{"gene":"NR3C1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2021,"finding":"Cryo-EM structure of the GR-loading complex (Hsp90-Hsp70-Hop-GR) reveals that GR is partially unfolded and recognized through an extended binding pocket composed of Hsp90, Hsp70, and Hop; two Hsp70 molecules are present—one delivers GR and one scaffolds Hop; Hop interacts with all components and poises Hsp90 for ATP hydrolysis, establishing the molecular mechanism of GR loading and inactivation.","method":"Cryo-electron microscopy structure determination","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation, published in Nature, complemented by companion maturation complex structure in same issue","pmids":["34937942"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of the GR-maturation complex (GR-Hsp90-p23) shows that the GR ligand-binding domain is restored to a folded, ligand-bound conformation while threaded through the Hsp90 lumen; p23 directly stabilizes native GR via a C-terminal helix, enhancing ligand binding, revealing that Hsp90 can directly dictate client-specific folding outcomes.","method":"Cryo-electron microscopy structure determination","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation, published in Nature, complemented by companion loading complex structure in same issue","pmids":["34937936"],"is_preprint":false},{"year":2005,"finding":"In living cells, GR and HMGB1 interact only within chromatin (not in the nucleoplasm) and mutually decrease each other's mobility, forming a potentially stable GR-HMGB1-chromatin complex whose disassembly requires active, ATP-consuming processes; this demonstrates kinetic cooperativity between transcription factors in chromatin binding.","method":"FRAP (fluorescence recovery after photobleaching) in living cells, fluorescence correlation spectroscopy","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell imaging with multiple biophysical methods (FRAP, FCS), rigorous controls distinguishing nucleoplasmic vs. chromatin interactions","pmids":["15808513"],"is_preprint":false},{"year":2011,"finding":"Coactivation of GR and RELA (p65/NF-κB) results in their mutual association with novel genomic binding sites not occupied by either factor alone; these novel sites predominantly cluster with target genes antagonized by the opposing factor, demonstrating that GR-NF-κB crosstalk alters the repertoire of binding sites and regulated genes in a mutually dependent manner.","method":"Genome-wide ChIP-seq for GR and p65 binding sites combined with gene expression profiling","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with expression profiling, mechanistic reciprocal dependency demonstrated","pmids":["21750107"],"is_preprint":false},{"year":2009,"finding":"GRβ isoform has intrinsic, GRα-independent transcriptional activity on endogenous genes, regulating a large and mostly distinct set of genes compared with GRα; in HCT116 cells, GRβ nuclear translocation and activation by RU486 (previously reported) was not observed.","method":"Stable EGFP-GRβ expression in HeLa cells, microarray gene expression analysis, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable cell line with microarray profiling, single lab, two orthogonal methods but no in vitro reconstitution","pmids":["19248771"],"is_preprint":false},{"year":2019,"finding":"Biochemical purification of the nuclear GR complex identified KDM1A (LSD1) as an integral component; in cell-free assays, GR modulates KDM1A-catalyzed H3K4 progressive demethylation by limiting loss of H3K4me1; in cells, KDM1A removes preprogrammed H3K4me2 at GR binding sites, promoting GR chromatin binding and glucocorticoid-induced gene transcription.","method":"Biochemical purification of GR nuclear complex, cell-free histone demethylation assay, ChIP-seq, KDM1A inhibition","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of enzymatic activity combined with biochemical purification and genome-wide ChIP-seq, multiple orthogonal methods","pmids":["31216473"],"is_preprint":false},{"year":2002,"finding":"GR is transcriptionally functional throughout the entire cell cycle including G2; GR responsiveness is repressed in mitosis due to chromatin condensation rather than cell cycle-dependent GR phosphorylation; the previously reported G2/M resistance was an artifact of the synchronization drug Hoechst 33342, which independently interferes with GR-dependent transcription.","method":"Cell synchronization, stable and transient MMTV-GFP reporter assays, flow cytometry in asynchronous populations","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple promoters and reporters tested, flow cytometry in asynchronous cells, single lab","pmids":["12040020"],"is_preprint":false},{"year":2007,"finding":"STAT5A (but not STAT5B) forms a complex with GR in adipocytes; the STAT5A associated with GR in the nucleus is tyrosine-phosphorylated; formation of nuclear STAT5A/GR complexes is regulated in both cytosol and nucleus at distinct times during adipogenesis and in mature adipocytes.","method":"Subcellular fractionation, co-immunoprecipitation, Western blotting in 3T3-L1 and 3T3-F442A adipocytes","journal":"Obesity","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with subcellular fractionation, two cell line models, single lab","pmids":["17372307"],"is_preprint":false},{"year":2011,"finding":"Multiple 5'-untranslated first exons of the GR gene drive alternative promoters that are differentially regulated by growth factor and depolarization-induced signaling; these alternative first exon transcripts differentially control RNA stability and translation efficiency, indicating multilayered transcriptional and posttranscriptional control of GR expression.","method":"Promoter characterization, luciferase reporter assays, mRNA stability assays, translation efficiency measurement in mouse tissues","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (reporter, mRNA stability, translation), single lab","pmids":["21527501"],"is_preprint":false},{"year":2021,"finding":"In skeletal muscle, GR and Myod1 co-occupy numerous muscle-specific enhancers; GR negatively controls muscle mass and strength by down-regulating anabolic pathways; enhancer-promoter communication occurs via CpG-bound transcription factor Nrf1 and Ctcf-anchored chromatin loops in a myofiber-specific manner.","method":"ChIP-seq, ATAC-seq, 3D chromatin capture (4C-seq/HiC), GR knockout mice, functional strength and mass measurements","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genomics approaches combined with in vivo knockout phenotype and functional measurements, single lab but multiple orthogonal methods","pmids":["33836079"],"is_preprint":false},{"year":2002,"finding":"Nuclear GR protein levels and DNA binding are decreased in aged rat hippocampus; chaperone proteins responsible for GR nuclear translocation are also decreased; intracellular trafficking of GR is specifically impaired in hippocampus with aging but not in hypothalamus, indicating regional specificity.","method":"Nuclear/cytosolic fractionation, Western blotting, electrophoretic mobility shift assay (EMSA) for DNA binding, immunostaining","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation with functional DNA-binding assay and chaperone measurements, single lab, two orthogonal methods","pmids":["11897693"],"is_preprint":false},{"year":2017,"finding":"Zebrafish nr3c1 null mutants generated by CRISPR/Cas9 are viable but show HPI axis dysregulation (elevated cortisol, overactivated crh and pomca), unresponsiveness to mechanical stressors, and abolished inflammatory and anti-inflammatory cytokine responses after intestinal damage, demonstrating GR's dual pro- and anti-inflammatory role in vivo.","method":"CRISPR/Cas9 knockout, cortisol measurement, qPCR, dextran sodium sulfate intestinal damage model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean null mutant with multiple specific phenotypic readouts, single lab","pmids":["28663543"],"is_preprint":false},{"year":2022,"finding":"In zebrafish, GR tethering activity (not direct DNA binding) is the primary mechanism for glucocorticoid-induced Stat3 target gene expression; Stat3 target genes are induced by GC in wild-type and in a DNA-binding mutant gr line, but not in gr knockouts. Additionally, mineralocorticoid receptor (MR/nr3c2) is required for correct transcription of several GC-target genes, revealing interplay between GR and MR in GC-dependent transcription.","method":"Zebrafish mutant lines (knockout and DNA-binding point mutation), RNA-seq, glucocorticoid treatment","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dissection using two distinct mutant alleles with transcriptomic readout, single lab","pmids":["35269817"],"is_preprint":false},{"year":2008,"finding":"Human relaxin-2 activates GR in a manner independent of the membrane receptor RXFP1: RXFP1-inactive modified relaxin retained ability to inhibit TNF-α and IL-6 secretion via GR (blocked by RU-486 and D-06 antagonists), induced Ser211 phosphorylation of GR (a biomarker of agonist-related activation), and caused accumulation of phospho-GR in cytoplasm and nucleus.","method":"Modified relaxin (RXFP1-inactive), cytokine secretion assay with GR antagonists, Ser211-phospho-GR immunostaining in HeLa and endothelial cells, AP-1-luciferase assay","journal":"Regulatory peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and biochemical GR activation assays with receptor-inactive ligand, multiple cell types, single lab","pmids":["19101597"],"is_preprint":false},{"year":2023,"finding":"NR3C1 activation in pancreatic β-cells under glucolipotoxic conditions upregulates the RNA demethylase FTO, which reduces m6A modifications on mRNAs of four core autophagy genes (Atg12, Atg5, Atg16l2, Atg9a), leading to hyperactive autophagy and defective insulin secretion; FTO inhibition prevented NR3C1-driven excessive autophagy.","method":"RNA-seq, m6A MeRIP-seq, adenoviral NR3C1 overexpression, FTO inhibitor (Dac51), β-cell-specific NR3C1 overexpression mice, glucose tolerance testing","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics (transcriptome + m6A methylome) combined with pharmacological and genetic intervention in vivo and in vitro, single lab","pmids":["37039556"],"is_preprint":false},{"year":2024,"finding":"Cardiac GR mediates a diurnal rhythm in ventricular arrhythmia susceptibility: GR motifs are enriched in open chromatin at ZT12 (peak corticosteroid time) in ventricular myocytes; GR transcriptionally controls ion channel genes (Scn5a, Kcnh2, Gja1); both pharmacological GR blockade and cardiomyocyte-specific GR knockout abolished ion channel expression rhythms and eliminated ZT12 susceptibility to pacing-induced ventricular arrhythmia.","method":"ATAC-seq in ventricular myocyte nuclei, cardiomyocyte-specific GR knockout, electrophysiology, in silico biophysical modeling, pharmacological GR blockade","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with specific cellular phenotype combined with genome-wide chromatin accessibility, electrophysiology, and pharmacological validation, multiple orthogonal methods","pmids":["38533639"],"is_preprint":false},{"year":2021,"finding":"NR3C1 transcriptionally regulates ferroptosis-related genes HSPB1 and NCOA4 in glioblastoma cells; ginsenoside Rg5 directly targets NR3C1 and alters HSPB1 and NCOA4 expression to activate ferroptosis and inhibit glioma stem cell properties.","method":"RNA sequencing, transcription factor database intersection analysis, luciferase reporter assay, ChIP (implied by transcriptional regulation claim), intracranial xenograft assay","journal":"Phytomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, transcriptional regulation inferred from expression data and computational analysis; direct binding/ChIP evidence not clearly described in abstract","pmids":["38640858"],"is_preprint":false},{"year":2021,"finding":"Three NR3C1 mutations found in Cushing disease corticotroph tumors (p.R469X, p.D590G, p.Y693D) cause decreased DEX-induced GR nuclear translocation, increased cell proliferation, and attenuated suppression of POMC transcription; the p.R469X truncation also increases ACTH secretion compared to wild-type GR in corticotroph cells.","method":"Next-generation sequencing of patient tumors, Western blot, immunofluorescence for nuclear translocation, transfection in AtT-20 corticotroph cells, ACTH secretion assay","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutagenesis in relevant cell line with multiple readouts (localization, proliferation, POMC suppression, ACTH secretion), single lab","pmids":["34427636"],"is_preprint":false},{"year":2022,"finding":"GR acts as a transcription factor that binds to glucocorticoid response elements in the ERβ promoter, inhibiting ERβ transcription; this GR-mediated repression of the ERβ/TPH2 pathway reduces serotonin production in male stressed and Ahi1 knockout mice, contributing to depression-like behavior; Ahi1 regulates this pathway by controlling GR nuclear translocation upon stress.","method":"Dual-luciferase reporter assay for GR binding to ERβ promoter GREs, Western blot, immunofluorescence, gene knockdown, rescue assay","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated by reporter assay with GRE elements, combined with in vivo rescue, single lab","pmids":["35643536"],"is_preprint":false},{"year":2021,"finding":"FKBP4 regulates NRF2 protein levels (not mRNA) through modulating nuclear translocation of NR3C1/GR in breast cancer cells; naringenin suppresses autophagy and proliferation through the FKBP4/NR3C1/NRF2 signaling axis.","method":"siRNA knockdown, Western blot, nuclear translocation assay, in vitro and in vivo tumor models","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic link between FKBP4, NR3C1 translocation, and NRF2 protein levels inferred without direct binding or structural evidence","pmids":["35087512"],"is_preprint":false},{"year":2021,"finding":"miR-19b directly targets NR3C1 (confirmed by dual luciferase reporter assay); miR-19b inhibition or NR3C1 overexpression inhibited colon cancer cell proliferation, induced G1/S cell cycle blockade, apoptosis, and chemosensitivity to oxaliplatin via the PI3K/AKT/mTOR pathway.","method":"Dual luciferase reporter assay, Western blot, flow cytometry, MTT assay, in vivo xenograft","journal":"Clinical Medicine Insights. Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR reporter assay confirming miR-19b targeting of NR3C1, combined with gain/loss-of-function and in vivo data, single lab","pmids":["34017210"],"is_preprint":false},{"year":2016,"finding":"Haploinsufficiency for NR3C1 in BPDCN results in lowered GR expression; functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion, establishing GR as a haploinsufficient tumor suppressor in this leukemia subset.","method":"Molecular cloning, FISH/molecular cytogenetics, targeted deep sequencing, functional assays, gene expression profiling","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular characterization of deletion with functional consequence analysis, multiple methods, single study","pmids":["27060168"],"is_preprint":false},{"year":2019,"finding":"In adipocyte-specific GR knockout mice under chronic corticosterone treatment, GR drives lipolysis through Atgl via a novel intronic glucocorticoid-responsive element; loss of adipocyte GR results in healthy adipose expansion with diminished ectopic lipid deposition and improved insulin sensitivity, revealing GR-mediated inhibition of healthy adipose expansion in Cushing syndrome.","method":"Adipocyte-specific GR knockout mice, RNA-seq, GRE identification in Atgl intron, clinical sample analysis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific knockout with defined molecular mechanism (intronic GRE for Atgl) and multiple phenotypic readouts, single lab","pmids":["30649271"],"is_preprint":false},{"year":2024,"finding":"SE-driven NR3C1 forms phase-separated condensates (demonstrated by FRAP) and, together with Mediator, promotes SE-related gene transcription via phase separation in gastric cancer; NR3C1 co-occupies super-enhancers (by CUT&Tag) to drive 5-FU resistance-related gene expression.","method":"ChIP-seq, CUT&Tag sequencing, FRAP for phase separation, siRNA knockdown, patient-derived organoids, patient-derived xenografts","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP demonstrating phase separation, genome-wide binding data, functional drug response, single lab with multiple methods","pmids":["39731339"],"is_preprint":false}],"current_model":"NR3C1/GR is a ligand-activated nuclear receptor that, after Hsp70-mediated inactivation and chaperone-cycle-dependent remodelling through Hsp90-Hop (loading) and Hsp90-p23 (maturation) complexes, translocates to the nucleus where it binds glucocorticoid response elements directly or tethers to other transcription factors (NF-κB/p65, AP-1, STAT3) to activate or repress target genes; GR recruits KDM1A to remove H3K4me2 at enhancers to facilitate its own chromatin binding, cooperates with HMGB1 within chromatin via kinetic cooperativity, partners with STAT5A and Myod1 in a tissue-specific manner, and drives distinct physiological programs including diurnal cardiac ion channel rhythms, adipose lipolysis via an intronic GRE in Atgl, and pancreatic β-cell autophagy through an NR3C1–FTO–m6A–Atg gene axis; its activity is modulated by multiple post-translational modifications and isoforms (GRα/GRβ), and loss-of-function mutations impair nuclear translocation and transcriptional suppression of POMC in corticotroph cells."},"narrative":{"mechanistic_narrative":"NR3C1 encodes the glucocorticoid receptor (GR), a ligand-activated transcription factor that translates corticosteroid signals into broad transcriptional programs governing inflammation, metabolism, and tissue-specific physiology [PMID:21750107, PMID:38533639]. Before activation, GR is held in a chaperone cycle: an Hsp90-Hsp70-Hop loading complex recognizes a partially unfolded GR through an extended pocket and poises Hsp90 for ATP hydrolysis, inactivating the receptor, after which an Hsp90-p23 maturation complex threads the ligand-binding domain through the Hsp90 lumen and restores a folded, ligand-bound conformation stabilized by a p23 C-terminal helix [PMID:34937942, PMID:34937936]. Once nuclear, GR regulates genes both by direct binding to glucocorticoid response elements and by tethering to partner factors; in zebrafish, tethering rather than direct DNA binding drives Stat3 target induction, and it represses target promoters such as ERβ via GREs [PMID:35269817, PMID:35643536]. GR cross-talk reshapes the genome: coactivation with RELA/NF-κB redirects both factors to novel binding sites enriched near mutually antagonized genes [PMID:21750107], GR recruits the demethylase KDM1A to remove preprogrammed H3K4me2 at its binding sites to promote chromatin occupancy [PMID:31216473], it forms a stable, ATP-dependent GR-HMGB1-chromatin complex reflecting kinetic cooperativity [PMID:15808513], and it partners with STAT5A in adipocytes and Myod1 at muscle enhancers in a tissue-specific manner [PMID:17372307, PMID:33836079]. These activities drive distinct physiological outputs—diurnal cardiac ion-channel rhythms and arrhythmia susceptibility (Scn5a, Kcnh2, Gja1) [PMID:38533639], adipose lipolysis through an intronic GRE in Atgl [PMID:30649271], muscle mass control [PMID:33836079], and β-cell autophagy via an NR3C1-FTO-m6A-Atg gene axis [PMID:37039556]. Loss-of-function NR3C1 mutations identified in Cushing-disease corticotroph tumors impair DEX-induced nuclear translocation and attenuate suppression of POMC transcription [PMID:34427636].","teleology":[{"year":2002,"claim":"Established that GR transcriptional competence persists across the cell cycle and that apparent G2/M resistance was a synchronization-drug artifact, while regional aging studies showed chaperone-dependent GR nuclear trafficking can be selectively impaired.","evidence":"MMTV reporter assays with cell synchronization and flow cytometry; nuclear/cytosolic fractionation, EMSA, and chaperone measurement in aged rat hippocampus","pmids":["12040020","11897693"],"confidence":"Medium","gaps":["Does not identify which chaperones limit translocation with age","Does not link cell-cycle competence to specific target-gene programs"]},{"year":2005,"claim":"Resolved how GR engages chromatin in living cells, showing GR-HMGB1 association is chromatin-restricted and mutually mobility-limiting, defining kinetic cooperativity as a mechanism of transcription-factor chromatin binding.","evidence":"FRAP and fluorescence correlation spectroscopy in living cells","pmids":["15808513"],"confidence":"High","gaps":["Does not map which GR target loci require HMGB1","ATP-consuming disassembly process not molecularly defined"]},{"year":2011,"claim":"Defined how GR cross-talk and GR gene regulation are achieved, showing NF-κB coactivation redirects both factors to novel mutually-antagonistic sites, and that alternative first exons impose multilayered control of GR expression.","evidence":"Genome-wide GR/p65 ChIP-seq with expression profiling; promoter/luciferase, mRNA stability and translation-efficiency assays","pmids":["21750107","21527501"],"confidence":"High","gaps":["Mechanism that recruits both factors to new sites unresolved","Promoter-specific physiological consequences of isoform usage not established"]},{"year":2009,"claim":"Showed that the GRβ isoform has intrinsic, GRα-independent transcriptional activity over a largely distinct gene set, distinguishing isoform-specific programs.","evidence":"Stable EGFP-GRβ HeLa lines with microarray profiling and immunofluorescence","pmids":["19248771"],"confidence":"Medium","gaps":["Single cell-system; no in vitro reconstitution","GRβ DNA-binding/tethering mechanism not defined"]},{"year":2007,"claim":"Identified STAT5A as a phosphorylation-dependent, tissue-specific nuclear partner of GR in adipocytes, expanding the GR tethering repertoire.","evidence":"Subcellular fractionation, co-immunoprecipitation and Western blot in 3T3-L1/3T3-F442A adipocytes","pmids":["17372307"],"confidence":"Medium","gaps":["Co-IP without reciprocal or genome-wide validation","Target genes of the STAT5A/GR complex not defined"]},{"year":2008,"claim":"Demonstrated a non-canonical GR activation route in which RXFP1-independent relaxin signaling drives Ser211 phosphorylation and GR-dependent anti-inflammatory output.","evidence":"Receptor-inactive modified relaxin, cytokine assays with GR antagonists, phospho-Ser211 immunostaining and AP-1 reporter in HeLa/endothelial cells","pmids":["19101597"],"confidence":"Medium","gaps":["Direct relaxin-GR engagement not shown","Upstream kinase mediating Ser211 phosphorylation unidentified"]},{"year":2016,"claim":"Established GR as a haploinsufficient tumor suppressor in BPDCN, linking reduced GR dosage to corticoresistance and loss of EZH2 function.","evidence":"Molecular cytogenetics, targeted deep sequencing, and gene-expression profiling of BPDCN samples","pmids":["27060168"],"confidence":"Medium","gaps":["Mechanistic link from GR loss to EZH2 dysfunction not resolved","Causality of haploinsufficiency not tested by rescue"]},{"year":2019,"claim":"Showed how GR shapes its own chromatin access and defined a metabolic target program, identifying KDM1A as an integral nuclear-complex component that erases H3K4me2 to enable GR binding, and an intronic Atgl GRE driving adipose lipolysis.","evidence":"Biochemical complex purification, cell-free demethylation assay and ChIP-seq; adipocyte-specific GR knockout mice with RNA-seq and GRE mapping","pmids":["31216473","30649271"],"confidence":"High","gaps":["How GR licenses KDM1A specificity at select sites unclear","Whether KDM1A recruitment generalizes across GR targets not established"]},{"year":2021,"claim":"Resolved the molecular basis of GR chaperone-dependent maturation, capturing the Hsp90-Hsp70-Hop loading complex that inactivates partially unfolded GR and the Hsp90-p23 maturation complex that restores ligand-bound folded GR.","evidence":"Cryo-EM structures of GR loading and maturation complexes with functional validation","pmids":["34937942","34937936"],"confidence":"High","gaps":["Kinetics of in-cell cycling between complexes not resolved","How client-specific folding selectivity is encoded not fully defined"]},{"year":2021,"claim":"Extended GR's tissue-specific genomic logic, showing GR co-occupies muscle enhancers with Myod1 and negatively controls muscle mass via Nrf1/Ctcf-anchored enhancer-promoter loops.","evidence":"ChIP-seq, ATAC-seq, 4C/HiC, GR knockout mice with strength/mass measurements","pmids":["33836079"],"confidence":"High","gaps":["Direct GR control of loop architecture versus correlation not separated","Anabolic target genes mediating mass loss not fully enumerated"]},{"year":2021,"claim":"Defined disease-causing GR mutations in Cushing-disease corticotroph tumors that impair nuclear translocation and POMC suppression while increasing proliferation and ACTH output.","evidence":"Tumor sequencing with functional mutagenesis, translocation imaging, proliferation and ACTH assays in AtT-20 cells","pmids":["34427636"],"confidence":"Medium","gaps":["Structural basis of each mutation's defect not resolved","Single corticotroph cell line tested"]},{"year":2022,"claim":"Genetically dissected GR action mechanisms in vivo, showing tethering (not direct DNA binding) drives Stat3 target induction and that MR cooperates with GR for correct GC-target transcription, and that GR can directly repress the ERβ/TPH2 serotonin pathway.","evidence":"Zebrafish knockout and DNA-binding-mutant lines with RNA-seq; GRE reporter assays and in vivo rescue in stressed/Ahi1-knockout mice","pmids":["35269817","35643536"],"confidence":"Medium","gaps":["Tethering partners beyond Stat3 not enumerated","Mechanism of GR/MR cooperativity at shared targets undefined"]},{"year":2023,"claim":"Identified an NR3C1-FTO-m6A axis whereby GR activation upregulates FTO to demethylate core autophagy gene mRNAs, causing hyperactive autophagy and defective insulin secretion in β-cells.","evidence":"RNA-seq, m6A MeRIP-seq, adenoviral overexpression, FTO inhibitor and β-cell-specific NR3C1 overexpression mice with glucose tolerance testing","pmids":["37039556"],"confidence":"Medium","gaps":["Whether FTO is a direct GR transcriptional target not shown","Causal step linking autophagy to secretory failure not isolated"]},{"year":2024,"claim":"Established cardiac GR as the driver of diurnal ion-channel rhythms and arrhythmia risk, and revealed GR super-enhancer condensate formation as a transcriptional mechanism in cancer.","evidence":"ATAC-seq, cardiomyocyte-specific GR knockout, electrophysiology and pharmacology; FRAP, ChIP-seq and CUT&Tag with patient-derived models","pmids":["38533639","39731339"],"confidence":"High","gaps":["Whether condensate formation generalizes beyond gastric cancer untested","Direct GR binding at all rhythmic ion-channel loci not fully mapped"]},{"year":null,"claim":"How GR integrates ligand-cycling, chaperone state, post-translational modifications, and partner availability to select tissue-specific direct-binding versus tethering programs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting chaperone-cycle output to genomic program choice","PTM-to-target-gene mapping incomplete","Determinants of direct-GRE versus tethered mode not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,5,9,15,18,22]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[12,18,22]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,7,10,17]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,5,18,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[14,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,11]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14]}],"complexes":["Hsp90-Hsp70-Hop GR loading complex","Hsp90-p23 GR maturation complex","GR-HMGB1-chromatin complex","GR-KDM1A nuclear complex"],"partners":["HSP90","HSP70","HOP","P23","HMGB1","KDM1A","RELA","STAT5A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P04150","full_name":"Glucocorticoid receptor","aliases":["Nuclear receptor subfamily 3 group C member 1"],"length_aa":777,"mass_kda":85.7,"function":"Receptor for glucocorticoids (GC) (PubMed:27120390, PubMed:37478846). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors (PubMed:28139699). Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Involved in chromatin remodeling (PubMed:9590696). Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay (PubMed:25775514). Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth (By similarity) Has transcriptional activation and repression activity (PubMed:11435610, PubMed:15769988, PubMed:15866175, PubMed:17635946, PubMed:19141540, PubMed:19248771, PubMed:20484466, PubMed:21664385, PubMed:23820903). Mediates glucocorticoid-induced apoptosis (PubMed:23303127). Promotes accurate chromosome segregation during mitosis (PubMed:25847991). May act as a tumor suppressor (PubMed:25847991). May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic gene expression (By similarity) Acts as a dominant negative inhibitor of isoform Alpha (PubMed:20484466, PubMed:7769088, PubMed:8621628). Has intrinsic transcriptional activity independent of isoform Alpha when both isoforms are coexpressed (PubMed:19248771, PubMed:26711253). Loses this transcription modulator function on its own (PubMed:20484466). Has no hormone-binding activity (PubMed:8621628). May play a role in controlling glucose metabolism by maintaining insulin sensitivity (By similarity). Reduces hepatic gluconeogenesis through down-regulation of PEPCK in an isoform Alpha-dependent manner (PubMed:26711253). Directly regulates STAT1 expression in isoform Alpha-independent manner (PubMed:26711253) Has lower transcriptional activation activity than isoform Alpha. Exerts a dominant negative effect on isoform Alpha trans-repression mechanism (PubMed:20484466) Increases activity of isoform Alpha More effective than isoform Alpha in transcriptional activation, but not repression activity Has transcriptional activation activity Has transcriptional activation activity Has transcriptional activation activity Has highest transcriptional activation activity of all isoforms created by alternative initiation (PubMed:15866175, PubMed:23820903). Has transcriptional repression activity (PubMed:23303127). Mediates glucocorticoid-induced apoptosis (PubMed:23303127, PubMed:23820903) Has transcriptional activation activity Has transcriptional activation activity Has lowest transcriptional activation activity of all isoforms created by alternative initiation (PubMed:15866175, PubMed:23820903). 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rhamnosus GG and GR-1 to express HIV-inhibiting griffithsin.","date":"2018","source":"International journal of antimicrobial agents","url":"https://pubmed.ncbi.nlm.nih.gov/30040991","citation_count":17,"is_preprint":false},{"pmid":"30999951","id":"PMC_30999951","title":"NR3C1 gene polymorphisms are associated with high-altitude pulmonary edema in Han Chinese.","date":"2019","source":"Journal of physiological anthropology","url":"https://pubmed.ncbi.nlm.nih.gov/30999951","citation_count":17,"is_preprint":false},{"pmid":"29762667","id":"PMC_29762667","title":"Single Nucleotide Variations of the Human GR Gene Manifested as Pathologic Mutations or Polymorphisms.","date":"2018","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29762667","citation_count":16,"is_preprint":false},{"pmid":"34768862","id":"PMC_34768862","title":"p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34768862","citation_count":16,"is_preprint":false},{"pmid":"33284958","id":"PMC_33284958","title":"Clinical Correlates of the NR3C1 Gene Methylation at Various Stages of Psychosis.","date":"2021","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33284958","citation_count":16,"is_preprint":false},{"pmid":"31053779","id":"PMC_31053779","title":"gr/gr deletion predisposes to testicular germ cell tumour independently from altered spermatogenesis: results from the largest European study.","date":"2019","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/31053779","citation_count":16,"is_preprint":false},{"pmid":"30649271","id":"PMC_30649271","title":"Adipocyte GR Inhibits Healthy Adipose Expansion Through Multiple Mechanisms in Cushing Syndrome.","date":"2019","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30649271","citation_count":16,"is_preprint":false},{"pmid":"34831409","id":"PMC_34831409","title":"NR3C1 Glucocorticoid Receptor Gene Polymorphisms Are Associated with Membranous and IgA Nephropathies.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34831409","citation_count":15,"is_preprint":false},{"pmid":"35661969","id":"PMC_35661969","title":"Hypothalamic NR3C1 DNA methylation in rats exposed to prenatal stress.","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/35661969","citation_count":15,"is_preprint":false},{"pmid":"23684967","id":"PMC_23684967","title":"Transcript variants of the porcine glucocorticoid receptor gene (NR3C1).","date":"2013","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23684967","citation_count":15,"is_preprint":false},{"pmid":"36933666","id":"PMC_36933666","title":"DNA methylation in regulatory elements of the FKBP5 and NR3C1 gene in mother-child binomials with depression.","date":"2023","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/36933666","citation_count":13,"is_preprint":false},{"pmid":"38084958","id":"PMC_38084958","title":"Specificity protein 1 (Sp1) and glucocorticoid receptor (GR) stimulate bovine alphaherpesvirus 1 (BoHV-1) replication and cooperatively transactivate the immediate early transcription unit 1 promoter.","date":"2023","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/38084958","citation_count":13,"is_preprint":false},{"pmid":"31724909","id":"PMC_31724909","title":"Role of NR3C1 and GAS5 genes polymorphisms in multiple sclerosis.","date":"2019","source":"The International journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31724909","citation_count":13,"is_preprint":false},{"pmid":"33562675","id":"PMC_33562675","title":"The Glucocorticoid Receptor Gene (NR3C1) 9β SNP Is Associated with Posttraumatic Stress Disorder.","date":"2021","source":"Healthcare (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33562675","citation_count":13,"is_preprint":false},{"pmid":"32032633","id":"PMC_32032633","title":"Dual biomarkers long non-coding RNA GAS5 and its target, NR3C1, contribute to acute myeloid leukemia.","date":"2020","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32032633","citation_count":13,"is_preprint":false},{"pmid":"27530348","id":"PMC_27530348","title":"Elevated utero/placental GR/NR3C1 is not required for the induction of parturition in the dog.","date":"2016","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27530348","citation_count":13,"is_preprint":false},{"pmid":"34017210","id":"PMC_34017210","title":"MicroRNA-19b Downregulates NR3C1 and Enhances Oxaliplatin Chemoresistance in Colon Cancer via the PI3K/AKT/mTOR Pathway.","date":"2021","source":"Clinical Medicine Insights. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34017210","citation_count":13,"is_preprint":false},{"pmid":"30278546","id":"PMC_30278546","title":"Association between NR3C1 rs41423247 polymorphism and depression: A PRISMA-compliant meta-analysis.","date":"2018","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30278546","citation_count":12,"is_preprint":false},{"pmid":"24759788","id":"PMC_24759788","title":"Y chromosome gr/gr subdeletion is associated with lower semen quality in young men from the general Japanese population but not in fertile Japanese Men.","date":"2014","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/24759788","citation_count":12,"is_preprint":false},{"pmid":"24503296","id":"PMC_24503296","title":"Porcine glucocorticoid receptor (NR3C1) gene: tissue-specificity of transcriptional strength and glucocorticoid responsiveness of alternative promoters.","date":"2014","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24503296","citation_count":12,"is_preprint":false},{"pmid":"35269817","id":"PMC_35269817","title":"Zebrafish Mutant Lines Reveal the Interplay between nr3c1 and nr3c2 in the GC-Dependent Regulation of Gene Transcription.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35269817","citation_count":12,"is_preprint":false},{"pmid":"38533639","id":"PMC_38533639","title":"Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility.","date":"2024","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/38533639","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53004,"output_tokens":5995,"usd":0.124468,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14789,"output_tokens":4937,"usd":0.098685,"stage2_stop_reason":"end_turn"},"total_usd":0.223153,"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\": 2021,\n      \"finding\": \"Cryo-EM structure of the GR-loading complex (Hsp90-Hsp70-Hop-GR) reveals that GR is partially unfolded and recognized through an extended binding pocket composed of Hsp90, Hsp70, and Hop; two Hsp70 molecules are present—one delivers GR and one scaffolds Hop; Hop interacts with all components and poises Hsp90 for ATP hydrolysis, establishing the molecular mechanism of GR loading and inactivation.\",\n      \"method\": \"Cryo-electron microscopy structure determination\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation, published in Nature, complemented by companion maturation complex structure in same issue\",\n      \"pmids\": [\"34937942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of the GR-maturation complex (GR-Hsp90-p23) shows that the GR ligand-binding domain is restored to a folded, ligand-bound conformation while threaded through the Hsp90 lumen; p23 directly stabilizes native GR via a C-terminal helix, enhancing ligand binding, revealing that Hsp90 can directly dictate client-specific folding outcomes.\",\n      \"method\": \"Cryo-electron microscopy structure determination\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation, published in Nature, complemented by companion loading complex structure in same issue\",\n      \"pmids\": [\"34937936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In living cells, GR and HMGB1 interact only within chromatin (not in the nucleoplasm) and mutually decrease each other's mobility, forming a potentially stable GR-HMGB1-chromatin complex whose disassembly requires active, ATP-consuming processes; this demonstrates kinetic cooperativity between transcription factors in chromatin binding.\",\n      \"method\": \"FRAP (fluorescence recovery after photobleaching) in living cells, fluorescence correlation spectroscopy\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell imaging with multiple biophysical methods (FRAP, FCS), rigorous controls distinguishing nucleoplasmic vs. chromatin interactions\",\n      \"pmids\": [\"15808513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Coactivation of GR and RELA (p65/NF-κB) results in their mutual association with novel genomic binding sites not occupied by either factor alone; these novel sites predominantly cluster with target genes antagonized by the opposing factor, demonstrating that GR-NF-κB crosstalk alters the repertoire of binding sites and regulated genes in a mutually dependent manner.\",\n      \"method\": \"Genome-wide ChIP-seq for GR and p65 binding sites combined with gene expression profiling\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with expression profiling, mechanistic reciprocal dependency demonstrated\",\n      \"pmids\": [\"21750107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GRβ isoform has intrinsic, GRα-independent transcriptional activity on endogenous genes, regulating a large and mostly distinct set of genes compared with GRα; in HCT116 cells, GRβ nuclear translocation and activation by RU486 (previously reported) was not observed.\",\n      \"method\": \"Stable EGFP-GRβ expression in HeLa cells, microarray gene expression analysis, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable cell line with microarray profiling, single lab, two orthogonal methods but no in vitro reconstitution\",\n      \"pmids\": [\"19248771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biochemical purification of the nuclear GR complex identified KDM1A (LSD1) as an integral component; in cell-free assays, GR modulates KDM1A-catalyzed H3K4 progressive demethylation by limiting loss of H3K4me1; in cells, KDM1A removes preprogrammed H3K4me2 at GR binding sites, promoting GR chromatin binding and glucocorticoid-induced gene transcription.\",\n      \"method\": \"Biochemical purification of GR nuclear complex, cell-free histone demethylation assay, ChIP-seq, KDM1A inhibition\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of enzymatic activity combined with biochemical purification and genome-wide ChIP-seq, multiple orthogonal methods\",\n      \"pmids\": [\"31216473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"GR is transcriptionally functional throughout the entire cell cycle including G2; GR responsiveness is repressed in mitosis due to chromatin condensation rather than cell cycle-dependent GR phosphorylation; the previously reported G2/M resistance was an artifact of the synchronization drug Hoechst 33342, which independently interferes with GR-dependent transcription.\",\n      \"method\": \"Cell synchronization, stable and transient MMTV-GFP reporter assays, flow cytometry in asynchronous populations\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple promoters and reporters tested, flow cytometry in asynchronous cells, single lab\",\n      \"pmids\": [\"12040020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"STAT5A (but not STAT5B) forms a complex with GR in adipocytes; the STAT5A associated with GR in the nucleus is tyrosine-phosphorylated; formation of nuclear STAT5A/GR complexes is regulated in both cytosol and nucleus at distinct times during adipogenesis and in mature adipocytes.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, Western blotting in 3T3-L1 and 3T3-F442A adipocytes\",\n      \"journal\": \"Obesity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with subcellular fractionation, two cell line models, single lab\",\n      \"pmids\": [\"17372307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Multiple 5'-untranslated first exons of the GR gene drive alternative promoters that are differentially regulated by growth factor and depolarization-induced signaling; these alternative first exon transcripts differentially control RNA stability and translation efficiency, indicating multilayered transcriptional and posttranscriptional control of GR expression.\",\n      \"method\": \"Promoter characterization, luciferase reporter assays, mRNA stability assays, translation efficiency measurement in mouse tissues\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (reporter, mRNA stability, translation), single lab\",\n      \"pmids\": [\"21527501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In skeletal muscle, GR and Myod1 co-occupy numerous muscle-specific enhancers; GR negatively controls muscle mass and strength by down-regulating anabolic pathways; enhancer-promoter communication occurs via CpG-bound transcription factor Nrf1 and Ctcf-anchored chromatin loops in a myofiber-specific manner.\",\n      \"method\": \"ChIP-seq, ATAC-seq, 3D chromatin capture (4C-seq/HiC), GR knockout mice, functional strength and mass measurements\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genomics approaches combined with in vivo knockout phenotype and functional measurements, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33836079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Nuclear GR protein levels and DNA binding are decreased in aged rat hippocampus; chaperone proteins responsible for GR nuclear translocation are also decreased; intracellular trafficking of GR is specifically impaired in hippocampus with aging but not in hypothalamus, indicating regional specificity.\",\n      \"method\": \"Nuclear/cytosolic fractionation, Western blotting, electrophoretic mobility shift assay (EMSA) for DNA binding, immunostaining\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation with functional DNA-binding assay and chaperone measurements, single lab, two orthogonal methods\",\n      \"pmids\": [\"11897693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Zebrafish nr3c1 null mutants generated by CRISPR/Cas9 are viable but show HPI axis dysregulation (elevated cortisol, overactivated crh and pomca), unresponsiveness to mechanical stressors, and abolished inflammatory and anti-inflammatory cytokine responses after intestinal damage, demonstrating GR's dual pro- and anti-inflammatory role in vivo.\",\n      \"method\": \"CRISPR/Cas9 knockout, cortisol measurement, qPCR, dextran sodium sulfate intestinal damage model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean null mutant with multiple specific phenotypic readouts, single lab\",\n      \"pmids\": [\"28663543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In zebrafish, GR tethering activity (not direct DNA binding) is the primary mechanism for glucocorticoid-induced Stat3 target gene expression; Stat3 target genes are induced by GC in wild-type and in a DNA-binding mutant gr line, but not in gr knockouts. Additionally, mineralocorticoid receptor (MR/nr3c2) is required for correct transcription of several GC-target genes, revealing interplay between GR and MR in GC-dependent transcription.\",\n      \"method\": \"Zebrafish mutant lines (knockout and DNA-binding point mutation), RNA-seq, glucocorticoid treatment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dissection using two distinct mutant alleles with transcriptomic readout, single lab\",\n      \"pmids\": [\"35269817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human relaxin-2 activates GR in a manner independent of the membrane receptor RXFP1: RXFP1-inactive modified relaxin retained ability to inhibit TNF-α and IL-6 secretion via GR (blocked by RU-486 and D-06 antagonists), induced Ser211 phosphorylation of GR (a biomarker of agonist-related activation), and caused accumulation of phospho-GR in cytoplasm and nucleus.\",\n      \"method\": \"Modified relaxin (RXFP1-inactive), cytokine secretion assay with GR antagonists, Ser211-phospho-GR immunostaining in HeLa and endothelial cells, AP-1-luciferase assay\",\n      \"journal\": \"Regulatory peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and biochemical GR activation assays with receptor-inactive ligand, multiple cell types, single lab\",\n      \"pmids\": [\"19101597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR3C1 activation in pancreatic β-cells under glucolipotoxic conditions upregulates the RNA demethylase FTO, which reduces m6A modifications on mRNAs of four core autophagy genes (Atg12, Atg5, Atg16l2, Atg9a), leading to hyperactive autophagy and defective insulin secretion; FTO inhibition prevented NR3C1-driven excessive autophagy.\",\n      \"method\": \"RNA-seq, m6A MeRIP-seq, adenoviral NR3C1 overexpression, FTO inhibitor (Dac51), β-cell-specific NR3C1 overexpression mice, glucose tolerance testing\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics (transcriptome + m6A methylome) combined with pharmacological and genetic intervention in vivo and in vitro, single lab\",\n      \"pmids\": [\"37039556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cardiac GR mediates a diurnal rhythm in ventricular arrhythmia susceptibility: GR motifs are enriched in open chromatin at ZT12 (peak corticosteroid time) in ventricular myocytes; GR transcriptionally controls ion channel genes (Scn5a, Kcnh2, Gja1); both pharmacological GR blockade and cardiomyocyte-specific GR knockout abolished ion channel expression rhythms and eliminated ZT12 susceptibility to pacing-induced ventricular arrhythmia.\",\n      \"method\": \"ATAC-seq in ventricular myocyte nuclei, cardiomyocyte-specific GR knockout, electrophysiology, in silico biophysical modeling, pharmacological GR blockade\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with specific cellular phenotype combined with genome-wide chromatin accessibility, electrophysiology, and pharmacological validation, multiple orthogonal methods\",\n      \"pmids\": [\"38533639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NR3C1 transcriptionally regulates ferroptosis-related genes HSPB1 and NCOA4 in glioblastoma cells; ginsenoside Rg5 directly targets NR3C1 and alters HSPB1 and NCOA4 expression to activate ferroptosis and inhibit glioma stem cell properties.\",\n      \"method\": \"RNA sequencing, transcription factor database intersection analysis, luciferase reporter assay, ChIP (implied by transcriptional regulation claim), intracranial xenograft assay\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, transcriptional regulation inferred from expression data and computational analysis; direct binding/ChIP evidence not clearly described in abstract\",\n      \"pmids\": [\"38640858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Three NR3C1 mutations found in Cushing disease corticotroph tumors (p.R469X, p.D590G, p.Y693D) cause decreased DEX-induced GR nuclear translocation, increased cell proliferation, and attenuated suppression of POMC transcription; the p.R469X truncation also increases ACTH secretion compared to wild-type GR in corticotroph cells.\",\n      \"method\": \"Next-generation sequencing of patient tumors, Western blot, immunofluorescence for nuclear translocation, transfection in AtT-20 corticotroph cells, ACTH secretion assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutagenesis in relevant cell line with multiple readouts (localization, proliferation, POMC suppression, ACTH secretion), single lab\",\n      \"pmids\": [\"34427636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GR acts as a transcription factor that binds to glucocorticoid response elements in the ERβ promoter, inhibiting ERβ transcription; this GR-mediated repression of the ERβ/TPH2 pathway reduces serotonin production in male stressed and Ahi1 knockout mice, contributing to depression-like behavior; Ahi1 regulates this pathway by controlling GR nuclear translocation upon stress.\",\n      \"method\": \"Dual-luciferase reporter assay for GR binding to ERβ promoter GREs, Western blot, immunofluorescence, gene knockdown, rescue assay\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated by reporter assay with GRE elements, combined with in vivo rescue, single lab\",\n      \"pmids\": [\"35643536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FKBP4 regulates NRF2 protein levels (not mRNA) through modulating nuclear translocation of NR3C1/GR in breast cancer cells; naringenin suppresses autophagy and proliferation through the FKBP4/NR3C1/NRF2 signaling axis.\",\n      \"method\": \"siRNA knockdown, Western blot, nuclear translocation assay, in vitro and in vivo tumor models\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic link between FKBP4, NR3C1 translocation, and NRF2 protein levels inferred without direct binding or structural evidence\",\n      \"pmids\": [\"35087512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-19b directly targets NR3C1 (confirmed by dual luciferase reporter assay); miR-19b inhibition or NR3C1 overexpression inhibited colon cancer cell proliferation, induced G1/S cell cycle blockade, apoptosis, and chemosensitivity to oxaliplatin via the PI3K/AKT/mTOR pathway.\",\n      \"method\": \"Dual luciferase reporter assay, Western blot, flow cytometry, MTT assay, in vivo xenograft\",\n      \"journal\": \"Clinical Medicine Insights. Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR reporter assay confirming miR-19b targeting of NR3C1, combined with gain/loss-of-function and in vivo data, single lab\",\n      \"pmids\": [\"34017210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Haploinsufficiency for NR3C1 in BPDCN results in lowered GR expression; functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion, establishing GR as a haploinsufficient tumor suppressor in this leukemia subset.\",\n      \"method\": \"Molecular cloning, FISH/molecular cytogenetics, targeted deep sequencing, functional assays, gene expression profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular characterization of deletion with functional consequence analysis, multiple methods, single study\",\n      \"pmids\": [\"27060168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In adipocyte-specific GR knockout mice under chronic corticosterone treatment, GR drives lipolysis through Atgl via a novel intronic glucocorticoid-responsive element; loss of adipocyte GR results in healthy adipose expansion with diminished ectopic lipid deposition and improved insulin sensitivity, revealing GR-mediated inhibition of healthy adipose expansion in Cushing syndrome.\",\n      \"method\": \"Adipocyte-specific GR knockout mice, RNA-seq, GRE identification in Atgl intron, clinical sample analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific knockout with defined molecular mechanism (intronic GRE for Atgl) and multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"30649271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SE-driven NR3C1 forms phase-separated condensates (demonstrated by FRAP) and, together with Mediator, promotes SE-related gene transcription via phase separation in gastric cancer; NR3C1 co-occupies super-enhancers (by CUT&Tag) to drive 5-FU resistance-related gene expression.\",\n      \"method\": \"ChIP-seq, CUT&Tag sequencing, FRAP for phase separation, siRNA knockdown, patient-derived organoids, patient-derived xenografts\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP demonstrating phase separation, genome-wide binding data, functional drug response, single lab with multiple methods\",\n      \"pmids\": [\"39731339\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR3C1/GR is a ligand-activated nuclear receptor that, after Hsp70-mediated inactivation and chaperone-cycle-dependent remodelling through Hsp90-Hop (loading) and Hsp90-p23 (maturation) complexes, translocates to the nucleus where it binds glucocorticoid response elements directly or tethers to other transcription factors (NF-κB/p65, AP-1, STAT3) to activate or repress target genes; GR recruits KDM1A to remove H3K4me2 at enhancers to facilitate its own chromatin binding, cooperates with HMGB1 within chromatin via kinetic cooperativity, partners with STAT5A and Myod1 in a tissue-specific manner, and drives distinct physiological programs including diurnal cardiac ion channel rhythms, adipose lipolysis via an intronic GRE in Atgl, and pancreatic β-cell autophagy through an NR3C1–FTO–m6A–Atg gene axis; its activity is modulated by multiple post-translational modifications and isoforms (GRα/GRβ), and loss-of-function mutations impair nuclear translocation and transcriptional suppression of POMC in corticotroph cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR3C1 encodes the glucocorticoid receptor (GR), a ligand-activated transcription factor that translates corticosteroid signals into broad transcriptional programs governing inflammation, metabolism, and tissue-specific physiology [#3, #15]. Before activation, GR is held in a chaperone cycle: an Hsp90-Hsp70-Hop loading complex recognizes a partially unfolded GR through an extended pocket and poises Hsp90 for ATP hydrolysis, inactivating the receptor, after which an Hsp90-p23 maturation complex threads the ligand-binding domain through the Hsp90 lumen and restores a folded, ligand-bound conformation stabilized by a p23 C-terminal helix [#0, #1]. Once nuclear, GR regulates genes both by direct binding to glucocorticoid response elements and by tethering to partner factors; in zebrafish, tethering rather than direct DNA binding drives Stat3 target induction, and it represses target promoters such as ERβ via GREs [#12, #18]. GR cross-talk reshapes the genome: coactivation with RELA/NF-κB redirects both factors to novel binding sites enriched near mutually antagonized genes [#3], GR recruits the demethylase KDM1A to remove preprogrammed H3K4me2 at its binding sites to promote chromatin occupancy [#5], it forms a stable, ATP-dependent GR-HMGB1-chromatin complex reflecting kinetic cooperativity [#2], and it partners with STAT5A in adipocytes and Myod1 at muscle enhancers in a tissue-specific manner [#7, #9]. These activities drive distinct physiological outputs—diurnal cardiac ion-channel rhythms and arrhythmia susceptibility (Scn5a, Kcnh2, Gja1) [#15], adipose lipolysis through an intronic GRE in Atgl [#22], muscle mass control [#9], and β-cell autophagy via an NR3C1-FTO-m6A-Atg gene axis [#14]. Loss-of-function NR3C1 mutations identified in Cushing-disease corticotroph tumors impair DEX-induced nuclear translocation and attenuate suppression of POMC transcription [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that GR transcriptional competence persists across the cell cycle and that apparent G2/M resistance was a synchronization-drug artifact, while regional aging studies showed chaperone-dependent GR nuclear trafficking can be selectively impaired.\",\n      \"evidence\": \"MMTV reporter assays with cell synchronization and flow cytometry; nuclear/cytosolic fractionation, EMSA, and chaperone measurement in aged rat hippocampus\",\n      \"pmids\": [\"12040020\", \"11897693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify which chaperones limit translocation with age\", \"Does not link cell-cycle competence to specific target-gene programs\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved how GR engages chromatin in living cells, showing GR-HMGB1 association is chromatin-restricted and mutually mobility-limiting, defining kinetic cooperativity as a mechanism of transcription-factor chromatin binding.\",\n      \"evidence\": \"FRAP and fluorescence correlation spectroscopy in living cells\",\n      \"pmids\": [\"15808513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not map which GR target loci require HMGB1\", \"ATP-consuming disassembly process not molecularly defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined how GR cross-talk and GR gene regulation are achieved, showing NF-κB coactivation redirects both factors to novel mutually-antagonistic sites, and that alternative first exons impose multilayered control of GR expression.\",\n      \"evidence\": \"Genome-wide GR/p65 ChIP-seq with expression profiling; promoter/luciferase, mRNA stability and translation-efficiency assays\",\n      \"pmids\": [\"21750107\", \"21527501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism that recruits both factors to new sites unresolved\", \"Promoter-specific physiological consequences of isoform usage not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that the GRβ isoform has intrinsic, GRα-independent transcriptional activity over a largely distinct gene set, distinguishing isoform-specific programs.\",\n      \"evidence\": \"Stable EGFP-GRβ HeLa lines with microarray profiling and immunofluorescence\",\n      \"pmids\": [\"19248771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-system; no in vitro reconstitution\", \"GRβ DNA-binding/tethering mechanism not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified STAT5A as a phosphorylation-dependent, tissue-specific nuclear partner of GR in adipocytes, expanding the GR tethering repertoire.\",\n      \"evidence\": \"Subcellular fractionation, co-immunoprecipitation and Western blot in 3T3-L1/3T3-F442A adipocytes\",\n      \"pmids\": [\"17372307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP without reciprocal or genome-wide validation\", \"Target genes of the STAT5A/GR complex not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated a non-canonical GR activation route in which RXFP1-independent relaxin signaling drives Ser211 phosphorylation and GR-dependent anti-inflammatory output.\",\n      \"evidence\": \"Receptor-inactive modified relaxin, cytokine assays with GR antagonists, phospho-Ser211 immunostaining and AP-1 reporter in HeLa/endothelial cells\",\n      \"pmids\": [\"19101597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct relaxin-GR engagement not shown\", \"Upstream kinase mediating Ser211 phosphorylation unidentified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established GR as a haploinsufficient tumor suppressor in BPDCN, linking reduced GR dosage to corticoresistance and loss of EZH2 function.\",\n      \"evidence\": \"Molecular cytogenetics, targeted deep sequencing, and gene-expression profiling of BPDCN samples\",\n      \"pmids\": [\"27060168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from GR loss to EZH2 dysfunction not resolved\", \"Causality of haploinsufficiency not tested by rescue\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed how GR shapes its own chromatin access and defined a metabolic target program, identifying KDM1A as an integral nuclear-complex component that erases H3K4me2 to enable GR binding, and an intronic Atgl GRE driving adipose lipolysis.\",\n      \"evidence\": \"Biochemical complex purification, cell-free demethylation assay and ChIP-seq; adipocyte-specific GR knockout mice with RNA-seq and GRE mapping\",\n      \"pmids\": [\"31216473\", \"30649271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GR licenses KDM1A specificity at select sites unclear\", \"Whether KDM1A recruitment generalizes across GR targets not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the molecular basis of GR chaperone-dependent maturation, capturing the Hsp90-Hsp70-Hop loading complex that inactivates partially unfolded GR and the Hsp90-p23 maturation complex that restores ligand-bound folded GR.\",\n      \"evidence\": \"Cryo-EM structures of GR loading and maturation complexes with functional validation\",\n      \"pmids\": [\"34937942\", \"34937936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of in-cell cycling between complexes not resolved\", \"How client-specific folding selectivity is encoded not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended GR's tissue-specific genomic logic, showing GR co-occupies muscle enhancers with Myod1 and negatively controls muscle mass via Nrf1/Ctcf-anchored enhancer-promoter loops.\",\n      \"evidence\": \"ChIP-seq, ATAC-seq, 4C/HiC, GR knockout mice with strength/mass measurements\",\n      \"pmids\": [\"33836079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GR control of loop architecture versus correlation not separated\", \"Anabolic target genes mediating mass loss not fully enumerated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined disease-causing GR mutations in Cushing-disease corticotroph tumors that impair nuclear translocation and POMC suppression while increasing proliferation and ACTH output.\",\n      \"evidence\": \"Tumor sequencing with functional mutagenesis, translocation imaging, proliferation and ACTH assays in AtT-20 cells\",\n      \"pmids\": [\"34427636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of each mutation's defect not resolved\", \"Single corticotroph cell line tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetically dissected GR action mechanisms in vivo, showing tethering (not direct DNA binding) drives Stat3 target induction and that MR cooperates with GR for correct GC-target transcription, and that GR can directly repress the ERβ/TPH2 serotonin pathway.\",\n      \"evidence\": \"Zebrafish knockout and DNA-binding-mutant lines with RNA-seq; GRE reporter assays and in vivo rescue in stressed/Ahi1-knockout mice\",\n      \"pmids\": [\"35269817\", \"35643536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tethering partners beyond Stat3 not enumerated\", \"Mechanism of GR/MR cooperativity at shared targets undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an NR3C1-FTO-m6A axis whereby GR activation upregulates FTO to demethylate core autophagy gene mRNAs, causing hyperactive autophagy and defective insulin secretion in β-cells.\",\n      \"evidence\": \"RNA-seq, m6A MeRIP-seq, adenoviral overexpression, FTO inhibitor and β-cell-specific NR3C1 overexpression mice with glucose tolerance testing\",\n      \"pmids\": [\"37039556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FTO is a direct GR transcriptional target not shown\", \"Causal step linking autophagy to secretory failure not isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established cardiac GR as the driver of diurnal ion-channel rhythms and arrhythmia risk, and revealed GR super-enhancer condensate formation as a transcriptional mechanism in cancer.\",\n      \"evidence\": \"ATAC-seq, cardiomyocyte-specific GR knockout, electrophysiology and pharmacology; FRAP, ChIP-seq and CUT&Tag with patient-derived models\",\n      \"pmids\": [\"38533639\", \"39731339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether condensate formation generalizes beyond gastric cancer untested\", \"Direct GR binding at all rhythmic ion-channel loci not fully mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GR integrates ligand-cycling, chaperone state, post-translational modifications, and partner availability to select tissue-specific direct-binding versus tethering programs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model connecting chaperone-cycle output to genomic program choice\", \"PTM-to-target-gene mapping incomplete\", \"Determinants of direct-GRE versus tethered mode not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 5, 9, 15, 18, 22]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [12, 18, 22]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 7, 10, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 5, 18, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [14, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\n      \"Hsp90-Hsp70-Hop GR loading complex\",\n      \"Hsp90-p23 GR maturation complex\",\n      \"GR-HMGB1-chromatin complex\",\n      \"GR-KDM1A nuclear complex\"\n    ],\n    \"partners\": [\n      \"HSP90\",\n      \"HSP70\",\n      \"HOP\",\n      \"p23\",\n      \"HMGB1\",\n      \"KDM1A\",\n      \"RELA\",\n      \"STAT5A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}