shh stimulation and phosphatase treatment)\",\n      \"pmids\": [\"9395397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cardiomyocyte-specific COUP-TFII ablation produces ventricularized atria with ventricle-like action potentials, larger cardiomyocyte size, and T-tubule development. ChIP assays identify Tbx5, Hey2, Irx4, MLC2v, MLC2a, and MLC1a as direct COUP-TFII target genes in atria, demonstrating that COUP-TFII directly binds and regulates atrial identity genes.\",\n      \"method\": \"Cardiomyocyte-specific conditional knockout; electrophysiology; chromatin immunoprecipitation with E13.5 atrial tissue; genome-wide gene expression profiling\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with functional electrophysiology phenotype, in vivo ChIP identifying direct targets, multiple orthogonal methods\",\n      \"pmids\": [\"23725765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"COUP-TFII in pericytes directly regulates transcription of Angiopoietin-1 to enhance tumor neoangiogenesis; provision of exogenous Angiopoietin-1 partially rescues angiogenic defects in COUP-TFII-deficient mice, demonstrating COUP-TFII controls Angiopoietin-1/Tie2 signaling.\",\n      \"method\": \"Conditional adult COUP-TFII knockout; xenograft tumor models; Angiopoietin-1 rescue experiment; transcriptional regulation assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with rescue experiment placing Ang-1 directly downstream, functional angiogenesis readout\",\n      \"pmids\": [\"20133706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"COUP-TFII suppresses VEGFR-1 transcription in endothelial cells to regulate VEGF/VEGFR-2 signaling balance during tumor angiogenesis; COUP-TFII plays a cell-autonomous role in endothelial cell proliferation and migration.\",\n      \"method\": \"Conditional COUP-TFII knockout in tumor microenvironment; RIP-Tag pancreatic islet tumor model; transcriptional repression assays for VEGFR-1\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout in defined model system, transcriptional mechanism identified for VEGFR-1, single lab\",\n      \"pmids\": [\"20978203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"COUP-TFII plays a pivotal role in white adipocyte development; COUP-TFII heterozygous mice have less white adipose tissue and decreased expression of key WAT regulators. ChIP analysis reveals Wnt10b is a direct transcriptional target of COUP-TFII, and knockdown of COUP-TFII in 3T3-L1 cells increases Wnt10b expression.\",\n      \"method\": \"Heterozygous knockout mice; 3T3-L1 knockdown; chromatin immunoprecipitation; gene expression analysis\",\n      \"journal\": \"Cell Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout phenotype combined with in vitro ChIP demonstrating direct target binding, two orthogonal methods\",\n      \"pmids\": [\"19117548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"COUP-TFII inactivation in mesenchymal progenitors shifts lineage fate toward osteoblast and myoblast development while impairing adipogenic and chondrogenic programs. COUP-TFII directs mesenchymal progenitor plasticity through combined modulation of Wnt signaling, Runx2 activity, and PPARγ and Sox9 expression.\",\n      \"method\": \"Conditional knockout in mesenchymal progenitors; in vivo bone density, muscle mass, and fat/cartilage quantification; pathway analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with multiple tissue phenotypes and pathway placement, single lab\",\n      \"pmids\": [\"21873211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"COUP-TFII directly regulates E2F1 transcription by tethering to Sp1 binding sites in the E2F1 promoter (demonstrated by ChIP) to modulate cell proliferation. COUP-TFII also directly regulates Foxc1, Np-1, and Hey2 (Notch pathway genes) as shown by ChIP in HUVECs.\",\n      \"method\": \"Microarray in COUP-TFII-depleted HUVECs; chromatin immunoprecipitation; gene expression analysis\",\n      \"journal\": \"Molecular Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding for E2F1 and Notch targets, single lab\",\n      \"pmids\": [\"22734039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BRG1 chromatin-remodeling enzyme promotes COUP-TFII expression in venous endothelial cells by binding conserved regulatory elements in the COUP-TFII promoter and remodeling chromatin accessibility; conditional deletion of Brg1 from vascular endothelium downregulates COUP-TFII and causes aberrant arterial marker expression on veins.\",\n      \"method\": \"Conditional endothelial Brg1 knockout; chromatin accessibility assays; ChIP for BRG1 binding to COUP-TFII promoter\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout placing BRG1 upstream of COUP-TFII, ChIP demonstrating direct promoter binding, single lab\",\n      \"pmids\": [\"23406903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tie2 signaling maintains COUP-TFII protein levels in venous endothelial cells via Akt-mediated stabilization; Ang-1 stimulation increases COUP-TFII protein, while Tie2 knockdown or PI3K/Akt pathway blockade reduces COUP-TFII levels, an effect reversed by proteasome inhibition.\",\n      \"method\": \"Tie2/Tek conditional knockout mice; Ang-1 stimulation assays; Tie2 knockdown in cultured ECs; PI3K/Akt inhibition; proteasome inhibitor rescue\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic approaches in vitro and in vivo, proteasome inhibitor rescue supporting post-translational regulation, single lab\",\n      \"pmids\": [\"28005008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"COUP-TFII is required for Leydig cell differentiation; ablation prior to puberty arrests Leydig cell differentiation at the progenitor stage, causing testosterone deficiency and spermatogenetic arrest. Testosterone administration rescues most but not all defects, while Leydig cell maturation failure persists, establishing COUP-TFII as intrinsically required for Leydig cell differentiation but not maintenance.\",\n      \"method\": \"Tamoxifen-inducible conditional knockout at different developmental stages; testosterone rescue experiment; histological analysis of Leydig cell differentiation\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — stage-specific conditional knockout with hormonal rescue experiment dissecting differentiation vs maintenance functions\",\n      \"pmids\": [\"18818749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"COUP-TFII (NR2F2) directly activates Star (steroidogenic acute regulatory protein) gene transcription in Leydig cells by binding to a DR1-like element between -131 and -95 bp of the Star promoter; mutation of the DR1-like element that prevents COUP-TFII binding blunts promoter activation. COUP-TFII also cooperates with SF1 via protein-protein interactions to further enhance INSL3 and Star transcription.\",\n      \"method\": \"siRNA knockdown in MA-10/MLTC-1 cells; promoter deletion analysis; ChIP; electrophoretic mobility shift assay; site-directed mutagenesis; cotransfection with SF1\",\n      \"journal\": \"Biology of Reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis of binding site combined with ChIP and EMSA establishing direct binding, functional steroidogenesis readout\",\n      \"pmids\": [\"24899578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"COUP-TFII directly binds a DR0-like element in the INSL3 promoter (-186 to -79 bp) to activate Insl3 transcription in Leydig cells; mutation of the DR0-like element prevents COUP-TFII binding. COUP-TFII also acts through protein-protein interactions with SF1 bound at the Insl3 promoter to further activate transcription.\",\n      \"method\": \"siRNA knockdown; promoter deletion assays; ChIP; DNA precipitation assay; DR0-like element mutagenesis; cotransfection with SF1\",\n      \"journal\": \"Journal of Molecular Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding confirmed by EMSA/ChIP plus mutagenesis of binding site, protein-protein interaction with SF1 demonstrated functionally\",\n      \"pmids\": [\"24780841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Increased COUP-TFII in adult cardiomyocytes causes heart failure by repressing genes critical for mitochondrial electron transport chain activity, oxidative stress detoxification, and mitochondrial dynamics, resulting in increased ROS and reduced oxygen consumption. COUP-TFII also suppresses the PGC-1 network and decreases glucose and lipid utilization gene expression. COUP-TFII haploinsufficiency attenuates dilated cardiomyopathy in a calcineurin transgenic model.\",\n      \"method\": \"Cardiac-specific COUP-TFII overexpression transgenic mice; cardiac-specific heterozygous knockout; mitochondrial respiration assays; ROS measurement; gene expression profiling\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both gain- and loss-of-function in vivo, direct functional measurement of mitochondrial respiration and ROS, pathway placement via PGC-1 network\",\n      \"pmids\": [\"26356605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COUP-TFII enhances glycolysis and suppresses fatty acid oxidation in myofibroblasts to drive kidney fibrosis; COUP-TFII binds the PGC1α promoter (ChIP-qPCR) and reduces PGC1α expression, thereby suppressing mitochondrial metabolism. Overexpression of COUP-TFII induces αSMA and collagen 1 production; knockout decreases glycolysis and collagen 1 levels.\",\n      \"method\": \"Conditional knockout in mice; fibroblast overexpression; ChIP-qPCR for PGC1α promoter; unbiased proteomics; glycolysis and FAO metabolic assays\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout, ChIP-qPCR for direct target, proteomic pathway analysis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"34031962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"COUP-TFII regulates satellite cell function in skeletal muscle; ectopic COUP-TFII expression in satellite cells causes Duchenne-like dystrophy through deficient SC proliferation and impaired myoblast fusion. Mechanistically, COUP-TFII represses expression of Npnt, Itgb1D, and Cav3 (genes important for cell-cell fusion) and reduces activation of focal adhesion kinase (FAK).\",\n      \"method\": \"Satellite cell-specific COUP-TFII overexpression transgenic mice; mdx dystrophic model; satellite cell functional assays; gene expression analysis; FAK activation assays\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with specific cellular phenotype, downstream target identification, FAK pathway placement, single lab\",\n      \"pmids\": [\"27617862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"COUP-TFII represses myoblast fusion during skeletal muscle development by transcriptionally repressing Npnt, Itgb1D, and Cav3, and reducing focal adhesion kinase (FAK) activation; maintaining COUP-TFII expression in myogenic precursors (via ectopic expression) causes inefficient skeletal muscle development in mice.\",\n      \"method\": \"Myogenic precursor-specific COUP-TFII overexpression mouse model; myoblast fusion assays; FAK activation measurement; gene expression analysis\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with specific fusion phenotype, downstream target and signaling pathway identified, single lab\",\n      \"pmids\": [\"28600496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"COUP-TFII is required for metanephric mesenchyme specification; deletion at E7.5 results in absence of Eya1, Six2, Pax2, and Gdnf in the metanephric mesenchyme. COUP-TFII directly regulates Eya1 and Wt1 expression in the metanephric mesenchyme.\",\n      \"method\": \"Conditional knockout at E7.5; ChIP; gene expression analysis of developmental regulators\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with specific developmental phenotype, ChIP supporting direct target regulation, single lab\",\n      \"pmids\": [\"22669823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"COUP-TFII controls amygdala development by directly regulating Nrp1 and Nrp2 (semaphorin receptors controlling neuronal migration) in CGE-derived cells; ChIP assays in telencephalon confirm Nrp1 and Nrp2 as direct COUP-TFII targets, and CGE-specific conditional knockout causes failure of Pax6+ cell migration into the BMA nucleus.\",\n      \"method\": \"Rx-Cre conditional knockout mice; in vivo ChIP in telencephalon for Nrp1/Nrp2 promoters; cell migration analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ChIP identifying direct targets, conditional knockout with specific migration phenotype, single lab\",\n      \"pmids\": [\"22492355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"COUP-TFII is preferentially expressed in caudal ganglionic eminence (CGE) neurons; transplantation of COUP-TFII-expressing MGE cells into CGE redirects their migration caudally, and knockdown of COUP-TFII inhibits caudal migration of CGE cells, demonstrating COUP-TFII is both necessary and sufficient for CGE-specific caudal migratory behavior.\",\n      \"method\": \"Transcriptome comparison of CGE/MGE/LGE; transplantation experiments; siRNA knockdown; migration assays\",\n      \"journal\": \"Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function (transplantation) and loss-of-function (knockdown) both demonstrate sufficiency and necessity for directional migration\",\n      \"pmids\": [\"19074032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"COUP-TFII-induced expression of Neuropilin-2 (Nrp2) controls the destination of POa-derived GABAergic neurons; suppression of COUP-TFII/Nrp2 redirects cells to the neocortex, while overexpression causes cells to end up in the medial amygdala, establishing COUP-TFII/Nrp2 as a molecular switch for migration pathway selection.\",\n      \"method\": \"In utero electroporation for gain- and loss-of-function; live cell migration tracking; Nrp2 expression analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function establishing sufficiency and necessity, clear downstream effector (Nrp2) identified\",\n      \"pmids\": [\"26305926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"OCT4 and OCT4-induced miR-302 directly repress NR2F2 transcription and translation in undifferentiated hESCs; conversely, NR2F2 directly inhibits OCT4 during differentiation, forming a mutual repression loop. NR2F2 is among the earliest neural markers detected during hESC differentiation.\",\n      \"method\": \"Reporter assays; siRNA knockdown; miR-302 overexpression; chromatin-based transcription analysis in hESCs\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal regulatory experiments demonstrating mutual repression, multiple reporter assay validations, single lab\",\n      \"pmids\": [\"21151097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-302 directly targets NR2F2 mRNA (confirmed by luciferase reporter assay); NR2F2 directly inhibits OCT4 promoter activity. shRNA knockdown of NR2F2 mimics miR-302 overexpression by enhancing iPSC reprogramming efficiency.\",\n      \"method\": \"Luciferase reporter assay with NR2F2 3'UTR; OCT4 promoter activity assay; shRNA knockdown; reprogramming efficiency quantification\",\n      \"journal\": \"Stem Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assay validating direct miRNA targeting, functional reprogramming phenotype, partially corroborates PMID:21151097\",\n      \"pmids\": [\"23136034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"ARP-1/COUP-TFII represses Oct-3/4 promoter activity through the RAREoct site in embryonal carcinoma cells in a dose-dependent manner; the C-terminal domain harbors the silencing region. COUP-TFII competes with and displaces RAR:RXR heterodimers from the RAREoct site due to higher binding affinity, thereby silencing Oct-3/4.\",\n      \"method\": \"Promoter-reporter assays; electrophoretic mobility shift assay (EMSA) for competitive binding; domain deletion analysis; P19 EC cell differentiation model\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA demonstrating competitive displacement of RAR:RXR, domain mapping, functional reporter assays, single lab\",\n      \"pmids\": [\"7823919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The C-terminal domain of ARP-1/COUP-TFII (residues 210-414, encompassing helices 3-12) confers active repressor activity when fused to a heterologous DBD. The domains required for transrepression include the DBD and residues 193-399. Transrepression (not active repression) is the predominant mechanism, likely involving interaction with coactivator proteins used by liver-enriched transactivators (HNF-3, C/EBP, HNF-4) but not Sp1 or ATF.\",\n      \"method\": \"GAL4-fusion domain deletion analysis; transcription assays; Flu-tagged mutant series; co-transfection with liver-enriched and ubiquitous transactivators\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain mapping with multiple deletion constructs and heterologous DBD fusions, functional distinction between active repression and transrepression\",\n      \"pmids\": [\"9271371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"COUP-TFII synergistically activates CYP7A1 (cholesterol 7α-hydroxylase) transcription together with HNF4; in vitro-translated COUP-TFII binds DR0 and DR4 elements in the CYP7A1 promoter. The synergistic effect of HNF4 and COUP-TFII results from protein-protein interactions facilitated by juxtaposition of their binding elements rather than absolute requirement for the COUP-TFII binding sites.\",\n      \"method\": \"Cotransfection reporter assays; EMSA with in vitro-translated COUP-TFII; promoter mutagenesis\",\n      \"journal\": \"Journal of Lipid Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA with in vitro-translated protein, mutagenesis of binding sites, functional reporter assays demonstrating protein-protein interaction mechanism\",\n      \"pmids\": [\"10627496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Glucocorticoid receptor (GR) physically interacts with COUP-TFII; GR stimulates COUP-TFII-induced transactivation via its AF-1 domain, while COUP-TFII represses GR-governed transcriptional activity by tethering corepressors SMRT and NCoR via its C-terminal domain.\",\n      \"method\": \"Co-immunoprecipitation; domain mapping; transcriptional assays with AF-1 mutants; corepressor recruitment assays\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP demonstrating physical interaction, domain-level mechanism proposed and partially validated, single lab\",\n      \"pmids\": [\"15265774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"COUP-TFII directly binds the miR-21 promoter (demonstrated by ChIP and luciferase assay) to transcriptionally activate miR-21 expression in CRC cells; miR-21 then targets Smad7, allowing COUP-TFII to promote TGF-β-induced EMT indirectly through this NR2F2→miR-21→Smad7 axis.\",\n      \"method\": \"ChIP; luciferase reporter assay; siRNA knockdown; EMT marker analysis\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assay demonstrating direct promoter binding, functional validation of downstream pathway, single lab\",\n      \"pmids\": [\"28192117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"COUP-TFII directly binds the COX-2 promoter to inhibit its transcription (demonstrated by ChIP and reporter assays); proinflammatory cytokines (IL-1β, TNF-α, TGF-β1) reduce COUP-TFII expression via microRNA-302a (which targets COUP-TFII 3'UTR), leading to de-repression of COX-2 in endometriosis.\",\n      \"method\": \"ChIP; luciferase reporter assay; miR-302a overexpression; COUP-TFII knockout mouse endometriosis transplantation model; primary human endometrial stromal cells\",\n      \"journal\": \"Journal of Clinical Endocrinology and Metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct COX-2 promoter binding, in vivo mouse model, mechanism validated in human primary cells\",\n      \"pmids\": [\"24423359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"COUP-TFII binds the ANG (angiogenin) promoter to suppress its transcription (demonstrated by ChIP and promoter activity assays); hypoxia reduces COUP-TFII levels leading to de-repression of ANG and enhanced angiogenesis in endometriosis.\",\n      \"method\": \"ChIP; luciferase promoter activity assay; siRNA knockdown and overexpression; HUVEC tube formation assay\",\n      \"journal\": \"Human Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, functional angiogenesis readout, reciprocal gain/loss-of-function experiments, single lab\",\n      \"pmids\": [\"29982401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"COUP-TFII directly targets the Snail1 promoter to regulate Snail1 transcription and expression in colorectal cancer cells; COUP-TFII together with Snail1 inhibits E-cadherin, ZO-1, and β-catenin expression to promote cell migration and metastasis.\",\n      \"method\": \"ChIP; promoter reporter assay; COUP-TFII overexpression/knockdown; tamoxifen-inducible knockout mice; cell migration and invasion assays\",\n      \"journal\": \"British Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct Snail1 promoter binding, in vivo knockout model for metastasis, single lab\",\n      \"pmids\": [\"25032732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KRAS/MEK signaling upregulates COUP-TFII, which increases LDHA (lactate dehydrogenase A) expression leading to lactate production; lactate then inhibits TSC2-Rheb interaction to activate mTORC1, connecting KRAS signaling to glycolysis and mTORC1 activation via COUP-TFII.\",\n      \"method\": \"COUP-TFII overexpression and knockdown; LDHA expression analysis; TSC2-Rheb interaction assays; mTORC1 activity measurements; MEK inhibition\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic dissection of KRAS→COUP-TFII→LDHA→lactate→mTORC1 pathway, mechanistic biochemical assays, single lab\",\n      \"pmids\": [\"30988000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A small-molecule COUP-TFII inhibitor (identified by high-throughput screening) directly binds the COUP-TFII ligand-binding domain and disrupts COUP-TFII interaction with FOXA1 and other transcription regulators, thereby repressing COUP-TFII transcriptional activity on target genes and exerting antitumor effects in prostate cancer models.\",\n      \"method\": \"High-throughput screening; ligand-binding domain binding assay; Co-IP for FOXA1-COUP-TFII interaction disruption; target gene expression; xenograft and patient-derived xenograft mouse models\",\n      \"journal\": \"Science Advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct LBD binding assay, protein-protein interaction disruption demonstrated, in vivo efficacy in multiple tumor models, multiple orthogonal methods\",\n      \"pmids\": [\"32494682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NR2F2 functions as a co-factor with pioneer factors FOXA1 and GATA3 to promote ERα-dependent transcription in breast cancer; NR2F2 binds to most ERα binding sites independently of estrogen. Perturbation of NR2F2 decreases ERα DNA binding, chromatin accessibility, and estrogen-dependent cell growth.\",\n      \"method\": \"ChIP-seq (40 transcription factors in ENCODE); ATAC-seq; RNA-seq; NR2F2 perturbation experiments; ERα binding analysis\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq combined with functional NR2F2 perturbation and ERα binding readout, single lab\",\n      \"pmids\": [\"31588232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"COUP-TFII haploinsufficiency is regulated by insulin and glucose: insulin represses COUP-TFII in pancreatic β-cells through Foxo1 signaling, and high glucose represses COUP-TFII in hepatocytes through both Foxo1 and ChREBP. Ex vivo, COUP-TFII reduces insulin production and secretion; pancreatic COUP-TFII expression is activated by TCF7L2 (Wnt signaling), creating a feedback loop.\",\n      \"method\": \"Pancreatic-specific conditional knockout mice; Foxo1 signaling inhibition; ChREBP knockdown in hepatocytes; islet isolation ex vivo experiments; TCF7L2 reporter assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological approaches establishing regulatory pathway, ex vivo functional assay for insulin secretion, single lab\",\n      \"pmids\": [\"18765640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"COUP-TFII induces β-catenin gene expression and its target genes (cyclin D1, axin 2) in pancreatic β-cells; GLP-1 activation of the β-catenin pathway is impaired in COUP-TFII-deficient islets. COUP-TFII expression is activated by TCF7L2 in human islets and rat β-cells, forming a feedback loop. COUP-TFII is required for GLP-1-mediated β-catenin signaling and neonatal β-cell mass determination.\",\n      \"method\": \"Pancreatic conditional knockout (pdx1-Cre); islet isolation; gain- and loss-of-function in cultured β-cells; GLP-1 stimulation assays; gene expression analysis\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with ex vivo islet functional assays, GLP-1 pathway rescue experiments, TCF7L2 feedback validated in human islets\",\n      \"pmids\": [\"22292058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-101 and miR-27a negatively regulate COUP-TFII expression; loss of miR-101 increases COUP-TFII, which in turn activates FOXM1 and CENPF expression to promote prostate cancer metastasis. COUP-TFII is a critical intermediate in the miRNA→COUP-TFII→FOXM1→CENPF metastatic cascade and also contributes to enzalutamide resistance.\",\n      \"method\": \"miRNA overexpression and inhibition; COUP-TFII knockdown/overexpression; downstream FOXM1/CENPF expression analysis; clinical PCa dataset correlation\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established through sequential knockdown/overexpression, correlation with clinical data, single lab\",\n      \"pmids\": [\"27108958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A 5 amino acid deletion in the hinge region of NR2F2 (from zinc-finger nuclease gene editing) reduces interaction between wild-type NR2F2 and Fog2 (Friend of Gata2); the mutant NR2F2 protein has greater interaction with Fog2, and Nr2f2-mutant rats have significantly lower systolic and diastolic blood pressure, establishing the hinge region-Fog2 interaction as critical for blood pressure regulation.\",\n      \"method\": \"Zinc-finger nuclease-generated Nr2f2 mutant rat; protein-protein interaction assays (co-IP); blood pressure measurement\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene-edited animal model with specific hinge-region deletion, protein-protein interaction assay linking Fog2 binding to BP phenotype, single lab\",\n      \"pmids\": [\"25687237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NR2F2 directly activates TFAP2A (AP-2α) promoter activity to promote human villous cytotrophoblast differentiation to syncytiotrophoblast; siRNA silencing of NR2F2 blocks induction of TFAP2A mRNA and STB marker genes (hPL, PSG1, CRH). NR2F2-mediated TFAP2A induction is potentiated by RAR-α and RXR-α.\",\n      \"method\": \"TFAP2A promoter reporter assays; siRNA knockdown in primary CTB cells and JEG-3 cells; cotransfection with RARA and RXRA\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter reporter assay and siRNA knockdown in primary human cells, cooperativity with other nuclear receptors demonstrated, single lab\",\n      \"pmids\": [\"20195529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COUP-TFII overexpression in fibroblasts induces αSMA and collagen 1 production; COUP-TFII binds the PGC1α promoter (by ChIP-qPCR) and represses PGC1α expression to suppress fatty acid oxidation and enhance glycolysis, driving myofibroblast activation and organ fibrosis. Knockout of COUP-TFII in mice attenuates injury-induced kidney fibrosis.\",\n      \"method\": \"Conditional fibroblast-specific knockout mice; unbiased proteomics; ChIP-qPCR; glycolysis/FAO metabolic assays; αSMA and collagen 1 quantification\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout phenotype, direct promoter binding by ChIP, proteomic pathway validation, multiple orthogonal methods\",\n      \"pmids\": [\"34031962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"An alternative NR2F2 isoform (NR2F2-Iso2), transcribed from an alternative TSS and lacking the N-terminal DNA-binding domain, is regulated by DNA methylation during melanocyte differentiation. NR2F2-Iso2 re-expression during metastatic melanoma progression drives EMT and neural crest cell-like features by modulating the activity of full-length NR2F2 (Iso1) on EMT- and NCC-associated target genes.\",\n      \"method\": \"DNA methylation profiling; alternative TSS identification; functional gain- and loss-of-function; EMT and NCC target gene expression analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic regulation of isoform-specific expression combined with functional studies in melanoma, mechanism of Iso2 modulating full-length NR2F2 activity established\",\n      \"pmids\": [\"37015919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fbxo21 (an F-box E3 ubiquitin ligase) ubiquitinates NR2F2 protein and targets it for proteasomal degradation in gastric cancer cells; Fbxo21 expression is negatively correlated with NR2F2 protein levels, and NR2F2 re-expression rescues EMT inhibition caused by Fbxo21 overexpression.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; proteasome inhibitor treatment; gain- and loss-of-function; EMT marker analysis\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay identifying Fbxo21 as E3 ligase for NR2F2, proteasomal degradation mechanism established, single lab\",\n      \"pmids\": [\"33531987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Elevated COUP-TFII in dopaminergic (DA) neurons represses cytosolic aldehyde dehydrogenase gene expression (epigenetic mechanism), leading to DOPAL accumulation, enhanced oxidative stress, and mitochondrial dysfunction with reduced cristae. Overexpression of COUP-TFII in DA neurons accelerates PD progression in MitoPark mice; underexpression of COUP-TFII slows motor deterioration.\",\n      \"method\": \"DA neuron-specific COUP-TFII overexpression and underexpression in mice; MitoPark PD model; mitochondrial morphology (EM); aldehyde dehydrogenase gene expression; epigenetic analysis\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain and loss-of-function in DA neurons, mitochondrial morphology and pathway analysis, mechanistic link to DOPAL via ALDH repression\",\n      \"pmids\": [\"32579581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"COUP-TFII regulates gene expression in human endometrial stromal cells involved in cell adhesion, angiogenesis, and inflammation, including inflammatory cytokines; ChIP-seq identifies direct COUP-TFII binding sites across the endometrial stromal transcriptome.\",\n      \"method\": \"siRNA knockdown in primary human endometrial stromal cells; microarray; ChIP followed by deep sequencing (ChIP-seq)\",\n      \"journal\": \"Molecular Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq identifying genome-wide direct binding combined with gene expression profiling after knockdown, single lab in primary human cells\",\n      \"pmids\": [\"24176914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NR2F2 (COUP-TFII) inhibits NFκB activation in breast cancer cells; COUP-TFII co-immunoprecipitates with NFκB subunits RelB and NFκB1 in MCF-7 cells; COUP-TFII inhibits NFκB-DNA binding in vitro and impairs coactivator-induced NFκB transactivation.\",\n      \"method\": \"Co-immunoprecipitation; EMSA for NFκB-DNA binding; NFκB reporter assays; COUP-TFII overexpression in LCC9 cells\",\n      \"journal\": \"Molecular and Cellular Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP demonstrating physical interaction with NFκB subunits, EMSA for DNA binding inhibition, functional reporter validation, single lab\",\n      \"pmids\": [\"24141032\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR2F2 (COUP-TFII) is an orphan nuclear receptor that functions as a context-dependent transcriptional activator or repressor; its ligand-binding domain adopts an autorepressed conformation that is relieved by ligand (including retinoic acid) to allow coactivator recruitment. NR2F2 operates at the top of the venous endothelial identity pathway by directly repressing Notch target genes (HEY1/2) as a homodimer to suppress arterial fate, while forming heterodimers with PROX1 to specify lymphatic endothelial identity; Tie2/Akt signaling stabilizes COUP-TFII protein against proteasomal degradation, and BRG1 chromatin remodeling promotes its expression in veins. Beyond vascular biology, NR2F2 directly regulates target gene promoters (Angiopoietin-1, VEGFR-1, E2F1, COX-2, Snail1, LDHA, PGC1α, STAR, INSL3, Nrp1/2, Wnt10b, and others) through DNA binding or by tethering to other transcription factors; it interacts physically with partners including Prox1, HNF4, GR, SF1, FOXA1, GATA3, and NFκB subunits to co-regulate transcription. NR2F2 controls cell fate decisions in multiple lineages—including venous vs. arterial, adipogenic vs. osteogenic/myogenic, atrial vs. ventricular cardiomyocyte, and Leydig cell differentiation—and its dysregulation drives pathological states including heart failure (via mitochondrial dysfunction and PGC-1 network suppression), fibrosis (via glycolysis enhancement through PGC1α repression), Parkinson's disease progression (via ALDH repression and DOPAL accumulation), and multiple cancers (via TGF-β/SMAD4 pathway antagonism, EMT promotion, and KRAS/MEK/LDHA/mTORC1 axis).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR2F2 (COUP-TFII) is an orphan nuclear receptor that acts as a context-dependent transcriptional regulator governing cell-fate decisions across vascular, cardiac, reproductive, neural, metabolic, and mesenchymal lineages [#0, #9, #13, #17]. Its ligand-binding domain adopts an autorepressed conformation in which helix \\u03b110 occupies the ligand pocket and the AF-2 helix folds into the cofactor groove; retinoic acid relieves this state to permit coactivator recruitment, and mutations disrupting cofactor binding, dimerization, or ligand binding abolish activity [#2]. NR2F2 can bind DNA directly at DR-type elements (e.g. the Star DR1-like and INSL3 DR0-like promoter sites) or operate by tethering to other transcription factors and by competitive displacement, as when it outcompetes RAR:RXR at the Oct-3/4 RAREoct site [#18, #19, #30]. In the vasculature it establishes venous identity by binding HEY1/HEY2 promoters as a homodimer to repress Notch-driven arterial differentiation, while heterodimerization with PROX1 abolishes this repression and instead activates lymphatic endothelial genes (VEGFR-3, FGFR-3, neuropilin-1) \\u2014 a dimer-state switch that partitions venous versus lymphatic fate [#0, #3, #4]. Its abundance and activity are tuned at multiple levels: BRG1 remodels its venous promoter, Tie2/Akt signaling stabilizes the protein against proteasomal turnover, the Fbxo21 E3 ligase targets it for degradation, and miR-302/miR-101/miR-27a repress its expression [#15, #16, #48, #29, #43]. Through this regulatory logic NR2F2 directs atrial versus ventricular cardiomyocyte identity, adipogenic versus osteo-/myogenic mesenchymal fate, Leydig cell differentiation and steroidogenesis, and GABAergic neuron migration via neuropilin induction [#9, #13, #17, #27]. Dysregulation drives disease: cardiac overexpression causes heart failure by repressing the PGC-1/mitochondrial network, fibroblast COUP-TFII enhances glycolysis and represses PGC1\\u03b1 to drive organ fibrosis, and in cancer it antagonizes SMAD4-dependent TGF-\\u03b2 checkpoints, promotes EMT and metastasis, and couples KRAS/MEK signaling to LDHA-driven glycolysis and mTORC1 activation [#20, #46, #5, #37, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the first molecular mechanism of COUP-TFII repression: it silences a target promoter by outcompeting an activating nuclear-receptor heterodimer rather than by a passive mechanism.\",\n      \"evidence\": \"Promoter-reporter assays, EMSA competition, and domain deletion in embryonal carcinoma cells showing displacement of RAR:RXR from the Oct-3/4 RAREoct site\",\n      \"pmids\": [\"7823919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve whether displacement operates at endogenous loci genome-wide\", \"C-terminal silencing domain partners not identified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapped the repression machinery, distinguishing active repression from transrepression and implicating shared coactivator squelching with liver-enriched factors.\",\n      \"evidence\": \"GAL4-fusion domain deletion series and co-transfection with HNF-3/C/EBP/HNF-4 transactivators\",\n      \"pmids\": [\"9271371\", \"9395397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific coactivators competed for were inferred, not biochemically isolated\", \"The Shh-responsive transcription factor activated by dephosphorylation was not identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined COUP-TFII as essential for cardiovascular morphogenesis and identified Angiopoietin-1 as a downstream effector linking it to mesenchymal-endothelial signaling.\",\n      \"evidence\": \"Targeted gene deletion in mice with in situ analysis of Ang-1\",\n      \"pmids\": [\"10215630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct promoter binding to Ang-1 not shown in this study\", \"Did not separate angiogenic from cardiac roles\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed COUP-TFII at the top of venous identity by showing it represses Notch signaling to prevent arterial fate, resolving how veins are molecularly specified.\",\n      \"evidence\": \"Endothelial conditional knockout and transgenic overexpression with arterial/venous marker analysis in mice\",\n      \"pmids\": [\"15875024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Notch-target promoter binding not yet demonstrated\", \"Did not address lymphatic fate\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided the structural basis for ligand-dependent regulation and defined the PROX1 partnership that switches COUP-TFII output toward lymphatic identity.\",\n      \"evidence\": \"1.48 \\u00c5 crystal structure with mutagenesis and coactivator assays; reciprocal Co-IP and target-gene analysis for the COUP-TFII/Prox1 complex; stage-specific Leydig knockout with testosterone rescue\",\n      \"pmids\": [\"18798693\", \"18815287\", \"18818749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological ligand remains unidentified\", \"Stoichiometry and DNA-binding mode of the COUP-TFII/Prox1 complex not structurally resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Unified vascular biology into a dimer-state model: homodimers repress HEY1/HEY2 to block arterial fate while NR2F2/PROX1 heterodimers relieve this and drive lymphatic genes; concurrently established direct atrial-identity target binding and an upstream BRG1 input.\",\n      \"evidence\": \"ChIP and promoter binding distinguishing homodimer vs heterodimer activity in ECs; cardiomyocyte conditional knockout with ChIP and electrophysiology; endothelial Brg1 knockout with ChIP on the COUP-TFII promoter\",\n      \"pmids\": [\"23345397\", \"23725765\", \"23406903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dimer choice is biochemically controlled in vivo not defined\", \"BRG1 study correlative for chromatin remodeling causality\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated COUP-TFII bidirectionally tunes the angiogenic program \\u2014 activating Angiopoietin-1 in pericytes while repressing VEGFR-1 in endothelium \\u2014 and defined a mutual repression loop with OCT4 governing pluripotency exit.\",\n      \"evidence\": \"Conditional knockouts in tumor and RIP-Tag models with Ang-1 rescue and VEGFR-1 repression assays; reporter and knockdown experiments mapping the OCT4/miR-302/NR2F2 loop in hESCs\",\n      \"pmids\": [\"20133706\", \"20978203\", \"21151097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type basis for activation vs repression of angiogenic targets not mechanistically explained\", \"Direct OCT4 promoter occupancy partly inferred\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Generalized COUP-TFII as a master fate selector by showing direct, lineage-specific target regulation in adipose, mesenchymal, renal, neural, and proliferative contexts.\",\n      \"evidence\": \"ChIP-validated direct targets (Wnt10b, Eya1/Wt1, Nrp1/Nrp2, E2F1 via Sp1 tethering) across knockout and knockdown systems; SMAD4 antagonism by genetic epistasis in PTEN-null prostate tumors\",\n      \"pmids\": [\"19117548\", \"21873211\", \"22669823\", \"22492355\", \"22734039\", \"23201680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether a single biochemical mode explains both DNA-direct and tethered regulation unresolved\", \"Lineage specificity of cofactor selection not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved direct DNA-binding mechanisms at steroidogenic promoters and showed cooperation with SF1, while extending the repertoire to EMT and inflammatory targets.\",\n      \"evidence\": \"ChIP, EMSA, and DR-element mutagenesis at Star and INSL3 promoters with SF1 cotransfection; ChIP and reporter assays on Snail1, COX-2, and endometrial ChIP-seq\",\n      \"pmids\": [\"24899578\", \"24780841\", \"25032732\", \"24423359\", \"24176914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the SF1 interaction not determined\", \"Genome-wide binding only mapped in select cell types\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established post-translational control of COUP-TFII abundance and connected it to oncogenic metabolic rewiring and inflammatory signaling.\",\n      \"evidence\": \"Tie2/Akt stabilization with proteasome-inhibitor rescue; ChIP/luciferase for the miR-21/Smad7 axis; miR-101/27a regulation of the FOXM1/CENPF cascade; Co-IP and EMSA showing NF\\u03baB inhibition\",\n      \"pmids\": [\"28005008\", \"28192117\", \"27108958\", \"24141032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The stabilizing E3/deubiquitinase machinery downstream of Akt not identified here\", \"NF\\u03baB interaction shown by single-lab Co-IP without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Integrated COUP-TFII into KRAS-driven glycolysis and cofactor networks with pioneer factors, defining actionable mechanisms.\",\n      \"evidence\": \"Genetic/pharmacological dissection of KRAS\\u2192COUP-TFII\\u2192LDHA\\u2192lactate\\u2192mTORC1; ChIP-seq/ATAC-seq showing NR2F2 cofactor activity with FOXA1/GATA3 at ER\\u03b1 sites\",\n      \"pmids\": [\"30988000\", \"31588232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LDHA promoter occupancy by COUP-TFII not fully resolved\", \"FOXA1/GATA3 cooperativity from single-lab genomic dataset\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined COUP-TFII as a druggable driver and disease node in heart failure, fibrosis, and Parkinson's via mitochondrial/metabolic gene repression.\",\n      \"evidence\": \"Small-molecule LBD binder disrupting FOXA1 interaction with in vivo antitumor efficacy; cardiac and fibroblast knockout/overexpression with ChIP on PGC1\\u03b1; DA-neuron gain/loss-of-function repressing ALDH in MitoPark mice\",\n      \"pmids\": [\"32494682\", \"26356605\", \"34031962\", \"32579581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether inhibitor selectivity extends beyond FOXA1-dependent complexes unknown\", \"Epigenetic mechanism of ALDH repression only partially characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed isoform-level and species-specific regulation expanding the mechanistic model: a DBD-lacking isoform modulates full-length activity, and a hinge-region/Fog2 interaction controls blood pressure.\",\n      \"evidence\": \"DNA-methylation-regulated alternative-TSS isoform with EMT/NCC functional assays in melanoma; zinc-finger-nuclease hinge-deletion rat with Co-IP and blood-pressure phenotyping\",\n      \"pmids\": [\"37015919\", \"25687237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Iso2 modulates full-length NR2F2 not biochemically defined\", \"Fog2 interaction effect on transcriptional targets not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous physiological ligand and the rules that select between DNA-direct binding, factor tethering, homodimer repression, and heterodimer activation in a given cell type remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No native ligand identified despite retinoic-acid responsiveness\", \"No unifying model for dimer-partner and cofactor selection across lineages\", \"Structural basis of most protein-protein tethering interactions unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 9, 18, 19, 30, 37]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 18, 19, 30, 50]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 32, 33, 40, 51]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4, 18, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 9, 13, 17, 26]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 18, 19, 30, 37]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 16, 38, 42]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [20, 38, 46]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 20, 37, 38, 46, 49]}\n    ],\n    \"complexes\": [\n      \"NR2F2/PROX1 lymphatic co-regulator complex\"\n    ],\n    \"partners\": [\n      \"PROX1\",\n      \"SF1\",\n      \"HNF4\",\n      \"GR\",\n      \"FOXA1\",\n      \"GATA3\",\n      \"Fog2\",\n      \"RelB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}