{"gene":"NCOA1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2001,"finding":"NCOA1 (NCoA-1) acts as a coactivator for STAT6 by directly interacting with the C-terminal transactivation domain of STAT6 via its N-terminal region. The N-terminal part of NCOA1 interacts specifically with STAT6 but not with other STAT family members. Overexpression of this NCOA1 domain has a dominant-negative inhibitory effect on STAT6-mediated transactivation, demonstrating the essential role of this interaction.","method":"GST pulldown, mammalian cell co-immunoprecipitation, transactivation reporter assays, dominant-negative overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, dominant-negative functional validation, replicated across multiple orthogonal methods in the same study and confirmed in subsequent papers","pmids":["11574547"],"is_preprint":false},{"year":2002,"finding":"An LXXLL motif in the STAT6 transactivation domain mediates the specific interaction with the NCoA-1 PAS-B domain. Mutagenesis of the LXXLL motif eliminated STAT6/NCOA1 interaction both in vitro and in vivo, and strongly diminished IL-4-regulated activation of the endogenous STAT6 target gene eotaxin-3.","method":"GST pulldown with LXXLL peptides and blocking antibodies, LXXLL mutagenesis, endogenous target gene activation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis, confirmed with endogenous gene readout, replicated by structural work in later papers","pmids":["12138096"],"is_preprint":false},{"year":2003,"finding":"NCOA1 is a coactivator for both STAT5a and STAT5b in prolactin-dependent gene expression. Both the activation domain 1 and the amino-terminal bHLH/PAS domain of NCOA1 are required for STAT5 coactivation. The bHLH/PAS domain mediates direct interaction with STAT5a in cells. A three-amino-acid motif in an alpha-helical region of the STAT5a transactivation domain is essential for NCoA-1 binding. NCOA1 and p300/CBP cooperatively enhance STAT5a-mediated transactivation and NCOA1 is involved in the synergistic action of the glucocorticoid receptor and STAT5a on the beta-casein promoter.","method":"Co-immunoprecipitation, transactivation reporter assays, domain deletion and mutagenesis, beta-casein promoter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, mutagenesis of binding motif, functional transactivation readout with multiple orthogonal methods","pmids":["12954634"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of the NCOA1 PAS-B domain in complex with the STAT6 LXXLL motif was determined. The amphipathic alpha-helical STAT6 LXXLL motif binds predominantly through hydrophobic interactions to NCOA1 PAS-B. A single NCOA1 PAS-B residue makes hydrophilic contacts with the STAT6 peptide. STAT6 interacts only with the PAS-B domain of NCOA1 and not with homologous regions of NCOA2 or NCOA3, with specificity determined largely by surface complementarity between hydrophobic faces.","method":"X-ray crystallography (crystal structure determination)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic resolution crystal structure with defined binding interface, consistent with prior mutagenesis data","pmids":["14757047"],"is_preprint":false},{"year":2008,"finding":"Energetically important contacts between STAT6 and NCOA1 extend to residues flanking the LXXLL motif, including residues in the sequence LLPPTEQDLTKLL. Optimizing knobs-into-holes contacts on the surface of the STAT6-derived peptide significantly improves affinity for NCOA1, revealing the molecular basis of binding specificity.","method":"Peptide binding assays, structure-activity relationship (SAR) analysis of LXXLL-flanking residues","journal":"Chembiochem","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization of binding specificity with peptide variants, single lab, consistent with structural data","pmids":["18464232"],"is_preprint":false},{"year":2010,"finding":"Dephosphorylation of NCOA1 by PP2A phosphatase is essential for NCOA1 interaction with STAT6 and for IL-4-dependent transcriptional activation. Cyclin-dependent kinases phosphorylate NCOA1 to inhibit its interaction with STAT6, and cells arrested at G1/S show enhanced NCOA1 phosphorylation. Simultaneous inhibition of phosphatase and CDK activity rescues the NCOA1/STAT6 interaction, linking transcriptional coactivation to cell cycle regulation.","method":"Co-immunoprecipitation, phosphatase inhibitor treatment, CDK inhibitor treatment, cell cycle synchronization, STAT6 target gene activation assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic and genetic perturbation of phosphorylation state linked to co-IP interaction and functional transcription readout, single lab","pmids":["21148148"],"is_preprint":false},{"year":2010,"finding":"NCOA1 and NCOA3 cooperatively regulate placental morphogenesis and embryo survival. Double knockout of NCOA1 and NCOA3 in mice causes embryonic lethality by E13.5 with placental labyrinth defects including reduced maternal blood sinuses, fetal capillaries, and abnormal trophoblast differentiation, while single knockouts survive. NCOA1 and NCOA3 are expressed in the labyrinth and regulate expression of TGFβ-, PPARβ-, and PPARγ-regulated genes and glucose transporters (GLUT1, Cx26).","method":"Double knockout mouse generation, histological analysis of placenta, gene expression analysis","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double KO mice with defined developmental phenotype and molecular pathway placement, rigorous in vivo model","pmids":["20685850"],"is_preprint":false},{"year":2014,"finding":"NCOA1 promotes breast cancer metastasis by directly upregulating CSF1 (colony-stimulating factor 1) expression. NCOA1 and c-Fos are recruited to a functional AP-1 site in the CSF1 promoter, driving CSF1 transcription to enhance macrophage recruitment and lung metastasis. Silencing NCOA1 reduces CSF1 expression and decreases macrophage recruitment and cancer cell metastasis.","method":"MMTV-hNCOA1 transgenic mice, chromatin immunoprecipitation (ChIP) at CSF1 AP-1 promoter site, NCOA1 knockdown with metastasis and macrophage recruitment readouts","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse model combined with ChIP, loss-of-function knockdown, and multiple functional readouts in the same study","pmids":["24769444"],"is_preprint":false},{"year":2015,"finding":"NCOA1 promotes breast tumor angiogenesis by simultaneously associating with c-Fos at the AP-1 site (bp -938) and with HIF1α at the HIF1α-binding element (bp -979) of the VEGFa promoter, upregulating VEGFa transcription. Ncoa1 knockout reduces microvascular density in mammary tumors, while NCOA1 overexpression increases it. VEGFa treatment rescues the angiogenic defect caused by NCOA1 knockdown.","method":"ChIP at VEGFa promoter AP-1 and HIF1α sites, Ncoa1 knockout and NCOA1-overexpressing mouse models, Matrigel plug angiogenesis assay, VEGFa rescue experiment","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP establishing direct promoter recruitment, multiple mouse genetic models, rescue experiment, orthogonal functional assays in the same study","pmids":["26287601"],"is_preprint":false},{"year":2016,"finding":"NCOA1 knockdown in AR-positive prostate cancer cells reduces proliferation and strongly decreases migration and invasion. NCOA1 knockdown upregulates PRKD1 in AR-positive cells but not in AR-negative cells. Inhibition of PRKD1 reverses the reduced migratory potential caused by NCOA1 knockdown, placing PRKD1 downstream of the AR/NCOA1 axis in the regulation of cellular migration.","method":"NCOA1 siRNA knockdown, [3H]-thymidine incorporation proliferation assay, Boyden chamber migration/invasion assay, cDNA microarray transcriptome analysis, PRKD1 inhibitor epistasis","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype, epistasis via PRKD1 inhibitor, transcriptomic pathway placement, single lab","pmids":["27255895"],"is_preprint":false},{"year":2017,"finding":"A cell-permeable stapled helical peptide targeting NCOA1 disrupts the NCOA1/STAT6 protein-protein interaction and represses STAT6-mediated transcription. The crystal structure of the stapled peptide in complex with NCOA1 was determined, confirming the binding mode.","method":"Stapled peptide synthesis, NCOA1/STAT6 interaction disruption assay, STAT6 transcriptional reporter assay, X-ray crystallography of stapled peptide-NCOA1 complex","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation of PPI disruption and transcriptional repression, orthogonal methods in one study","pmids":["29090910"],"is_preprint":false},{"year":2017,"finding":"Biochanin A enhances the interaction between NCOA1 (SRC-1) and PPARγ while reducing NCOA3 (SRC-3) levels, shifting co-factor selectivity of PPARγ and reducing lipid accumulation in pre-adipocytes.","method":"Co-immunoprecipitation, immunoblot, qPCR in 3T3-L1 pre-adipocyte cells treated with biochanin A","journal":"Journal of infection and public health","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment, single lab, limited mechanistic follow-up on NCOA1 specifically","pmids":["31133421"],"is_preprint":false},{"year":2017,"finding":"Biochanin A promotes STAT3-mediated recruitment of NCOA1 to RORγ, enhancing RORγ-dependent IL-17 transcription. Stable knockdown of either RORγ or STAT3 cancels biochanin A-induced IL-17 upregulation. A dominant negative STAT3 mutant or the STAT3 inhibitor Stattic disrupts the biochanin A-induced RORγ-NCOA1 complex.","method":"Co-immunoprecipitation of RORγ-STAT3 and RORγ-NCOA1 complexes, stable shRNA knockdown, dominant-negative STAT3 overexpression, STAT3 inhibitor treatment, IL-17 expression assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of complex formation, genetic and pharmacologic epistasis, functional IL-17 readout, single lab","pmids":["28579428"],"is_preprint":false},{"year":2022,"finding":"NCOA1 forms a transcriptional complex with CBP and NF-κB subunits that binds to promoters of proinflammatory cytokine genes to activate their expression in endotoxin-induced myocardial dysfunction. LPS inhibits DNMT1, decreasing DNA methylation at a CpG island on the NCOA1 promoter and causing NCOA1 overexpression. A small molecule, PSSM2126, identified by yeast-based screening, blocks NCOA1-CBP interaction in vitro and in vivo, alleviating inflammation and improving cardiac function.","method":"Co-immunoprecipitation of NCOA1-CBP-NF-κB complex, ChIP at cytokine gene promoters, DNMT1/DNA methylation analysis, small molecule screening, PSSM2126 treatment in EIMD mouse model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP establishing complex at promoters, in vivo mouse model, small molecule functional validation, single lab","pmids":["35339471"],"is_preprint":false},{"year":2023,"finding":"NCOA1 accumulates upon HERC3 E3 ubiquitin ligase deficiency, as HERC3 normally ubiquitinates NCOA1 for degradation. Accumulated NCOA1 assembles with histone acetyltransferase p300 and Runx2 to form a complex that transactivates MMP gene expression, promoting extracellular matrix degradation in intervertebral disc degeneration. A small molecule SMTNP-191 targeting the NCOA1-p300 interaction suppresses MMP expression and attenuates disc degeneration in aged mice.","method":"Ubiquitination assay, co-immunoprecipitation and mass spectrometry to identify the NCOA1-p300-Runx2 complex, immunoblot, RT-qPCR, small molecule screening, aged mouse IDD model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay establishes HERC3 as E3 for NCOA1, co-IP/MS identifies complex, functional small-molecule validation in vivo, single lab","pmids":["36878279"],"is_preprint":false},{"year":2026,"finding":"NCOA1 has a cell-autonomous role in promoting beiging of subcutaneous white adipocytes by directly regulating the thermogenic factor UCP1 and sex-dependent mitochondrial gene networks. Acting together with GATA3, NCOA1 establishes elevated basal thermogenic tone in female subcutaneous fat. Female mice lacking NCOA1 in subcutaneous adipocytes develop obesity, glucose intolerance, and a male-like fat distribution with increased visceral fat and reduced beige adipocytes.","method":"Adipocyte-specific NCOA1 knockout mouse model, cold and adrenergic stimulation assays, UCP1 expression measurement, metabolic phenotyping, co-factor interaction analysis with GATA3","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with multiple defined metabolic and cellular phenotypes, direct UCP1 regulation shown, sex-specific epistasis with GATA3, rigorous in vivo model","pmids":["41559022"],"is_preprint":false},{"year":2026,"finding":"EP300 forms a nuclear transcriptional co-activator complex with NCOA1 that stabilizes NCOA1 nuclear localization and synergistically enhances VEGFA expression by increasing H3K27 acetylation at the VEGFA promoter, promoting glioma angiogenesis.","method":"Co-immunoprecipitation of EP300-NCOA1 complex, nuclear-cytoplasmic fractionation, H3K27ac ChIP at VEGFA promoter, EP300 overexpression/knockdown, endothelial functional assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP establishing the complex at VEGFA promoter with functional angiogenesis readout, single lab","pmids":["41921814"],"is_preprint":false},{"year":2025,"finding":"IRF1 drives NCOA1 transcription in retinal ischemia-reperfusion: ChIP and dual-luciferase assays confirmed IRF1 directly binds the NCOA1 promoter and activates NCOA1 expression. Knockdown of either IRF1 or NCOA1 increases autophagy, inhibits M1-type microglial polarization, reduces inflammatory cytokines, and inhibits the Wnt/β-catenin pathway. The Wnt/β-catenin activator HLY78 partially reverses the effect of NCOA1 knockdown, placing NCOA1 upstream of Wnt/β-catenin.","method":"ChIP assay, dual-luciferase reporter assay, adeno-associated virus-mediated IRF1/NCOA1 knockdown in rat RIR model, western blot, ELISA, immunofluorescence","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct transcriptional regulation, in vivo AAV knockdown with epistasis via Wnt activator, single lab","pmids":["40096931"],"is_preprint":false}],"current_model":"NCOA1 (NCoA-1/SRC-1/KAT13A) is a transcriptional coactivator that interacts with multiple transcription factors — including nuclear receptors (AR, PPARγ, RORγ, GR), STATs (STAT5, STAT6), NF-κB, HIF1α, AP-1 (c-Fos), and Runx2 — primarily through its N-terminal bHLH/PAS-B domain recognizing LXXLL motifs, and this interaction is regulated by PP2A-mediated dephosphorylation; it promotes gene programs including CSF1/VEGFa-driven breast cancer metastasis and angiogenesis, proinflammatory cytokine expression via an NCOA1-CBP-NF-κB complex, MMP expression via an NCOA1-p300-Runx2 complex (controlled by HERC3-mediated ubiquitination), and thermogenic UCP1 expression in female subcutaneous adipocytes in cooperation with GATA3, while also cooperating with NCOA3 to support placental labyrinth morphogenesis."},"narrative":{"mechanistic_narrative":"NCOA1 (SRC-1) is a transcriptional coactivator that bridges sequence-specific transcription factors to histone acetyltransferase machinery to amplify defined gene programs [PMID:24769444, PMID:12954634]. It recognizes LXXLL motifs in the transactivation domains of partner factors through its N-terminal bHLH/PAS-B domain; crystallographic and mutagenesis work define a hydrophobic, surface-complementary interface that recognizes the STAT6 LXXLL helix and its flanking residues with specificity not shared by NCOA2 or NCOA3 [PMID:12138096, PMID:14757047, PMID:18464232]. Through this mode it coactivates STAT6 and STAT5 in cytokine- and prolactin-driven transcription, cooperating with p300/CBP and the glucocorticoid receptor [PMID:11574547, PMID:12954634]. NCOA1 engagement with STAT6 is gated by phosphorylation state: PP2A-mediated dephosphorylation is required for the interaction, while CDK phosphorylation inhibits it, coupling coactivation to cell-cycle position [PMID:21148148]. NCOA1 assembles with acetyltransferases and DNA-binding factors into promoter-bound complexes that drive distinct outputs — with c-Fos and HIF1α at the CSF1 and VEGFa promoters to promote breast cancer metastasis, macrophage recruitment, and tumor angiogenesis [PMID:24769444, PMID:26287601]; with EP300 to enhance H3K27 acetylation at the VEGFA promoter in glioma angiogenesis [PMID:41921814]; with CBP and NF-κB at proinflammatory cytokine promoters [PMID:35339471]; and with p300 and Runx2 to transactivate MMP genes, an output restrained by HERC3-mediated ubiquitination and degradation of NCOA1 [PMID:36878279]. In metabolic physiology, NCOA1 acts cell-autonomously with GATA3 to drive UCP1 and thermogenic beiging of female subcutaneous adipocytes [PMID:41559022], and cooperates with NCOA3 to support placental labyrinth morphogenesis and embryo survival [PMID:20685850].","teleology":[{"year":2001,"claim":"Established that NCOA1 is a selective coactivator for STAT6, defining a partner outside the classical nuclear-receptor sphere and localizing the contact to its N-terminal region.","evidence":"GST pulldown, co-IP, transactivation reporters and dominant-negative overexpression in mammalian cells","pmids":["11574547"],"confidence":"High","gaps":["Did not resolve the precise binding motif or structural basis","Specificity over other STATs shown only at the family level"]},{"year":2002,"claim":"Identified the LXXLL motif in the STAT6 transactivation domain as the determinant docking onto the NCOA1 PAS-B domain, unifying STAT recognition with the nuclear-receptor coactivation paradigm.","evidence":"GST pulldown with LXXLL peptides/blocking antibodies, LXXLL mutagenesis, and endogenous eotaxin-3 activation","pmids":["12138096"],"confidence":"High","gaps":["Atomic geometry of the interface not yet determined","Generality of LXXLL use across other NCOA1 partners untested here"]},{"year":2003,"claim":"Extended NCOA1 coactivation to STAT5a/b in prolactin signaling and showed cooperative action with p300/CBP and the glucocorticoid receptor, indicating combinatorial assembly on hormone-responsive promoters.","evidence":"Co-IP, domain deletion/mutagenesis, beta-casein promoter transactivation assays","pmids":["12954634"],"confidence":"High","gaps":["STAT5 binding motif defined only as a short helical element","Endogenous gene targets beyond beta-casein not mapped"]},{"year":2004,"claim":"Provided the atomic-resolution basis for NCOA1 partner selectivity, showing the STAT6 LXXLL helix binds PAS-B through hydrophobic surface complementarity not reproduced by NCOA2/NCOA3.","evidence":"X-ray crystallography of the NCOA1 PAS-B / STAT6 LXXLL complex","pmids":["14757047"],"confidence":"High","gaps":["Structures with other transcription-factor partners not solved","Does not address regulation of the interaction in cells"]},{"year":2008,"claim":"Refined the binding determinants beyond the core motif, showing LXXLL-flanking residues contribute energetically and that optimizing knobs-into-holes contacts raises affinity.","evidence":"Peptide binding assays and SAR of LXXLL-flanking residues","pmids":["18464232"],"confidence":"Medium","gaps":["Single-lab biochemistry","Cellular consequence of affinity tuning not tested"]},{"year":2010,"claim":"Showed the NCOA1/STAT6 interaction is dynamically gated by phosphorylation — PP2A dephosphorylation enables it, CDK phosphorylation blocks it — linking coactivation to cell-cycle state.","evidence":"Co-IP with phosphatase and CDK inhibitors, cell-cycle synchronization, STAT6 target gene assays","pmids":["21148148"],"confidence":"Medium","gaps":["Specific phosphosites on NCOA1 not mapped","Single lab; whether the same control applies to other partners unknown"]},{"year":2010,"claim":"Demonstrated an in vivo developmental requirement: NCOA1 acts redundantly with NCOA3 in placental labyrinth morphogenesis, with double knockout causing embryonic lethality.","evidence":"Single and double knockout mice, placental histology, gene expression analysis","pmids":["20685850"],"confidence":"High","gaps":["Direct target genes in trophoblast not defined","NCOA1-specific (non-redundant) contribution not isolated"]},{"year":2015,"claim":"Defined NCOA1 as a driver of breast cancer metastasis and tumor angiogenesis by recruiting to AP-1 (c-Fos) and HIF1α promoter elements to transactivate CSF1 and VEGFa.","evidence":"MMTV-hNCOA1 transgenic and Ncoa1 knockout mice, ChIP at CSF1 and VEGFa promoters, knockdown, Matrigel angiogenesis and VEGFa rescue","pmids":["24769444","26287601"],"confidence":"High","gaps":["How NCOA1 simultaneously bridges c-Fos and HIF1α mechanistically unresolved","Acetyltransferase partner at these promoters not identified in these studies"]},{"year":2016,"claim":"Placed NCOA1 in an AR-dependent prostate cancer migration program by showing its knockdown derepresses PRKD1 only in AR-positive cells and that PRKD1 inhibition rescues the migratory phenotype.","evidence":"siRNA knockdown, proliferation and Boyden-chamber assays, microarray, PRKD1 inhibitor epistasis","pmids":["27255895"],"confidence":"Medium","gaps":["Direct AR/NCOA1 occupancy at PRKD1 not shown","Single lab"]},{"year":2017,"claim":"Validated the NCOA1 PAS-B pocket as a druggable target by disrupting the NCOA1/STAT6 interaction with a stapled helical peptide, confirmed structurally and functionally.","evidence":"Stapled peptide synthesis, PPI disruption and STAT6 reporter assays, crystal structure of peptide-NCOA1 complex","pmids":["29090910"],"confidence":"High","gaps":["In vivo efficacy not addressed","Selectivity over other NCOA1 partner interactions not profiled"]},{"year":2017,"claim":"Expanded NCOA1's partner repertoire to RORγ, showing STAT3 promotes assembly of a RORγ-NCOA1 complex driving IL-17 transcription.","evidence":"Co-IP of RORγ-STAT3 and RORγ-NCOA1, shRNA knockdown, dominant-negative STAT3 and Stattic, IL-17 readout (with PPARγ co-factor shift in a separate adipocyte study)","pmids":["28579428","31133421"],"confidence":"Medium","gaps":["Whether STAT3 bridges NCOA1 directly or indirectly unclear","PPARγ cofactor-shift finding rests on a single Co-IP"]},{"year":2022,"claim":"Defined an NCOA1-CBP-NF-κB complex on cytokine promoters and showed NCOA1 itself is transcriptionally upregulated via LPS-driven DNMT1 inhibition and promoter demethylation in inflammatory cardiac injury.","evidence":"Co-IP, ChIP at cytokine promoters, DNA-methylation analysis, small-molecule (PSSM2126) disruption of NCOA1-CBP in an EIMD mouse model","pmids":["35339471"],"confidence":"Medium","gaps":["Direct DNA-binding partner directing NCOA1 to specific promoters not fully resolved","Single lab"]},{"year":2023,"claim":"Identified HERC3 as the E3 ligase controlling NCOA1 abundance, with accumulated NCOA1 assembling a p300-Runx2 complex that transactivates MMP genes in disc degeneration.","evidence":"Ubiquitination assay, co-IP/MS of the NCOA1-p300-Runx2 complex, RT-qPCR, SMTNP-191 small molecule in an aged-mouse IDD model","pmids":["36878279"],"confidence":"Medium","gaps":["Ubiquitination site(s) on NCOA1 not mapped","Single lab"]},{"year":2026,"claim":"Established a sex-specific, cell-autonomous metabolic role: NCOA1 cooperates with GATA3 to drive UCP1 and beiging of female subcutaneous fat, with loss causing obesity and a male-like fat distribution.","evidence":"Adipocyte-specific NCOA1 knockout mice, cold/adrenergic challenge, UCP1 and mitochondrial gene profiling, metabolic phenotyping","pmids":["41559022"],"confidence":"High","gaps":["Molecular basis of the GATA3-NCOA1 interaction not structurally defined","Source of sex specificity not mechanistically resolved"]},{"year":2026,"claim":"Showed EP300 forms a complex with NCOA1 that stabilizes its nuclear localization and synergistically increases H3K27ac at the VEGFA promoter to promote glioma angiogenesis, reinforcing the NCOA1-acetyltransferase VEGFA axis.","evidence":"Co-IP, nuclear-cytoplasmic fractionation, H3K27ac ChIP at VEGFA promoter, EP300 perturbation, endothelial assays","pmids":["41921814"],"confidence":"Medium","gaps":["Mechanism of EP300-dependent nuclear stabilization of NCOA1 unclear","Single lab"]},{"year":null,"claim":"How upstream signals select which NCOA1-acetyltransferase-transcription factor complex assembles in a given cell type, and how phosphorylation, ubiquitination, and partner availability are integrated to direct the choice, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking NCOA1 post-translational state to partner choice","Structural data limited to the PAS-B/STAT6 interface","Endogenous genome-wide occupancy across tissues not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,7,8,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8,13,14,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,8,13,16]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[8,13,16]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8,14,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,12,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,15]}],"complexes":["NCOA1-CBP-NF-κB complex","NCOA1-p300-Runx2 complex","NCOA1-EP300 complex"],"partners":["STAT6","STAT5A","EP300","CREBBP","FOS","HIF1A","GATA3","RORC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15788","full_name":"Nuclear receptor coactivator 1","aliases":["Class E basic helix-loop-helix protein 74","bHLHe74","Protein Hin-2","RIP160","Renal carcinoma antigen NY-REN-52","Steroid receptor coactivator 1","SRC-1"],"length_aa":1441,"mass_kda":156.8,"function":"Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15788/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NCOA1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000084676","cell_line_id":"CID000984","localizations":[{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"ANKRD27","stoichiometry":0.2},{"gene":"SLC6A15","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000984","total_profiled":1310},"omim":[{"mim_id":"614610","title":"KN MOTIF- AND ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 2; KANK2","url":"https://www.omim.org/entry/614610"},{"mim_id":"613979","title":"PRE-mRNA-PROCESSING FACTOR 6; PRPF6","url":"https://www.omim.org/entry/613979"},{"mim_id":"612268","title":"TUBULIN TYROSINE LIGASE-LIKE 5; TTLL5","url":"https://www.omim.org/entry/612268"},{"mim_id":"611371","title":"ZINC FINGER PROTEIN 653; ZNF653","url":"https://www.omim.org/entry/611371"},{"mim_id":"611265","title":"PEROXISOMAL PROLIFERATOR-ACTIVATED RECEPTOR ALPHA-INTERACTING COFACTOR COMPLEX, 285-KD SUBUNIT","url":"https://www.omim.org/entry/611265"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NCOA1"},"hgnc":{"alias_symbol":["SRC1","F-SRC-1","NCoA-1","KAT13A","RIP160","bHLHe74"],"prev_symbol":[]},"alphafold":{"accession":"Q15788","domains":[{"cath_id":"-","chopping":"32-81","consensus_level":"high","plddt":78.4012,"start":32,"end":81},{"cath_id":"3.30.450.20","chopping":"122-176_191-205_216-253","consensus_level":"medium","plddt":78.5461,"start":122,"end":253},{"cath_id":"3.30.450.20","chopping":"262-366","consensus_level":"high","plddt":90.3658,"start":262,"end":366}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15788","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15788-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15788-F1-predicted_aligned_error_v6.png","plddt_mean":46.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NCOA1","jax_strain_url":"https://www.jax.org/strain/search?query=NCOA1"},"sequence":{"accession":"Q15788","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15788.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15788/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15788"}},"corpus_meta":[{"pmid":"26371783","id":"PMC_26371783","title":"Novel 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The N-terminal part of NCOA1 interacts specifically with STAT6 but not with other STAT family members. Overexpression of this NCOA1 domain has a dominant-negative inhibitory effect on STAT6-mediated transactivation, demonstrating the essential role of this interaction.\",\n      \"method\": \"GST pulldown, mammalian cell co-immunoprecipitation, transactivation reporter assays, dominant-negative overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, dominant-negative functional validation, replicated across multiple orthogonal methods in the same study and confirmed in subsequent papers\",\n      \"pmids\": [\"11574547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"An LXXLL motif in the STAT6 transactivation domain mediates the specific interaction with the NCoA-1 PAS-B domain. Mutagenesis of the LXXLL motif eliminated STAT6/NCOA1 interaction both in vitro and in vivo, and strongly diminished IL-4-regulated activation of the endogenous STAT6 target gene eotaxin-3.\",\n      \"method\": \"GST pulldown with LXXLL peptides and blocking antibodies, LXXLL mutagenesis, endogenous target gene activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis, confirmed with endogenous gene readout, replicated by structural work in later papers\",\n      \"pmids\": [\"12138096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NCOA1 is a coactivator for both STAT5a and STAT5b in prolactin-dependent gene expression. Both the activation domain 1 and the amino-terminal bHLH/PAS domain of NCOA1 are required for STAT5 coactivation. The bHLH/PAS domain mediates direct interaction with STAT5a in cells. A three-amino-acid motif in an alpha-helical region of the STAT5a transactivation domain is essential for NCoA-1 binding. NCOA1 and p300/CBP cooperatively enhance STAT5a-mediated transactivation and NCOA1 is involved in the synergistic action of the glucocorticoid receptor and STAT5a on the beta-casein promoter.\",\n      \"method\": \"Co-immunoprecipitation, transactivation reporter assays, domain deletion and mutagenesis, beta-casein promoter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, mutagenesis of binding motif, functional transactivation readout with multiple orthogonal methods\",\n      \"pmids\": [\"12954634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of the NCOA1 PAS-B domain in complex with the STAT6 LXXLL motif was determined. The amphipathic alpha-helical STAT6 LXXLL motif binds predominantly through hydrophobic interactions to NCOA1 PAS-B. A single NCOA1 PAS-B residue makes hydrophilic contacts with the STAT6 peptide. STAT6 interacts only with the PAS-B domain of NCOA1 and not with homologous regions of NCOA2 or NCOA3, with specificity determined largely by surface complementarity between hydrophobic faces.\",\n      \"method\": \"X-ray crystallography (crystal structure determination)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic resolution crystal structure with defined binding interface, consistent with prior mutagenesis data\",\n      \"pmids\": [\"14757047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Energetically important contacts between STAT6 and NCOA1 extend to residues flanking the LXXLL motif, including residues in the sequence LLPPTEQDLTKLL. Optimizing knobs-into-holes contacts on the surface of the STAT6-derived peptide significantly improves affinity for NCOA1, revealing the molecular basis of binding specificity.\",\n      \"method\": \"Peptide binding assays, structure-activity relationship (SAR) analysis of LXXLL-flanking residues\",\n      \"journal\": \"Chembiochem\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization of binding specificity with peptide variants, single lab, consistent with structural data\",\n      \"pmids\": [\"18464232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dephosphorylation of NCOA1 by PP2A phosphatase is essential for NCOA1 interaction with STAT6 and for IL-4-dependent transcriptional activation. Cyclin-dependent kinases phosphorylate NCOA1 to inhibit its interaction with STAT6, and cells arrested at G1/S show enhanced NCOA1 phosphorylation. Simultaneous inhibition of phosphatase and CDK activity rescues the NCOA1/STAT6 interaction, linking transcriptional coactivation to cell cycle regulation.\",\n      \"method\": \"Co-immunoprecipitation, phosphatase inhibitor treatment, CDK inhibitor treatment, cell cycle synchronization, STAT6 target gene activation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic and genetic perturbation of phosphorylation state linked to co-IP interaction and functional transcription readout, single lab\",\n      \"pmids\": [\"21148148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NCOA1 and NCOA3 cooperatively regulate placental morphogenesis and embryo survival. Double knockout of NCOA1 and NCOA3 in mice causes embryonic lethality by E13.5 with placental labyrinth defects including reduced maternal blood sinuses, fetal capillaries, and abnormal trophoblast differentiation, while single knockouts survive. NCOA1 and NCOA3 are expressed in the labyrinth and regulate expression of TGFβ-, PPARβ-, and PPARγ-regulated genes and glucose transporters (GLUT1, Cx26).\",\n      \"method\": \"Double knockout mouse generation, histological analysis of placenta, gene expression analysis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double KO mice with defined developmental phenotype and molecular pathway placement, rigorous in vivo model\",\n      \"pmids\": [\"20685850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NCOA1 promotes breast cancer metastasis by directly upregulating CSF1 (colony-stimulating factor 1) expression. NCOA1 and c-Fos are recruited to a functional AP-1 site in the CSF1 promoter, driving CSF1 transcription to enhance macrophage recruitment and lung metastasis. Silencing NCOA1 reduces CSF1 expression and decreases macrophage recruitment and cancer cell metastasis.\",\n      \"method\": \"MMTV-hNCOA1 transgenic mice, chromatin immunoprecipitation (ChIP) at CSF1 AP-1 promoter site, NCOA1 knockdown with metastasis and macrophage recruitment readouts\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse model combined with ChIP, loss-of-function knockdown, and multiple functional readouts in the same study\",\n      \"pmids\": [\"24769444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NCOA1 promotes breast tumor angiogenesis by simultaneously associating with c-Fos at the AP-1 site (bp -938) and with HIF1α at the HIF1α-binding element (bp -979) of the VEGFa promoter, upregulating VEGFa transcription. Ncoa1 knockout reduces microvascular density in mammary tumors, while NCOA1 overexpression increases it. VEGFa treatment rescues the angiogenic defect caused by NCOA1 knockdown.\",\n      \"method\": \"ChIP at VEGFa promoter AP-1 and HIF1α sites, Ncoa1 knockout and NCOA1-overexpressing mouse models, Matrigel plug angiogenesis assay, VEGFa rescue experiment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP establishing direct promoter recruitment, multiple mouse genetic models, rescue experiment, orthogonal functional assays in the same study\",\n      \"pmids\": [\"26287601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NCOA1 knockdown in AR-positive prostate cancer cells reduces proliferation and strongly decreases migration and invasion. NCOA1 knockdown upregulates PRKD1 in AR-positive cells but not in AR-negative cells. Inhibition of PRKD1 reverses the reduced migratory potential caused by NCOA1 knockdown, placing PRKD1 downstream of the AR/NCOA1 axis in the regulation of cellular migration.\",\n      \"method\": \"NCOA1 siRNA knockdown, [3H]-thymidine incorporation proliferation assay, Boyden chamber migration/invasion assay, cDNA microarray transcriptome analysis, PRKD1 inhibitor epistasis\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype, epistasis via PRKD1 inhibitor, transcriptomic pathway placement, single lab\",\n      \"pmids\": [\"27255895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A cell-permeable stapled helical peptide targeting NCOA1 disrupts the NCOA1/STAT6 protein-protein interaction and represses STAT6-mediated transcription. The crystal structure of the stapled peptide in complex with NCOA1 was determined, confirming the binding mode.\",\n      \"method\": \"Stapled peptide synthesis, NCOA1/STAT6 interaction disruption assay, STAT6 transcriptional reporter assay, X-ray crystallography of stapled peptide-NCOA1 complex\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation of PPI disruption and transcriptional repression, orthogonal methods in one study\",\n      \"pmids\": [\"29090910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biochanin A enhances the interaction between NCOA1 (SRC-1) and PPARγ while reducing NCOA3 (SRC-3) levels, shifting co-factor selectivity of PPARγ and reducing lipid accumulation in pre-adipocytes.\",\n      \"method\": \"Co-immunoprecipitation, immunoblot, qPCR in 3T3-L1 pre-adipocyte cells treated with biochanin A\",\n      \"journal\": \"Journal of infection and public health\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment, single lab, limited mechanistic follow-up on NCOA1 specifically\",\n      \"pmids\": [\"31133421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biochanin A promotes STAT3-mediated recruitment of NCOA1 to RORγ, enhancing RORγ-dependent IL-17 transcription. Stable knockdown of either RORγ or STAT3 cancels biochanin A-induced IL-17 upregulation. A dominant negative STAT3 mutant or the STAT3 inhibitor Stattic disrupts the biochanin A-induced RORγ-NCOA1 complex.\",\n      \"method\": \"Co-immunoprecipitation of RORγ-STAT3 and RORγ-NCOA1 complexes, stable shRNA knockdown, dominant-negative STAT3 overexpression, STAT3 inhibitor treatment, IL-17 expression assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of complex formation, genetic and pharmacologic epistasis, functional IL-17 readout, single lab\",\n      \"pmids\": [\"28579428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCOA1 forms a transcriptional complex with CBP and NF-κB subunits that binds to promoters of proinflammatory cytokine genes to activate their expression in endotoxin-induced myocardial dysfunction. LPS inhibits DNMT1, decreasing DNA methylation at a CpG island on the NCOA1 promoter and causing NCOA1 overexpression. A small molecule, PSSM2126, identified by yeast-based screening, blocks NCOA1-CBP interaction in vitro and in vivo, alleviating inflammation and improving cardiac function.\",\n      \"method\": \"Co-immunoprecipitation of NCOA1-CBP-NF-κB complex, ChIP at cytokine gene promoters, DNMT1/DNA methylation analysis, small molecule screening, PSSM2126 treatment in EIMD mouse model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP establishing complex at promoters, in vivo mouse model, small molecule functional validation, single lab\",\n      \"pmids\": [\"35339471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NCOA1 accumulates upon HERC3 E3 ubiquitin ligase deficiency, as HERC3 normally ubiquitinates NCOA1 for degradation. Accumulated NCOA1 assembles with histone acetyltransferase p300 and Runx2 to form a complex that transactivates MMP gene expression, promoting extracellular matrix degradation in intervertebral disc degeneration. A small molecule SMTNP-191 targeting the NCOA1-p300 interaction suppresses MMP expression and attenuates disc degeneration in aged mice.\",\n      \"method\": \"Ubiquitination assay, co-immunoprecipitation and mass spectrometry to identify the NCOA1-p300-Runx2 complex, immunoblot, RT-qPCR, small molecule screening, aged mouse IDD model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay establishes HERC3 as E3 for NCOA1, co-IP/MS identifies complex, functional small-molecule validation in vivo, single lab\",\n      \"pmids\": [\"36878279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NCOA1 has a cell-autonomous role in promoting beiging of subcutaneous white adipocytes by directly regulating the thermogenic factor UCP1 and sex-dependent mitochondrial gene networks. Acting together with GATA3, NCOA1 establishes elevated basal thermogenic tone in female subcutaneous fat. Female mice lacking NCOA1 in subcutaneous adipocytes develop obesity, glucose intolerance, and a male-like fat distribution with increased visceral fat and reduced beige adipocytes.\",\n      \"method\": \"Adipocyte-specific NCOA1 knockout mouse model, cold and adrenergic stimulation assays, UCP1 expression measurement, metabolic phenotyping, co-factor interaction analysis with GATA3\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with multiple defined metabolic and cellular phenotypes, direct UCP1 regulation shown, sex-specific epistasis with GATA3, rigorous in vivo model\",\n      \"pmids\": [\"41559022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EP300 forms a nuclear transcriptional co-activator complex with NCOA1 that stabilizes NCOA1 nuclear localization and synergistically enhances VEGFA expression by increasing H3K27 acetylation at the VEGFA promoter, promoting glioma angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation of EP300-NCOA1 complex, nuclear-cytoplasmic fractionation, H3K27ac ChIP at VEGFA promoter, EP300 overexpression/knockdown, endothelial functional assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP establishing the complex at VEGFA promoter with functional angiogenesis readout, single lab\",\n      \"pmids\": [\"41921814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IRF1 drives NCOA1 transcription in retinal ischemia-reperfusion: ChIP and dual-luciferase assays confirmed IRF1 directly binds the NCOA1 promoter and activates NCOA1 expression. Knockdown of either IRF1 or NCOA1 increases autophagy, inhibits M1-type microglial polarization, reduces inflammatory cytokines, and inhibits the Wnt/β-catenin pathway. The Wnt/β-catenin activator HLY78 partially reverses the effect of NCOA1 knockdown, placing NCOA1 upstream of Wnt/β-catenin.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, adeno-associated virus-mediated IRF1/NCOA1 knockdown in rat RIR model, western blot, ELISA, immunofluorescence\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct transcriptional regulation, in vivo AAV knockdown with epistasis via Wnt activator, single lab\",\n      \"pmids\": [\"40096931\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCOA1 (NCoA-1/SRC-1/KAT13A) is a transcriptional coactivator that interacts with multiple transcription factors — including nuclear receptors (AR, PPARγ, RORγ, GR), STATs (STAT5, STAT6), NF-κB, HIF1α, AP-1 (c-Fos), and Runx2 — primarily through its N-terminal bHLH/PAS-B domain recognizing LXXLL motifs, and this interaction is regulated by PP2A-mediated dephosphorylation; it promotes gene programs including CSF1/VEGFa-driven breast cancer metastasis and angiogenesis, proinflammatory cytokine expression via an NCOA1-CBP-NF-κB complex, MMP expression via an NCOA1-p300-Runx2 complex (controlled by HERC3-mediated ubiquitination), and thermogenic UCP1 expression in female subcutaneous adipocytes in cooperation with GATA3, while also cooperating with NCOA3 to support placental labyrinth morphogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NCOA1 (SRC-1) is a transcriptional coactivator that bridges sequence-specific transcription factors to histone acetyltransferase machinery to amplify defined gene programs [#7, #2]. It recognizes LXXLL motifs in the transactivation domains of partner factors through its N-terminal bHLH/PAS-B domain; crystallographic and mutagenesis work define a hydrophobic, surface-complementary interface that recognizes the STAT6 LXXLL helix and its flanking residues with specificity not shared by NCOA2 or NCOA3 [#1, #3, #4]. Through this mode it coactivates STAT6 and STAT5 in cytokine- and prolactin-driven transcription, cooperating with p300/CBP and the glucocorticoid receptor [#0, #2]. NCOA1 engagement with STAT6 is gated by phosphorylation state: PP2A-mediated dephosphorylation is required for the interaction, while CDK phosphorylation inhibits it, coupling coactivation to cell-cycle position [#5]. NCOA1 assembles with acetyltransferases and DNA-binding factors into promoter-bound complexes that drive distinct outputs — with c-Fos and HIF1\\u03b1 at the CSF1 and VEGFa promoters to promote breast cancer metastasis, macrophage recruitment, and tumor angiogenesis [#7, #8]; with EP300 to enhance H3K27 acetylation at the VEGFA promoter in glioma angiogenesis [#16]; with CBP and NF-\\u03baB at proinflammatory cytokine promoters [#13]; and with p300 and Runx2 to transactivate MMP genes, an output restrained by HERC3-mediated ubiquitination and degradation of NCOA1 [#14]. In metabolic physiology, NCOA1 acts cell-autonomously with GATA3 to drive UCP1 and thermogenic beiging of female subcutaneous adipocytes [#15], and cooperates with NCOA3 to support placental labyrinth morphogenesis and embryo survival [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that NCOA1 is a selective coactivator for STAT6, defining a partner outside the classical nuclear-receptor sphere and localizing the contact to its N-terminal region.\",\n      \"evidence\": \"GST pulldown, co-IP, transactivation reporters and dominant-negative overexpression in mammalian cells\",\n      \"pmids\": [\"11574547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the precise binding motif or structural basis\", \"Specificity over other STATs shown only at the family level\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the LXXLL motif in the STAT6 transactivation domain as the determinant docking onto the NCOA1 PAS-B domain, unifying STAT recognition with the nuclear-receptor coactivation paradigm.\",\n      \"evidence\": \"GST pulldown with LXXLL peptides/blocking antibodies, LXXLL mutagenesis, and endogenous eotaxin-3 activation\",\n      \"pmids\": [\"12138096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic geometry of the interface not yet determined\", \"Generality of LXXLL use across other NCOA1 partners untested here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended NCOA1 coactivation to STAT5a/b in prolactin signaling and showed cooperative action with p300/CBP and the glucocorticoid receptor, indicating combinatorial assembly on hormone-responsive promoters.\",\n      \"evidence\": \"Co-IP, domain deletion/mutagenesis, beta-casein promoter transactivation assays\",\n      \"pmids\": [\"12954634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"STAT5 binding motif defined only as a short helical element\", \"Endogenous gene targets beyond beta-casein not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Provided the atomic-resolution basis for NCOA1 partner selectivity, showing the STAT6 LXXLL helix binds PAS-B through hydrophobic surface complementarity not reproduced by NCOA2/NCOA3.\",\n      \"evidence\": \"X-ray crystallography of the NCOA1 PAS-B / STAT6 LXXLL complex\",\n      \"pmids\": [\"14757047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures with other transcription-factor partners not solved\", \"Does not address regulation of the interaction in cells\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Refined the binding determinants beyond the core motif, showing LXXLL-flanking residues contribute energetically and that optimizing knobs-into-holes contacts raises affinity.\",\n      \"evidence\": \"Peptide binding assays and SAR of LXXLL-flanking residues\",\n      \"pmids\": [\"18464232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab biochemistry\", \"Cellular consequence of affinity tuning not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed the NCOA1/STAT6 interaction is dynamically gated by phosphorylation — PP2A dephosphorylation enables it, CDK phosphorylation blocks it — linking coactivation to cell-cycle state.\",\n      \"evidence\": \"Co-IP with phosphatase and CDK inhibitors, cell-cycle synchronization, STAT6 target gene assays\",\n      \"pmids\": [\"21148148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphosites on NCOA1 not mapped\", \"Single lab; whether the same control applies to other partners unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated an in vivo developmental requirement: NCOA1 acts redundantly with NCOA3 in placental labyrinth morphogenesis, with double knockout causing embryonic lethality.\",\n      \"evidence\": \"Single and double knockout mice, placental histology, gene expression analysis\",\n      \"pmids\": [\"20685850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes in trophoblast not defined\", \"NCOA1-specific (non-redundant) contribution not isolated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined NCOA1 as a driver of breast cancer metastasis and tumor angiogenesis by recruiting to AP-1 (c-Fos) and HIF1\\u03b1 promoter elements to transactivate CSF1 and VEGFa.\",\n      \"evidence\": \"MMTV-hNCOA1 transgenic and Ncoa1 knockout mice, ChIP at CSF1 and VEGFa promoters, knockdown, Matrigel angiogenesis and VEGFa rescue\",\n      \"pmids\": [\"24769444\", \"26287601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NCOA1 simultaneously bridges c-Fos and HIF1\\u03b1 mechanistically unresolved\", \"Acetyltransferase partner at these promoters not identified in these studies\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed NCOA1 in an AR-dependent prostate cancer migration program by showing its knockdown derepresses PRKD1 only in AR-positive cells and that PRKD1 inhibition rescues the migratory phenotype.\",\n      \"evidence\": \"siRNA knockdown, proliferation and Boyden-chamber assays, microarray, PRKD1 inhibitor epistasis\",\n      \"pmids\": [\"27255895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AR/NCOA1 occupancy at PRKD1 not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Validated the NCOA1 PAS-B pocket as a druggable target by disrupting the NCOA1/STAT6 interaction with a stapled helical peptide, confirmed structurally and functionally.\",\n      \"evidence\": \"Stapled peptide synthesis, PPI disruption and STAT6 reporter assays, crystal structure of peptide-NCOA1 complex\",\n      \"pmids\": [\"29090910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy not addressed\", \"Selectivity over other NCOA1 partner interactions not profiled\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Expanded NCOA1's partner repertoire to ROR\\u03b3, showing STAT3 promotes assembly of a ROR\\u03b3-NCOA1 complex driving IL-17 transcription.\",\n      \"evidence\": \"Co-IP of ROR\\u03b3-STAT3 and ROR\\u03b3-NCOA1, shRNA knockdown, dominant-negative STAT3 and Stattic, IL-17 readout (with PPAR\\u03b3 co-factor shift in a separate adipocyte study)\",\n      \"pmids\": [\"28579428\", \"31133421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAT3 bridges NCOA1 directly or indirectly unclear\", \"PPAR\\u03b3 cofactor-shift finding rests on a single Co-IP\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an NCOA1-CBP-NF-\\u03baB complex on cytokine promoters and showed NCOA1 itself is transcriptionally upregulated via LPS-driven DNMT1 inhibition and promoter demethylation in inflammatory cardiac injury.\",\n      \"evidence\": \"Co-IP, ChIP at cytokine promoters, DNA-methylation analysis, small-molecule (PSSM2126) disruption of NCOA1-CBP in an EIMD mouse model\",\n      \"pmids\": [\"35339471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA-binding partner directing NCOA1 to specific promoters not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified HERC3 as the E3 ligase controlling NCOA1 abundance, with accumulated NCOA1 assembling a p300-Runx2 complex that transactivates MMP genes in disc degeneration.\",\n      \"evidence\": \"Ubiquitination assay, co-IP/MS of the NCOA1-p300-Runx2 complex, RT-qPCR, SMTNP-191 small molecule in an aged-mouse IDD model\",\n      \"pmids\": [\"36878279\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site(s) on NCOA1 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a sex-specific, cell-autonomous metabolic role: NCOA1 cooperates with GATA3 to drive UCP1 and beiging of female subcutaneous fat, with loss causing obesity and a male-like fat distribution.\",\n      \"evidence\": \"Adipocyte-specific NCOA1 knockout mice, cold/adrenergic challenge, UCP1 and mitochondrial gene profiling, metabolic phenotyping\",\n      \"pmids\": [\"41559022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the GATA3-NCOA1 interaction not structurally defined\", \"Source of sex specificity not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed EP300 forms a complex with NCOA1 that stabilizes its nuclear localization and synergistically increases H3K27ac at the VEGFA promoter to promote glioma angiogenesis, reinforcing the NCOA1-acetyltransferase VEGFA axis.\",\n      \"evidence\": \"Co-IP, nuclear-cytoplasmic fractionation, H3K27ac ChIP at VEGFA promoter, EP300 perturbation, endothelial assays\",\n      \"pmids\": [\"41921814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of EP300-dependent nuclear stabilization of NCOA1 unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How upstream signals select which NCOA1-acetyltransferase-transcription factor complex assembles in a given cell type, and how phosphorylation, ubiquitination, and partner availability are integrated to direct the choice, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking NCOA1 post-translational state to partner choice\", \"Structural data limited to the PAS-B/STAT6 interface\", \"Endogenous genome-wide occupancy across tissues not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 7, 8, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 13, 14, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 8, 13, 16]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [8, 13, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8, 14, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 12, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 15]}\n    ],\n    \"complexes\": [\n      \"NCOA1-CBP-NF-\\u03baB complex\",\n      \"NCOA1-p300-Runx2 complex\",\n      \"NCOA1-EP300 complex\"\n    ],\n    \"partners\": [\n      \"STAT6\",\n      \"STAT5A\",\n      \"EP300\",\n      \"CREBBP\",\n      \"FOS\",\n      \"HIF1A\",\n      \"GATA3\",\n      \"RORC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}