{"gene":"NCOA6","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2000,"finding":"RAP250 (NCOA6) interacts with nuclear receptors in a ligand-dependent or ligand-enhanced manner through a single LXXLL motif (nuclear receptor box), and contains a potent glutamine-rich N-terminal activation domain that enhances transcriptional activity of multiple nuclear receptors.","method":"In vitro binding assays and transient transfection/reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo interaction assays, reporter gene assays, single lab with two orthogonal methods","pmids":["10681503"],"is_preprint":false},{"year":2002,"finding":"NRC-interacting factor 1 (NIF-1) directly interacts with NRC (NCOA6) in vivo and in vitro, and enhances ligand-dependent transcriptional activation by nuclear hormone receptors, c-Fos, and c-Jun through NRC, defining NIF-1 as a cotransducer that functions as part of or downstream of an NRC coactivator complex.","method":"Yeast two-hybrid cloning, reciprocal co-immunoprecipitation (in vivo), in vitro binding assays, transient transfection reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP (in vivo and in vitro), domain mapping, functional reporter assays; multiple orthogonal methods in single focused study","pmids":["12215545"],"is_preprint":false},{"year":2003,"finding":"Genetic deletion of Rap250 (NCOA6) in mice causes embryonic lethality at E13.5 with dramatically reduced spongiotrophoblast layer and collapse of placental blood vessels; transcriptional activity of PPARγ is reduced in Rap250-null fibroblasts, indicating RAP250 is an essential coactivator for PPARγ in placental development.","method":"Gene targeting/knockout in mice, histological analysis, embryonic fibroblast transcriptional assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined developmental phenotype and direct molecular readout (PPARγ target gene activity), replicated independently by a second lab (PMID 12368298)","pmids":["12556486","12368298"],"is_preprint":false},{"year":2002,"finding":"AIB3/NCOA6 deletion in mice causes embryonic lethality at E9.75–11.5 due to failure of placental labyrinthine development and cardiac hypoplasia, and significantly reduces PPARγ transcriptional activity in mouse embryonic fibroblasts, demonstrating non-redundancy with PBP/TRAP220 and SRC coactivators.","method":"Homologous recombination knockout in mice, histological analysis, transcriptional activity assays in MEFs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined phenotype, PPARγ activity measured, independently replicated by Antonson et al. (PMID 12556486)","pmids":["12368298"],"is_preprint":false},{"year":2004,"finding":"NRC (NCOA6) is required for cell survival: NRC-/- mouse embryonic fibroblasts undergo high-rate spontaneous apoptosis, and siRNA knockdown of NRC in wild-type MEFs enhances apoptosis, establishing NRC as a pro-survival/anti-apoptotic coregulator. NRC+/- mice on the 129S6 background show infertility, growth retardation, and a spontaneous wound healing defect.","method":"MEF derivation from knockout embryos, siRNA knockdown, apoptosis assays, phenotypic analysis of heterozygous mice","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO/KD with defined apoptosis phenotype, multiple in vivo readouts, multiple orthogonal methods","pmids":["15143190"],"is_preprint":false},{"year":2007,"finding":"NRC (NCOA6) dimerizes through a 146-amino-acid region including LxxLL-1; the activation domain AD2 (just C-terminal to LxxLL-1) is central for ligand-dependent nuclear receptor activation even though AD1 has greater intrinsic activity; NRC also functions as a coactivator for STAT-2 and p53, with p53 activation mediated indirectly through Trap80–NIF-1–NRC interaction.","method":"Domain mapping by deletion/mutation analysis, co-immunoprecipitation, reporter/transcriptional assays","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis and Co-IP, single lab, multiple functional readouts","pmids":["17536006"],"is_preprint":false},{"year":2007,"finding":"The C-terminal LXXLL-2 motif of NCoA6 (NCOA6) is specifically required for LXRα-regulated lipogenesis and cholesterol/bile acid homeostasis in the liver, but is dispensable for ERα function in mammary gland, demonstrating tissue- and nuclear receptor-specific roles of this motif in vivo.","method":"Knock-in mice carrying LXXLL-2 to AXXAL mutation, LXRα agonist treatment, target gene expression analysis, biochemical measurements of cholesterol and bile acids","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — precise in vivo mutagenesis of a functional motif with multiple orthogonal phenotypic readouts, single lab","pmids":["17908797"],"is_preprint":false},{"year":2008,"finding":"CCR4/CNOT6 and RCD1/CNOT9 (members of the CCR4-NOT complex) function as nuclear hormone receptor coactivators through interaction with NIF-1 (the NRC-interacting factor); CCR4 associates with NIF-1 in vivo and its coactivator effect on nuclear receptors (including RARα target genes Sox9 and HoxA1) is dependent on NIF-1, which in turn interacts with NRC (NCOA6).","method":"Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown, reporter assays, qRT-PCR of endogenous target genes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, siRNA rescue experiments, endogenous gene readouts; single lab, multiple methods","pmids":["18180299"],"is_preprint":false},{"year":2008,"finding":"RAP250 (NCOA6) directly interacts with Smad2 and Smad3 via its second LXXLL motif (interacting with the Smad MH2 domain), acts as a coactivator in TGF-β signaling, and mediates cross-talk between TGF-β and LXR signaling pathways; RAP250-null MEFs show reduced PAI-1 expression after TGF-β stimulation.","method":"Yeast two-hybrid screen, co-immunoprecipitation, domain mapping (LXXLL mutants, MH2 domain), luciferase reporter assays, RAP250-null MEF analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction assays, domain mutagenesis, KO MEF functional validation, multiple orthogonal methods in single study","pmids":["18263591"],"is_preprint":false},{"year":2010,"finding":"Expression of a dominant-negative fragment of NCOA6 (dnNCOA6, containing the N-terminal LXXLL motif) in transgenic mouse lens fiber cells causes reduced growth, disrupted fiber cell differentiation, impaired gamma-crystallin expression, cataract, and stalled denucleation (karyolysis), with apoptosis proceeding through both p53-dependent and p53-independent pathways; lens-specific conditional deletion of Ncoa6 also disrupts fiber cell differentiation, establishing a cell-autonomous role.","method":"Transgenic dominant-negative expression, lens-specific conditional knockout, genetic epistasis with p53 null background, caspase-3 activation, γ-H2AX and TUNEL assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two independent genetic models (dn transgenic + conditional KO), multiple orthogonal apoptosis markers, genetic epistasis","pmids":["20484573"],"is_preprint":false},{"year":2014,"finding":"Drosophila Ncoa6, a subunit of the Trithorax-related (Trr) histone H3K4 methyltransferase complex, is a direct binding partner of the Hippo pathway transcriptional coactivator Yorkie (Yki); Ncoa6, Trr, and Yki are all required for Hippo-mediated growth control and target gene expression; artificial tethering of Ncoa6 to the TEAD factor Scalloped (Sd) promotes tissue overgrowth even without Yki, and Yki/Ncoa6/Trr are required for normal H3K4 methylation at Hippo target gene loci.","method":"Protein interaction (co-IP/pulldown), genetic epistasis (loss-of-function), targeted tethering experiment, ChIP-based H3K4me measurement at target loci","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding demonstrated, chromatin modification assay (ChIP), tethering rescue, genetic epistasis; multiple orthogonal methods in one study","pmids":["25027438"],"is_preprint":false},{"year":2014,"finding":"Perturbation of NCOA6 (germline or cardiac-specific depletion) in mice causes severe dilated cardiomyopathy with impaired mitochondrial function and reduced activity of PPARδ, an NCOA6 target nuclear receptor critical for normal heart function; three independent non-synonymous NCOA6 mutations were identified in 10% of idiopathic DCM patients.","method":"Two independent mouse models (germline and cardiac-specific conditional KO/hypomorphic), echocardiography, mitochondrial function assays, PPARδ target gene expression, human patient sequencing","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two independent animal models with defined cardiac phenotype and molecular mechanism (PPARδ activity), multiple orthogonal methods","pmids":["25131203"],"is_preprint":false},{"year":2011,"finding":"NCOA6 is required for synergistic activation of CYP2C9 by PXR and HNF4α: NCOA6 interacts with HNF4α (identified by two-hybrid screen) and with PXR through its first LXXLL motif (GST pulldown and mammalian two-hybrid), bridges the HNF4α and PXR binding sites on the CYP2C9 promoter (ChIP), and its silencing abolishes synergistic induction of CYP2C9 but not CYP3A4.","method":"Yeast two-hybrid, GST pulldown, mammalian two-hybrid, ChIP, siRNA knockdown, promoter-reporter assays","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple interaction methods and ChIP, functional siRNA validation; single lab","pmids":["21292004"],"is_preprint":false},{"year":2017,"finding":"NCOA6 regulates Nampt (nicotinamide phosphoribosyltransferase) expression in pancreatic β-cells by cooperating with SREBP-1c at the Nampt promoter SRE element; ChIP confirmed direct NCOA6 recruitment to the SRE region; treatment with NMN (Nampt reaction product) partially rescues impaired glucose-stimulated insulin secretion in NCOA6+/- islets.","method":"Islet transcriptomics (NCOA6+/- vs +/+), promoter-reporter assays with SREBP-1c and NCOA6 co-expression, mutant promoter analysis, ChIP, NMN rescue experiment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays plus in vivo genetic model; single lab","pmids":["28435063"],"is_preprint":false},{"year":2019,"finding":"NCOA6 is essential for estradiol/ERα-activated GREB1 transcription in endometrial cells: NCOA6 associates with the GREB1 promoter and enhancer in an E2-independent manner, maintains chromatin looping and enhancer-promoter interactions at basal state, and upon E2 stimulation recruits ERα, p300, MLL4, and RNA Pol II to drive H3K4me1/3, H3K9ac, and H3K27ac increases and robust GREB1 transcription; NCOA6 knockout abolishes all these events.","method":"NCOA6 knockout (CRISPR), ChIP-seq/ChIP, chromosome conformation capture (chromatin looping), RNA Pol II and histone modification analysis, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — KO with multiple ChIP endpoints, chromatin looping measurement, and transcriptional readouts; multiple orthogonal methods in single study","pmids":["31744881"],"is_preprint":false}],"current_model":"NCOA6 (NRC/RAP250/AIB3) is a large nuclear scaffold coactivator that binds ligand-activated nuclear receptors and other transcription factors (Smad2/3, STAT-2, p53, SREBP-1c) via LXXLL motifs, nucleates multi-subunit chromatin-modifying complexes containing Set/MLL-family H3K4 methyltransferases (e.g., the Trr/MLL4 complex), promotes enhancer-promoter looping and recruitment of p300, MLL4, and RNA Pol II to target loci, and is an essential pro-survival coregulator whose loss causes embryonic lethality, placental failure, cardiac dysfunction (DCM), and tissue-specific differentiation defects."},"narrative":{"mechanistic_narrative":"NCOA6 (RAP250/NRC/AIB3) is a large nuclear scaffold coactivator that bridges ligand-activated nuclear receptors and other transcription factors to chromatin-modifying machinery, functioning as an essential, non-redundant pro-survival coregulator in development and tissue homeostasis [PMID:12556486, PMID:12368298, PMID:15143190]. It contacts nuclear receptors through multiple LXXLL (nuclear receptor box) motifs in a ligand-dependent manner and drives transcription via a glutamine-rich N-terminal activation domain, with distinct activation domains (AD1/AD2) and dimerization mediated by a region overlapping LXXLL-1 [PMID:10681503, PMID:17536006]. The individual LXXLL motifs are functionally specialized in vivo: the C-terminal LXXLL-2 is selectively required for LXRα-driven hepatic lipogenesis and cholesterol/bile acid homeostasis while dispensable for ERα in mammary gland, and the same motif mediates direct binding to the Smad2/3 MH2 domain to coactivate TGF-β signaling [PMID:17908797, PMID:18263591]. Beyond classical receptors, NCOA6 coactivates STAT-2 and p53, the latter indirectly through a Trap80–NIF-1–NCOA6 axis, and partners with the cotransducer NIF-1, which couples NCOA6 to CCR4-NOT (CNOT6/CNOT9) components [PMID:12215545, PMID:17536006, PMID:18180299]. Mechanistically, NCOA6 nucleates H3K4 methyltransferase activity: it is a subunit of the Drosophila Trr (MLL-family) complex and a direct partner of the Hippo coactivator Yorkie required for H3K4 methylation at target loci [PMID:25027438]. At mammalian enhancers it constitutively maintains enhancer-promoter chromatin looping and, upon estradiol stimulation, recruits ERα, p300, MLL4, and RNA Pol II to deposit activating histone marks (H3K4me1/3, H3K9ac, H3K27ac) and drive target gene transcription [PMID:31744881]. NCOA6 also bridges combinatorial transcription-factor inputs, mediating PXR/HNF4α synergy at CYP2C9 and SREBP-1c-dependent Nampt induction in β-cells [PMID:21292004, PMID:28435063]. Genetic loss is embryonic lethal with placental and cardiac failure, and tissue-specific perturbation causes dilated cardiomyopathy linked to reduced PPARδ activity; non-synonymous NCOA6 mutations were found in ~10% of idiopathic dilated cardiomyopathy patients [PMID:12556486, PMID:12368298, PMID:25131203].","teleology":[{"year":2000,"claim":"Established NCOA6 as a bona fide nuclear receptor coactivator, defining the LXXLL-based interaction and an intrinsic activation domain as the basis of its transcriptional enhancement.","evidence":"In vitro binding and transient transfection reporter assays in cells","pmids":["10681503"],"confidence":"Medium","gaps":["Did not resolve which endogenous target genes are controlled","No structural or in vivo functional context"]},{"year":2002,"claim":"Identified NIF-1 as a direct NCOA6 partner that extends coactivation to c-Fos/c-Jun, framing NCOA6 as the core of a larger cotransducer complex rather than a standalone bridge.","evidence":"Yeast two-hybrid, reciprocal Co-IP, in vitro binding, reporter assays","pmids":["12215545"],"confidence":"High","gaps":["Composition of the full NCOA6/NIF-1 complex unresolved","Endogenous target loci not mapped"]},{"year":2002,"claim":"Knockout established NCOA6 as developmentally essential and non-redundant with other coactivators, tying lethality to placental and cardiac failure and reduced PPARγ activity.","evidence":"Two independent mouse knockouts, histology, PPARγ transcriptional assays in MEFs","pmids":["12368298","12556486"],"confidence":"High","gaps":["Mechanism distinguishing placental vs cardiac requirement unclear","Direct chromatin recruitment not assessed"]},{"year":2004,"claim":"Demonstrated that NCOA6 is a pro-survival coregulator whose loss triggers apoptosis, linking its coactivator function to cell viability beyond transcriptional output.","evidence":"KO/siRNA MEF apoptosis assays and heterozygous mouse phenotyping","pmids":["15143190"],"confidence":"High","gaps":["Apoptotic effector pathway downstream of NCOA6 loss not defined","Survival target genes unidentified"]},{"year":2007,"claim":"Domain dissection assigned dimerization and activation functions to specific regions and expanded NCOA6 coactivation to STAT-2 and p53, with p53 acting indirectly via Trap80–NIF-1.","evidence":"Deletion/mutation domain mapping, Co-IP, reporter assays","pmids":["17536006"],"confidence":"Medium","gaps":["p53 link is indirect and not validated at endogenous targets","Single-lab domain assignments"]},{"year":2007,"claim":"In vivo motif mutagenesis showed individual LXXLL motifs are receptor- and tissue-specific, with LXXLL-2 dedicated to hepatic LXRα lipid metabolism but dispensable for ERα.","evidence":"Knock-in LXXLL-2 mutant mice, agonist treatment, metabolite and target-gene measurement","pmids":["17908797"],"confidence":"High","gaps":["Roles of other LXXLL motifs in vivo not addressed here","Chromatin-level mechanism not examined"]},{"year":2008,"claim":"Defined NCOA6 as a TGF-β pathway coactivator binding Smad2/3 MH2 domains via LXXLL-2, providing a mechanism for nuclear-receptor/TGF-β cross-talk.","evidence":"Y2H, Co-IP, domain mutagenesis, reporter assays, KO MEF target-gene analysis","pmids":["18263591"],"confidence":"High","gaps":["Genome-wide Smad-dependent targets not mapped","Physiological context of cross-talk untested"]},{"year":2008,"claim":"Connected the CCR4-NOT components CNOT6/CNOT9 to nuclear receptor coactivation through NIF-1–NCOA6, broadening the coactivator complex membership.","evidence":"Co-IP, siRNA rescue, endogenous target-gene qRT-PCR, reporter assays","pmids":["18180299"],"confidence":"Medium","gaps":["Stoichiometry of NCOA6/NIF-1/CCR4-NOT assembly unknown","Single-lab evidence"]},{"year":2010,"claim":"Cell-autonomous lens models showed NCOA6 is required for fiber-cell differentiation and crystallin expression, with apoptosis through both p53-dependent and -independent routes.","evidence":"Dominant-negative transgenic and conditional KO lens models, p53 epistasis, apoptosis markers","pmids":["20484573"],"confidence":"High","gaps":["Direct NCOA6 target genes in lens not defined","Receptor partner driving differentiation unclear"]},{"year":2011,"claim":"Showed NCOA6 bridges two transcription factors on a single promoter, mediating PXR/HNF4α synergy at CYP2C9 with gene specificity.","evidence":"Y2H, GST pulldown, mammalian two-hybrid, ChIP, siRNA, reporter assays","pmids":["21292004"],"confidence":"Medium","gaps":["Mechanism of promoter selectivity (CYP2C9 vs CYP3A4) unexplained","Single-lab study"]},{"year":2014,"claim":"Placed NCOA6 in the Trr/MLL-family H3K4 methyltransferase complex and as a direct Yorkie partner required for Hippo-pathway target H3K4 methylation, linking coactivation to a defined chromatin-modifying activity.","evidence":"Co-IP/pulldown, genetic epistasis, TEAD-tethering, ChIP H3K4me at target loci in Drosophila","pmids":["25027438"],"confidence":"High","gaps":["Conservation of Yki/YAP–NCOA6 link in mammals not tested here","Methyltransferase subunit interactions not biochemically mapped"]},{"year":2014,"claim":"Connected NCOA6 to cardiac function and human disease, tying dilated cardiomyopathy to impaired PPARδ-driven mitochondrial gene programs and identifying patient mutations.","evidence":"Two mouse models, echocardiography, mitochondrial assays, PPARδ target expression, patient sequencing","pmids":["25131203"],"confidence":"High","gaps":["Functional impact of specific patient variants not characterized","Direct PPARδ chromatin recruitment in heart not shown"]},{"year":2019,"claim":"Resolved the chromatin mechanism: NCOA6 constitutively maintains enhancer-promoter looping and, upon estrogen, recruits ERα, p300, MLL4 and Pol II to deposit activating histone marks and drive transcription.","evidence":"CRISPR KO, ChIP/ChIP-seq, chromosome conformation capture, histone-mark and Pol II analysis","pmids":["31744881"],"confidence":"High","gaps":["Generality of constitutive looping role at other loci untested","Order of recruitment events not fully dissected"]},{"year":null,"claim":"How NCOA6 selects specific transcription-factor partners and target loci across tissues, and how its distinct LXXLL motifs and activation domains are deployed combinatorially in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No genome-wide partner-resolved binding map across cell types","Structural basis of motif/partner specificity unknown","Causality of human DCM variants uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,8,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,14]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[14,10]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[10,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3,11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,11,13]}],"complexes":["Trr/MLL4 H3K4 methyltransferase complex"],"partners":["NIF-1","SMAD2","SMAD3","HNF4A","PXR","SREBF1","YORKIE/YKI","ESR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14686","full_name":"Nuclear receptor coactivator 6","aliases":["Activating signal cointegrator 2","ASC-2","Amplified in breast cancer protein 3","Cancer-amplified transcriptional coactivator ASC-2","Nuclear receptor coactivator RAP250","NRC RAP250","Nuclear receptor-activating protein, 250 kDa","Peroxisome proliferator-activated receptor-interacting protein","PPAR-interacting protein","PRIP","Thyroid hormone receptor-binding protein"],"length_aa":2063,"mass_kda":219.1,"function":"Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Coactivates expression in an agonist- and AF2-dependent manner. Involved in the coactivation of different nuclear receptors, such as for steroids (GR and ERs), retinoids (RARs and RXRs), thyroid hormone (TRs), vitamin D3 (VDR) and prostanoids (PPARs). Probably functions as a general coactivator, rather than just a nuclear receptor coactivator. May also be involved in the coactivation of the NF-kappa-B pathway. 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NRC-1 gas vesicle nanoparticles with GvpC fusion protein produced in E. coli.","date":"2022","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35230496","citation_count":8,"is_preprint":false},{"pmid":"19799870","id":"PMC_19799870","title":"Nrc of Streptococcus pneumoniae suppresses capsule expression and enhances anti-phagocytosis.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19799870","citation_count":8,"is_preprint":false},{"pmid":"28435063","id":"PMC_28435063","title":"Regulation of Nampt expression by transcriptional coactivator NCOA6 in pancreatic β-cells.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28435063","citation_count":7,"is_preprint":false},{"pmid":"33010908","id":"PMC_33010908","title":"Evaluation of predicted ration nutritional values by NRC (2001) and INRA (2018) feed evaluation systems, and implications for the prediction of milk response.","date":"2020","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/33010908","citation_count":7,"is_preprint":false},{"pmid":"10231710","id":"PMC_10231710","title":"Solution structure of a novel ETB receptor selective agonist ET1-21 [Cys(Acm)1,15, Aib3,11, Leu7] by nuclear magnetic resonance spectroscopy and molecular modelling.","date":"1999","source":"The journal of peptide research : official journal of the American Peptide Society","url":"https://pubmed.ncbi.nlm.nih.gov/10231710","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50888,"output_tokens":4073,"usd":0.10688,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12020,"output_tokens":4474,"usd":0.085975,"stage2_stop_reason":"end_turn"},"total_usd":0.192855,"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\": 2000,\n      \"finding\": \"RAP250 (NCOA6) interacts with nuclear receptors in a ligand-dependent or ligand-enhanced manner through a single LXXLL motif (nuclear receptor box), and contains a potent glutamine-rich N-terminal activation domain that enhances transcriptional activity of multiple nuclear receptors.\",\n      \"method\": \"In vitro binding assays and transient transfection/reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo interaction assays, reporter gene assays, single lab with two orthogonal methods\",\n      \"pmids\": [\"10681503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NRC-interacting factor 1 (NIF-1) directly interacts with NRC (NCOA6) in vivo and in vitro, and enhances ligand-dependent transcriptional activation by nuclear hormone receptors, c-Fos, and c-Jun through NRC, defining NIF-1 as a cotransducer that functions as part of or downstream of an NRC coactivator complex.\",\n      \"method\": \"Yeast two-hybrid cloning, reciprocal co-immunoprecipitation (in vivo), in vitro binding assays, transient transfection reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP (in vivo and in vitro), domain mapping, functional reporter assays; multiple orthogonal methods in single focused study\",\n      \"pmids\": [\"12215545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Genetic deletion of Rap250 (NCOA6) in mice causes embryonic lethality at E13.5 with dramatically reduced spongiotrophoblast layer and collapse of placental blood vessels; transcriptional activity of PPARγ is reduced in Rap250-null fibroblasts, indicating RAP250 is an essential coactivator for PPARγ in placental development.\",\n      \"method\": \"Gene targeting/knockout in mice, histological analysis, embryonic fibroblast transcriptional assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined developmental phenotype and direct molecular readout (PPARγ target gene activity), replicated independently by a second lab (PMID 12368298)\",\n      \"pmids\": [\"12556486\", \"12368298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AIB3/NCOA6 deletion in mice causes embryonic lethality at E9.75–11.5 due to failure of placental labyrinthine development and cardiac hypoplasia, and significantly reduces PPARγ transcriptional activity in mouse embryonic fibroblasts, demonstrating non-redundancy with PBP/TRAP220 and SRC coactivators.\",\n      \"method\": \"Homologous recombination knockout in mice, histological analysis, transcriptional activity assays in MEFs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined phenotype, PPARγ activity measured, independently replicated by Antonson et al. (PMID 12556486)\",\n      \"pmids\": [\"12368298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NRC (NCOA6) is required for cell survival: NRC-/- mouse embryonic fibroblasts undergo high-rate spontaneous apoptosis, and siRNA knockdown of NRC in wild-type MEFs enhances apoptosis, establishing NRC as a pro-survival/anti-apoptotic coregulator. NRC+/- mice on the 129S6 background show infertility, growth retardation, and a spontaneous wound healing defect.\",\n      \"method\": \"MEF derivation from knockout embryos, siRNA knockdown, apoptosis assays, phenotypic analysis of heterozygous mice\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO/KD with defined apoptosis phenotype, multiple in vivo readouts, multiple orthogonal methods\",\n      \"pmids\": [\"15143190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NRC (NCOA6) dimerizes through a 146-amino-acid region including LxxLL-1; the activation domain AD2 (just C-terminal to LxxLL-1) is central for ligand-dependent nuclear receptor activation even though AD1 has greater intrinsic activity; NRC also functions as a coactivator for STAT-2 and p53, with p53 activation mediated indirectly through Trap80–NIF-1–NRC interaction.\",\n      \"method\": \"Domain mapping by deletion/mutation analysis, co-immunoprecipitation, reporter/transcriptional assays\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis and Co-IP, single lab, multiple functional readouts\",\n      \"pmids\": [\"17536006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The C-terminal LXXLL-2 motif of NCoA6 (NCOA6) is specifically required for LXRα-regulated lipogenesis and cholesterol/bile acid homeostasis in the liver, but is dispensable for ERα function in mammary gland, demonstrating tissue- and nuclear receptor-specific roles of this motif in vivo.\",\n      \"method\": \"Knock-in mice carrying LXXLL-2 to AXXAL mutation, LXRα agonist treatment, target gene expression analysis, biochemical measurements of cholesterol and bile acids\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — precise in vivo mutagenesis of a functional motif with multiple orthogonal phenotypic readouts, single lab\",\n      \"pmids\": [\"17908797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CCR4/CNOT6 and RCD1/CNOT9 (members of the CCR4-NOT complex) function as nuclear hormone receptor coactivators through interaction with NIF-1 (the NRC-interacting factor); CCR4 associates with NIF-1 in vivo and its coactivator effect on nuclear receptors (including RARα target genes Sox9 and HoxA1) is dependent on NIF-1, which in turn interacts with NRC (NCOA6).\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown, reporter assays, qRT-PCR of endogenous target genes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, siRNA rescue experiments, endogenous gene readouts; single lab, multiple methods\",\n      \"pmids\": [\"18180299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RAP250 (NCOA6) directly interacts with Smad2 and Smad3 via its second LXXLL motif (interacting with the Smad MH2 domain), acts as a coactivator in TGF-β signaling, and mediates cross-talk between TGF-β and LXR signaling pathways; RAP250-null MEFs show reduced PAI-1 expression after TGF-β stimulation.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, domain mapping (LXXLL mutants, MH2 domain), luciferase reporter assays, RAP250-null MEF analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction assays, domain mutagenesis, KO MEF functional validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"18263591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Expression of a dominant-negative fragment of NCOA6 (dnNCOA6, containing the N-terminal LXXLL motif) in transgenic mouse lens fiber cells causes reduced growth, disrupted fiber cell differentiation, impaired gamma-crystallin expression, cataract, and stalled denucleation (karyolysis), with apoptosis proceeding through both p53-dependent and p53-independent pathways; lens-specific conditional deletion of Ncoa6 also disrupts fiber cell differentiation, establishing a cell-autonomous role.\",\n      \"method\": \"Transgenic dominant-negative expression, lens-specific conditional knockout, genetic epistasis with p53 null background, caspase-3 activation, γ-H2AX and TUNEL assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent genetic models (dn transgenic + conditional KO), multiple orthogonal apoptosis markers, genetic epistasis\",\n      \"pmids\": [\"20484573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila Ncoa6, a subunit of the Trithorax-related (Trr) histone H3K4 methyltransferase complex, is a direct binding partner of the Hippo pathway transcriptional coactivator Yorkie (Yki); Ncoa6, Trr, and Yki are all required for Hippo-mediated growth control and target gene expression; artificial tethering of Ncoa6 to the TEAD factor Scalloped (Sd) promotes tissue overgrowth even without Yki, and Yki/Ncoa6/Trr are required for normal H3K4 methylation at Hippo target gene loci.\",\n      \"method\": \"Protein interaction (co-IP/pulldown), genetic epistasis (loss-of-function), targeted tethering experiment, ChIP-based H3K4me measurement at target loci\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding demonstrated, chromatin modification assay (ChIP), tethering rescue, genetic epistasis; multiple orthogonal methods in one study\",\n      \"pmids\": [\"25027438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Perturbation of NCOA6 (germline or cardiac-specific depletion) in mice causes severe dilated cardiomyopathy with impaired mitochondrial function and reduced activity of PPARδ, an NCOA6 target nuclear receptor critical for normal heart function; three independent non-synonymous NCOA6 mutations were identified in 10% of idiopathic DCM patients.\",\n      \"method\": \"Two independent mouse models (germline and cardiac-specific conditional KO/hypomorphic), echocardiography, mitochondrial function assays, PPARδ target gene expression, human patient sequencing\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent animal models with defined cardiac phenotype and molecular mechanism (PPARδ activity), multiple orthogonal methods\",\n      \"pmids\": [\"25131203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NCOA6 is required for synergistic activation of CYP2C9 by PXR and HNF4α: NCOA6 interacts with HNF4α (identified by two-hybrid screen) and with PXR through its first LXXLL motif (GST pulldown and mammalian two-hybrid), bridges the HNF4α and PXR binding sites on the CYP2C9 promoter (ChIP), and its silencing abolishes synergistic induction of CYP2C9 but not CYP3A4.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, mammalian two-hybrid, ChIP, siRNA knockdown, promoter-reporter assays\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple interaction methods and ChIP, functional siRNA validation; single lab\",\n      \"pmids\": [\"21292004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NCOA6 regulates Nampt (nicotinamide phosphoribosyltransferase) expression in pancreatic β-cells by cooperating with SREBP-1c at the Nampt promoter SRE element; ChIP confirmed direct NCOA6 recruitment to the SRE region; treatment with NMN (Nampt reaction product) partially rescues impaired glucose-stimulated insulin secretion in NCOA6+/- islets.\",\n      \"method\": \"Islet transcriptomics (NCOA6+/- vs +/+), promoter-reporter assays with SREBP-1c and NCOA6 co-expression, mutant promoter analysis, ChIP, NMN rescue experiment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays plus in vivo genetic model; single lab\",\n      \"pmids\": [\"28435063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NCOA6 is essential for estradiol/ERα-activated GREB1 transcription in endometrial cells: NCOA6 associates with the GREB1 promoter and enhancer in an E2-independent manner, maintains chromatin looping and enhancer-promoter interactions at basal state, and upon E2 stimulation recruits ERα, p300, MLL4, and RNA Pol II to drive H3K4me1/3, H3K9ac, and H3K27ac increases and robust GREB1 transcription; NCOA6 knockout abolishes all these events.\",\n      \"method\": \"NCOA6 knockout (CRISPR), ChIP-seq/ChIP, chromosome conformation capture (chromatin looping), RNA Pol II and histone modification analysis, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — KO with multiple ChIP endpoints, chromatin looping measurement, and transcriptional readouts; multiple orthogonal methods in single study\",\n      \"pmids\": [\"31744881\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCOA6 (NRC/RAP250/AIB3) is a large nuclear scaffold coactivator that binds ligand-activated nuclear receptors and other transcription factors (Smad2/3, STAT-2, p53, SREBP-1c) via LXXLL motifs, nucleates multi-subunit chromatin-modifying complexes containing Set/MLL-family H3K4 methyltransferases (e.g., the Trr/MLL4 complex), promotes enhancer-promoter looping and recruitment of p300, MLL4, and RNA Pol II to target loci, and is an essential pro-survival coregulator whose loss causes embryonic lethality, placental failure, cardiac dysfunction (DCM), and tissue-specific differentiation defects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NCOA6 (RAP250/NRC/AIB3) is a large nuclear scaffold coactivator that bridges ligand-activated nuclear receptors and other transcription factors to chromatin-modifying machinery, functioning as an essential, non-redundant pro-survival coregulator in development and tissue homeostasis [#2, #3, #4]. It contacts nuclear receptors through multiple LXXLL (nuclear receptor box) motifs in a ligand-dependent manner and drives transcription via a glutamine-rich N-terminal activation domain, with distinct activation domains (AD1/AD2) and dimerization mediated by a region overlapping LXXLL-1 [#0, #5]. The individual LXXLL motifs are functionally specialized in vivo: the C-terminal LXXLL-2 is selectively required for LXR\\u03b1-driven hepatic lipogenesis and cholesterol/bile acid homeostasis while dispensable for ER\\u03b1 in mammary gland, and the same motif mediates direct binding to the Smad2/3 MH2 domain to coactivate TGF-\\u03b2 signaling [#6, #8]. Beyond classical receptors, NCOA6 coactivates STAT-2 and p53, the latter indirectly through a Trap80\\u2013NIF-1\\u2013NCOA6 axis, and partners with the cotransducer NIF-1, which couples NCOA6 to CCR4-NOT (CNOT6/CNOT9) components [#1, #5, #7]. Mechanistically, NCOA6 nucleates H3K4 methyltransferase activity: it is a subunit of the Drosophila Trr (MLL-family) complex and a direct partner of the Hippo coactivator Yorkie required for H3K4 methylation at target loci [#10]. At mammalian enhancers it constitutively maintains enhancer-promoter chromatin looping and, upon estradiol stimulation, recruits ER\\u03b1, p300, MLL4, and RNA Pol II to deposit activating histone marks (H3K4me1/3, H3K9ac, H3K27ac) and drive target gene transcription [#14]. NCOA6 also bridges combinatorial transcription-factor inputs, mediating PXR/HNF4\\u03b1 synergy at CYP2C9 and SREBP-1c-dependent Nampt induction in \\u03b2-cells [#12, #13]. Genetic loss is embryonic lethal with placental and cardiac failure, and tissue-specific perturbation causes dilated cardiomyopathy linked to reduced PPAR\\u03b4 activity; non-synonymous NCOA6 mutations were found in ~10% of idiopathic dilated cardiomyopathy patients [#2, #3, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established NCOA6 as a bona fide nuclear receptor coactivator, defining the LXXLL-based interaction and an intrinsic activation domain as the basis of its transcriptional enhancement.\",\n      \"evidence\": \"In vitro binding and transient transfection reporter assays in cells\",\n      \"pmids\": [\"10681503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve which endogenous target genes are controlled\", \"No structural or in vivo functional context\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified NIF-1 as a direct NCOA6 partner that extends coactivation to c-Fos/c-Jun, framing NCOA6 as the core of a larger cotransducer complex rather than a standalone bridge.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, in vitro binding, reporter assays\",\n      \"pmids\": [\"12215545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Composition of the full NCOA6/NIF-1 complex unresolved\", \"Endogenous target loci not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Knockout established NCOA6 as developmentally essential and non-redundant with other coactivators, tying lethality to placental and cardiac failure and reduced PPAR\\u03b3 activity.\",\n      \"evidence\": \"Two independent mouse knockouts, histology, PPAR\\u03b3 transcriptional assays in MEFs\",\n      \"pmids\": [\"12368298\", \"12556486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing placental vs cardiac requirement unclear\", \"Direct chromatin recruitment not assessed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that NCOA6 is a pro-survival coregulator whose loss triggers apoptosis, linking its coactivator function to cell viability beyond transcriptional output.\",\n      \"evidence\": \"KO/siRNA MEF apoptosis assays and heterozygous mouse phenotyping\",\n      \"pmids\": [\"15143190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apoptotic effector pathway downstream of NCOA6 loss not defined\", \"Survival target genes unidentified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Domain dissection assigned dimerization and activation functions to specific regions and expanded NCOA6 coactivation to STAT-2 and p53, with p53 acting indirectly via Trap80\\u2013NIF-1.\",\n      \"evidence\": \"Deletion/mutation domain mapping, Co-IP, reporter assays\",\n      \"pmids\": [\"17536006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p53 link is indirect and not validated at endogenous targets\", \"Single-lab domain assignments\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In vivo motif mutagenesis showed individual LXXLL motifs are receptor- and tissue-specific, with LXXLL-2 dedicated to hepatic LXR\\u03b1 lipid metabolism but dispensable for ER\\u03b1.\",\n      \"evidence\": \"Knock-in LXXLL-2 mutant mice, agonist treatment, metabolite and target-gene measurement\",\n      \"pmids\": [\"17908797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Roles of other LXXLL motifs in vivo not addressed here\", \"Chromatin-level mechanism not examined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined NCOA6 as a TGF-\\u03b2 pathway coactivator binding Smad2/3 MH2 domains via LXXLL-2, providing a mechanism for nuclear-receptor/TGF-\\u03b2 cross-talk.\",\n      \"evidence\": \"Y2H, Co-IP, domain mutagenesis, reporter assays, KO MEF target-gene analysis\",\n      \"pmids\": [\"18263591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide Smad-dependent targets not mapped\", \"Physiological context of cross-talk untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected the CCR4-NOT components CNOT6/CNOT9 to nuclear receptor coactivation through NIF-1\\u2013NCOA6, broadening the coactivator complex membership.\",\n      \"evidence\": \"Co-IP, siRNA rescue, endogenous target-gene qRT-PCR, reporter assays\",\n      \"pmids\": [\"18180299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of NCOA6/NIF-1/CCR4-NOT assembly unknown\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Cell-autonomous lens models showed NCOA6 is required for fiber-cell differentiation and crystallin expression, with apoptosis through both p53-dependent and -independent routes.\",\n      \"evidence\": \"Dominant-negative transgenic and conditional KO lens models, p53 epistasis, apoptosis markers\",\n      \"pmids\": [\"20484573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NCOA6 target genes in lens not defined\", \"Receptor partner driving differentiation unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed NCOA6 bridges two transcription factors on a single promoter, mediating PXR/HNF4\\u03b1 synergy at CYP2C9 with gene specificity.\",\n      \"evidence\": \"Y2H, GST pulldown, mammalian two-hybrid, ChIP, siRNA, reporter assays\",\n      \"pmids\": [\"21292004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of promoter selectivity (CYP2C9 vs CYP3A4) unexplained\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed NCOA6 in the Trr/MLL-family H3K4 methyltransferase complex and as a direct Yorkie partner required for Hippo-pathway target H3K4 methylation, linking coactivation to a defined chromatin-modifying activity.\",\n      \"evidence\": \"Co-IP/pulldown, genetic epistasis, TEAD-tethering, ChIP H3K4me at target loci in Drosophila\",\n      \"pmids\": [\"25027438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of Yki/YAP\\u2013NCOA6 link in mammals not tested here\", \"Methyltransferase subunit interactions not biochemically mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected NCOA6 to cardiac function and human disease, tying dilated cardiomyopathy to impaired PPAR\\u03b4-driven mitochondrial gene programs and identifying patient mutations.\",\n      \"evidence\": \"Two mouse models, echocardiography, mitochondrial assays, PPAR\\u03b4 target expression, patient sequencing\",\n      \"pmids\": [\"25131203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional impact of specific patient variants not characterized\", \"Direct PPAR\\u03b4 chromatin recruitment in heart not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the chromatin mechanism: NCOA6 constitutively maintains enhancer-promoter looping and, upon estrogen, recruits ER\\u03b1, p300, MLL4 and Pol II to deposit activating histone marks and drive transcription.\",\n      \"evidence\": \"CRISPR KO, ChIP/ChIP-seq, chromosome conformation capture, histone-mark and Pol II analysis\",\n      \"pmids\": [\"31744881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of constitutive looping role at other loci untested\", \"Order of recruitment events not fully dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NCOA6 selects specific transcription-factor partners and target loci across tissues, and how its distinct LXXLL motifs and activation domains are deployed combinatorially in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide partner-resolved binding map across cell types\", \"Structural basis of motif/partner specificity unknown\", \"Causality of human DCM variants uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 8, 14]},\n      {\"term_id\": \"GO:0003712\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [14, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [10, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 11, 13]}\n    ],\n    \"complexes\": [\"Trr/MLL4 H3K4 methyltransferase complex\"],\n    \"partners\": [\"NIF-1\", \"Smad2\", \"Smad3\", \"HNF4A\", \"PXR\", \"SREBF1\", \"Yorkie/Yki\", \"ESR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}