{"gene":"RORC","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1994,"finding":"RORγ (encoded by RORC) was identified as a novel member of the nuclear receptor superfamily, belonging to the ROR/RZR orphan receptor subfamily. It encodes a 560-amino-acid protein (~63 kDa) with a DNA-binding domain highly homologous to RORα/RZRα and RZRβ, and is most highly expressed in skeletal muscle, with the gene localized to human chromosome 1.","method":"cDNA cloning, Northern blot analysis, chromosomal localization","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — original molecular identification with sequence and expression characterization","pmids":["7811290"],"is_preprint":false},{"year":2000,"finding":"RORγ is required for thymocyte survival: mice lacking RORγ show loss of thymic Bcl-xL expression, increased apoptosis of CD4+CD8+ thymocytes, and failure of positive selection. RORγ is also essential for lymph node and Peyer's patch organogenesis, associated with loss of a CD3-CD4+CD45+ lymphoid tissue-inducer progenitor population.","method":"Targeted gene disruption (knockout mice), flow cytometry, TUNEL staining, Bcl-xL expression analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotypes, replicated across two independent KO studies","pmids":["10875923","10963675"],"is_preprint":false},{"year":2000,"finding":"RORγ knockout mice exhibit a 4-fold increase in thymocyte apoptosis associated with greatly reduced Bcl-XL expression, and a 6-fold rise in S-phase cells among thymocytes, establishing RORγ as a negative regulator of apoptosis in thymocytes, likely through transcriptional control of Bcl-XL.","method":"Targeted disruption of RORγ, TUNEL staining, annexin V staining, flow cytometry, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — KO with multiple orthogonal phenotypic readouts in independent study","pmids":["10963675"],"is_preprint":false},{"year":2008,"finding":"RORγt (the T-cell-specific isoform encoded by RORC) drives Th17 cell differentiation and IL-17A transcription. Foxp3, induced by high concentrations of TGF-β, directly binds RORγt protein and inhibits its transcriptional activity, thereby suppressing IL-17 production and Th17 differentiation. IL-6 and IL-21 relieve Foxp3-mediated inhibition of RORγt to promote Th17 differentiation.","method":"Genetic mouse models, co-immunoprecipitation, reporter assays, cytokine measurement, in vitro differentiation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal protein interaction demonstrated with functional rescue, replicated by independent lab","pmids":["18368049"],"is_preprint":false},{"year":2008,"finding":"Foxp3 directly interacts with RORγt through the exon 2 region of Foxp3 and inhibits RORγt-mediated IL-17A promoter activation. The exon 2 region and forkhead (FKH) domain of Foxp3 are both necessary for suppression of RORγt transcriptional activity on the IL-17A minimum promoter.","method":"Reporter gene assays (IL-17A promoter-luciferase), co-immunoprecipitation, domain mapping by deletion mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct protein interaction with domain mapping and functional promoter assays","pmids":["18434325"],"is_preprint":false},{"year":2008,"finding":"RORγt expression defines a previously unrecognized NKp46+CD3- lymphocyte subset in the intestinal lamina propria that produces IL-22 but has diminished degranulation and IFN-γ capacity. RORγt, previously known for its role in lymphoid tissue-inducer cell development, is thus required for this innate lymphoid subset's identity and function.","method":"Flow cytometry, intracellular cytokine staining, RORγt-GFP reporter mice, functional cytotoxicity and cytokine assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic reporter system with multiple functional readouts","pmids":["19029904"],"is_preprint":false},{"year":2009,"finding":"IL-27 suppresses Th17 development by inhibiting RORγt (RORc) expression in a STAT1-dependent manner. IL-27 acts upstream of RORγt transcription to block IL-17A and IL-17F production during TGF-β plus IL-6 or IL-23-driven Th17 differentiation in both mouse and human systems.","method":"Cytokine treatment, gene expression analysis, STAT1-deficient cells, in vivo EAE and DTH models with IL-27p28-deficient mice","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (STAT1 dependence) plus in vivo KO validation","pmids":["19380822"],"is_preprint":false},{"year":2009,"finding":"Notch ligand DLL4, induced on dendritic cells by TLR activation, upregulates Rorc expression in T cells and directly promotes IL-17 production. Both the Rorc and Il17 gene promoters are direct transcriptional Notch targets, establishing a DLL4-Notch-RORγt-IL-17 axis in Th17 differentiation.","method":"In vitro T cell culture with DLL4, gene expression analysis, promoter reporter assays for Rorc and Il17, Notch inhibitor experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct promoter targeting shown by reporter assay, single lab","pmids":["19494260"],"is_preprint":false},{"year":2010,"finding":"Hydroxycholesterols function as natural ligands of RORγ by binding in the ligand-binding domain (LBD) and promoting coactivator recruitment. Crystal structures of the RORγ LBD bound to multiple hydroxycholesterols reveal binding modes in the canonical active conformation; mutations disrupting hydroxycholesterol binding abolish constitutive RORγ activity.","method":"Crystal structure determination of RORγ LBD, biochemical coactivator recruitment assays, site-directed mutagenesis","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and biochemical validation","pmids":["20203100"],"is_preprint":false},{"year":2011,"finding":"Ursolic acid (UA), a natural small molecule, selectively inhibits RORγt transcriptional function, resulting in decreased IL-17 expression in developing and differentiated Th17 cells and amelioration of EAE in vivo. UA acts as a selective RORγt antagonist without broadly affecting other nuclear receptors.","method":"In vitro Th17 differentiation, reporter gene assays, IL-17 ELISA, EAE mouse model, selectivity profiling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional cellular assays with in vivo validation, single lab","pmids":["21566134"],"is_preprint":false},{"year":2014,"finding":"RORC (RORγt) directly silences PTGER2 (encoding prostaglandin receptor EP2) transcription in Th17 cells. Chromatin immunoprecipitation-sequencing (ChIP-seq) in mouse Th17 cells showed RORγt binds directly to the Ptger2 locus; RORC knockdown in human Th17 cells restored EP2 expression. In MS patients, reduced RORC binding to the PTGER2 promoter correlated with higher EP2 levels and a pathogenic Th17 phenotype (elevated IFN-γ and GM-CSF).","method":"ChIP-seq, RORC knockdown (siRNA), gene expression analysis, EP2 overexpression in primary human Th17 cells","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — direct ChIP-seq binding combined with loss-of-function and gain-of-function experiments in primary human cells","pmids":["24812667"],"is_preprint":false},{"year":2014,"finding":"RORγ (RORc) and RORα expressed in human skin serve as receptors for endogenously produced noncalcemic vitamin D derivatives (20(OH)D3 and 20,23(OH)2D3), which act as antagonists/inverse agonists. This was demonstrated by ligand binding assays, ROR-responsive element luciferase reporter assays, and molecular docking to crystal structures of RORα and RORγ LBDs, with 20(OH)D3 inhibiting IL-17 promoter activity in cells overexpressing RORγ.","method":"Stable cell line reporter assays, mammalian 2-hybrid LBD interaction assay, molecular docking, IL-17 promoter-luciferase assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 1-2 — structural modeling plus cell-based functional assays; binding not confirmed by direct crystallography","pmids":["24668754"],"is_preprint":false},{"year":2014,"finding":"RORc (RORγ) structural biology and pharmacology: the LBD of RORc adopts an active conformation and is amenable to small-molecule modulation. Inverse agonists occupying the ligand-binding pocket suppress coactivator recruitment and IL-17 production, providing a structural basis for targeting RORc in autoimmune disease.","method":"Review integrating crystal structures, biochemical assays, medicinal chemistry SAR, cellular IL-17 inhibition assays","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — synthesizes multiple crystal structure and functional studies; review paper","pmids":["24502334"],"is_preprint":false},{"year":2015,"finding":"Bi-allelic loss-of-function mutations in RORC in humans result in absence of IL-17A/F-producing T cells (explaining chronic mucocutaneous candidiasis) and unexpectedly impaired IFN-γ production, particularly by circulating γδ T cells and CD4+CCR6+CXCR3+ αβ T cells, demonstrating that both RORγ and RORγT isoforms are required for systemic immunity to Mycobacterium in humans.","method":"Human genetics (bi-allelic RORC mutations), immunophenotyping of patient cells, cytokine production assays, T cell subset analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — natural human loss-of-function with comprehensive immune characterization across multiple kindreds","pmids":["26160376"],"is_preprint":false},{"year":2015,"finding":"Potent and selective imidazo[1,5-a]pyridine and -pyrimidine compounds were identified as RORc inverse agonists with >300-fold selectivity over other ROR family members and other nuclear receptors, demonstrating that inverse agonist occupancy of the RORc LBD suppresses IL-17 production in human primary cells.","method":"Biochemical binding assays, cellular selectivity profiling, IL-17 suppression in human primary cells","journal":"Bioorganic & medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 2 — rigorous selectivity panel with primary human cell functional validation","pmids":["26048793"],"is_preprint":false},{"year":2016,"finding":"Transient pharmacological inhibition of ROR-γt (encoded by Rorc) selectively reduces cytokine production from TH17 cells but not from group 3 ILCs (ILC3s) in vivo. Temporal deletion of Rorc in mature ILCs did not impair their cytokine response, revealing that ongoing ROR-γt activity is differentially required for TH17 maintenance versus ILC3 function.","method":"Pharmacological ROR-γt inhibition in mice, conditional/temporal Rorc deletion, infection models, cytokine assays, IBD patient tissue analysis","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological approaches combined with in vivo infection models and human tissue validation","pmids":["26878233"],"is_preprint":false},{"year":2019,"finding":"The bile acid metabolite 3-oxoLCA inhibits TH17 cell differentiation by directly binding to RORγt (encoded by RORC) and blocking coactivator recruitment. Biochemical binding assays confirmed direct physical interaction between 3-oxoLCA and the RORγt LBD, establishing bile acid metabolites as endogenous RORγt ligands that modulate the TH17/Treg balance in the intestine.","method":"Bile acid metabolite library screen, direct binding assays (competitive binding to RORγt LBD), Th17 differentiation assays, in vivo intestinal lamina propria analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — direct ligand-binding demonstrated biochemically with functional cellular and in vivo validation","pmids":["31776512"],"is_preprint":false},{"year":2019,"finding":"NFAT proteins bind to newly defined regulatory elements at the human RORC locus and activate RORγt transcription in cooperation with NF-κB in CD4+ T cells. T cell receptor stimulation induces cyclosporine A-sensitive (calcineurin/NFAT-dependent) histone modifications and P300/CBP acetylase recruitment at these RORC regulatory elements; CRISPR/Cas9-guided deletion of these elements reduced RORγt expression.","method":"CRISPR/Cas9 deletion of regulatory elements, ChIP assays, NFAT overexpression/inhibition (cyclosporine A), histone modification analysis, reporter assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — CRISPR deletion of cis-elements combined with ChIP and functional assays","pmids":["31619674"],"is_preprint":false},{"year":2019,"finding":"RORγt+ iNKT and γδ-T cell subsets expressing a Th17-like profile are enriched in inflamed joints of spondyloarthritis patients and act as major IL-17 secretors. RORγt inhibition blocks IL-17 production by these innate-like T cells while selectively sparing IL-22-producing subsets, demonstrating that RORγt is required for the IL-17 effector program of both iNKT17 and γδ17 cells.","method":"Flow cytometry, gene expression profiling, RORγt pharmacological inhibition, cytokine production assays in patient cells and healthy donors","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibition with comprehensive phenotyping in primary human patient cells","pmids":["30602780"],"is_preprint":false},{"year":2022,"finding":"RORα cooperatively binds with RORγt to a previously unidentified Rorc cis-regulatory element and is required for maintenance of RORγt expression and Th17 effector function in peripheral tissues in vivo. RORα-deficient T cells show reduced RORγt expression and impaired Th17 responses, while cooperative RORα/RORγt binding to this element is essential for Th17 lineage stability.","method":"T cell-specific RORα conditional knockout mice, ChIP assays, CRISPR/Cas9 deletion of Rorc cis-regulatory element, flow cytometry, cytokine assays, in vivo tissue analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with ChIP and CRISPR deletion providing mechanistic and in vivo validation","pmids":["36243007"],"is_preprint":false}],"current_model":"RORC encodes the nuclear receptor RORγ (and its T-cell-specific isoform RORγt), which drives Th17 cell differentiation by directly binding the IL-17A promoter and silencing PTGER2 (EP2 receptor); its LBD binds endogenous ligands including hydroxycholesterols and bile acid metabolites (3-oxoLCA) that modulate coactivator recruitment; Foxp3 and ursolic acid antagonize its transcriptional activity through direct protein-protein interaction or LBD occupancy, respectively; NFAT/NF-κB and Notch signaling regulate its own transcription at defined RORC cis-regulatory elements; and in vivo it is essential for thymocyte survival via Bcl-xL regulation, lymphoid organogenesis, ILC3 identity, and both mucocutaneous (Candida) and systemic (Mycobacterium) immunity in humans."},"narrative":{"teleology":[{"year":1994,"claim":"Identification of RORγ as a novel orphan nuclear receptor established the existence of a third ROR subfamily member with tissue-selective expression, opening the question of its physiological function.","evidence":"cDNA cloning from human skeletal muscle with Northern blot expression profiling and chromosomal mapping","pmids":["7811290"],"confidence":"High","gaps":["No ligand or target gene identified","Function in immune cells unknown","No loss-of-function data"]},{"year":2000,"claim":"Gene-targeted deletion revealed that RORγ is required for thymocyte survival via Bcl-xL regulation and for lymph node/Peyer's patch organogenesis, establishing its first in vivo functions.","evidence":"Two independent RORγ-knockout mouse lines with flow cytometry, TUNEL staining, and lymphoid organ histology","pmids":["10875923","10963675"],"confidence":"High","gaps":["Mechanism of Bcl-xL transcriptional control not defined at the promoter level","Role of the T-cell-specific isoform (RORγt) not yet distinguished from full-length RORγ"]},{"year":2008,"claim":"RORγt was established as the lineage-defining transcription factor for Th17 differentiation, and Foxp3 was shown to directly bind and antagonize RORγt, explaining how TGF-β concentration reciprocally regulates Th17 versus Treg fate.","evidence":"Co-immunoprecipitation, domain-mapping mutagenesis, IL-17A promoter-luciferase assays, and in vitro Th17/Treg differentiation in mouse genetic models","pmids":["18368049","18434325"],"confidence":"High","gaps":["Structural basis of Foxp3–RORγt interaction unknown","Endogenous ligand for RORγt LBD not yet identified"]},{"year":2008,"claim":"Discovery that RORγt marks an intestinal NKp46+ innate lymphoid subset (later classified as ILC3) producing IL-22 expanded RORγt's role beyond adaptive Th17 cells to innate immunity.","evidence":"RORγt-GFP reporter mice with flow cytometry and intracellular cytokine staining of intestinal lamina propria lymphocytes","pmids":["19029904"],"confidence":"High","gaps":["Whether RORγt is continuously required for ILC3 maintenance versus initial specification was unresolved"]},{"year":2009,"claim":"Upstream regulation of RORC transcription was delineated: IL-27/STAT1 suppresses Rorc expression, while Notch/DLL4 signaling directly activates the Rorc promoter, placing RORγt as an integrator of cytokine and Notch inputs.","evidence":"STAT1-deficient T cells, Notch inhibition, Rorc promoter reporter assays, EAE and DTH in vivo models","pmids":["19380822","19494260"],"confidence":"High","gaps":["Full cis-regulatory architecture of the RORC locus not mapped","Notch-Rorc promoter binding shown by reporter assay only, not ChIP"]},{"year":2010,"claim":"Crystal structures of the RORγ LBD bound to hydroxycholesterols identified the first endogenous ligands and showed that ligand occupancy stabilizes the active conformation for coactivator recruitment, resolving the receptor's 'orphan' status.","evidence":"X-ray crystallography of RORγ LBD, site-directed mutagenesis, coactivator peptide recruitment assays","pmids":["20203100"],"confidence":"High","gaps":["Physiological relevance of hydroxycholesterol ligands in T cell differentiation not demonstrated in vivo","Selectivity among different oxysterol species unclear"]},{"year":2014,"claim":"ChIP-seq in Th17 cells revealed RORγt directly binds and silences PTGER2, uncovering a repressive function beyond its well-known activating role on IL-17, with clinical relevance in multiple sclerosis patients.","evidence":"ChIP-seq in mouse Th17 cells, RORC siRNA knockdown in human Th17 cells, EP2 gain-of-function, MS patient immunophenotyping","pmids":["24812667"],"confidence":"High","gaps":["Genome-wide repressive target repertoire of RORγt not fully catalogued","Mechanism of transcriptional repression (corepressor identity) not defined"]},{"year":2015,"claim":"Human bi-allelic RORC loss-of-function mutations demonstrated that both RORγ isoforms are essential for mucocutaneous and systemic immunity, causing candidiasis and mycobacterial susceptibility through combined loss of IL-17 and impaired IFN-γ production by γδ T cells.","evidence":"Identification of patients with homozygous RORC mutations, deep immunophenotyping, cytokine production assays across multiple kindreds","pmids":["26160376"],"confidence":"High","gaps":["How RORγ regulates IFN-γ production mechanistically remains undefined","Whether full-length RORγ versus RORγt is responsible for the mycobacterial phenotype is unresolved"]},{"year":2016,"claim":"Pharmacological and temporal genetic ablation showed that ongoing RORγt activity is required to maintain Th17 cytokine output but is dispensable for ILC3 effector function, resolving a key question about differential RORγt dependency across lymphocyte lineages.","evidence":"Pharmacological RORγt inhibition in mice, conditional/temporal Rorc deletion, infection models, IBD patient tissue analysis","pmids":["26878233"],"confidence":"High","gaps":["Molecular basis for differential RORγt dependency in ILC3 versus Th17 cells unknown","Long-term consequences of RORγt inhibition on ILC3 homeostasis not assessed"]},{"year":2019,"claim":"The bile acid metabolite 3-oxoLCA was identified as a direct endogenous RORγt antagonist linking gut microbial metabolism to Th17/Treg balance, and NFAT/NF-κB-dependent cis-regulatory elements at the RORC locus were mapped, completing a circuit from TCR signaling to RORγt expression.","evidence":"Bile acid library screen with direct LBD binding assays and intestinal Th17 analysis; CRISPR/Cas9 deletion of RORC cis-elements with ChIP and histone modification profiling in human CD4+ T cells","pmids":["31776512","31619674"],"confidence":"High","gaps":["In vivo contribution of 3-oxoLCA to intestinal RORγt regulation quantitatively uncertain","Interplay between NFAT/NF-κB elements and Notch-responsive elements at the RORC locus not integrated"]},{"year":2022,"claim":"RORα was found to cooperatively bind with RORγt to a Rorc cis-regulatory element required for sustained RORγt expression and Th17 lineage stability in vivo, revealing a feed-forward loop between the two ROR family members.","evidence":"T-cell-specific RORα conditional knockout, ChIP assays, CRISPR/Cas9 deletion of the cooperative binding element, in vivo Th17 analysis","pmids":["36243007"],"confidence":"High","gaps":["Structural basis of cooperative RORα/RORγt DNA binding unknown","Whether this feed-forward loop operates in ILC3 or other RORγt+ lineages not tested"]},{"year":null,"claim":"Major unresolved questions include the genome-wide repressive target repertoire of RORγt, the structural basis of the Foxp3–RORγt interaction, the mechanism by which RORγ controls IFN-γ production, and how microbiota-derived ligands quantitatively tune RORγt activity across different tissue niches in vivo.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of Foxp3–RORγt complex","Mechanism of RORγ-dependent IFN-γ regulation unknown","Quantitative in vivo contributions of individual endogenous ligands not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,4,8,10,16]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,8,10,17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8,11,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,4,8,10,17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,3,5,6,13,15,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,9,16,17]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,5]}],"complexes":[],"partners":["FOXP3","RORA","BCL2L1","IL17A","PTGER2"],"other_free_text":[]},"mechanistic_narrative":"RORC encodes the nuclear receptor RORγ and its T-cell-specific isoform RORγt, serving as a master transcriptional regulator of type-17 immunity and lymphoid organ development. RORγt directly activates IL-17A transcription and silences PTGER2 in Th17 cells, and its ligand-binding domain is occupied by endogenous hydroxycholesterols and bile acid metabolites (e.g., 3-oxoLCA) that modulate coactivator recruitment to tune transcriptional output [PMID:20203100, PMID:31776512]. In thymocytes, RORγ sustains Bcl-xL expression to prevent apoptosis and is essential for lymph node and Peyer's patch organogenesis, while in the periphery it defines ILC3 identity and drives IL-17 production by iNKT17, γδT17, and conventional Th17 cells [PMID:10875923, PMID:19029904, PMID:30602780]. Bi-allelic loss-of-function RORC mutations in humans cause chronic mucocutaneous candidiasis and susceptibility to mycobacterial disease due to combined loss of IL-17- and IFN-γ-producing T cell subsets [PMID:26160376]."},"prefetch_data":{"uniprot":{"accession":"P51449","full_name":"Nuclear receptor ROR-gamma","aliases":["Nuclear receptor RZR-gamma","Nuclear receptor subfamily 1 group F member 3","RAR-related orphan receptor C","Retinoid-related orphan receptor-gamma"],"length_aa":518,"mass_kda":58.2,"function":"Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of cellular differentiation, immunity, peripheral circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism (PubMed:19381306, PubMed:19965867, PubMed:20203100, PubMed:22789990, PubMed:26160376). Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively (PubMed:19965867, PubMed:22789990). Recruits distinct combinations of cofactors to target gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A (PubMed:19965867). Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA as positive or negative modulator of expression of genes encoding phase I and Phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as SULT1E1. Also plays a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC1 and PCK1 (PubMed:19965867). Regulates the rhythmic expression of PROX1 and promotes its nuclear localization (PubMed:19381306, PubMed:19965867, PubMed:20203100, PubMed:22789990, PubMed:26160376). Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity (PubMed:26160376) Nuclear receptor essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes and Peyer's patches (PubMed:21499262). Required for the generation of LTi (lymphoid tissue inducer) cells (By similarity). Regulates thymocyte survival through DNA-binding on ROREs of target gene promoter regions and recruitment of coactivaros via the AF-2 (By similarity). Also plays a key role, downstream of IL6 and TGFB and synergistically with RORA, for lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program (PubMed:21499262). Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus (PubMed:21499262). Plays a key role in tolerance to gut microbiota and foreign antigens in food by mediating differentiation of peripherally-induced regulatory T-cells (pTreg), which suppress inflammatory responses to commensal microorganisms and food proteins (By similarity). Specifically expressed in antigen-presenting cell populations, such as (1) type 3 innate lymphoid cells (ILC3s), which are required for tolerance to gut microbiota, (2) Thetis cells, also named Janus cells, which are enriched in gut lymph nodes during early life and are required for oral tolerance, and (3) a subset of dendritic cells (By similarity). Following activation by an unknown ligand in antigen-presenting cells, promotes recruitment of transcription regulators, such as PRDM16 or ZBTB46, and drives differentiation of pTreg cells, which maintain immune tolerance and prevent autoimmune diseases (By similarity). May also play a role in the pre-TCR activation cascade leading to the maturation of alpha/beta T-cells and may participate in the regulation of DNA accessibility in the TCR-J(alpha) locus (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P51449/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RORC","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RORC","total_profiled":1310},"omim":[{"mim_id":"621004","title":"AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 4; ADMIO4","url":"https://www.omim.org/entry/621004"},{"mim_id":"616622","title":"IMMUNODEFICIENCY 42; IMD42","url":"https://www.omim.org/entry/616622"},{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"614397","title":"MAJOR FACILITATOR SUPERFAMILY DOMAIN-CONTAINING PROTEIN 2A; MFSD2A","url":"https://www.omim.org/entry/614397"},{"mim_id":"612476","title":"BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR, ATF-LIKE; BATF","url":"https://www.omim.org/entry/612476"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":100.2}],"url":"https://www.proteinatlas.org/search/RORC"},"hgnc":{"alias_symbol":["RZRG","RORG","NR1F3","TOR"],"prev_symbol":[]},"alphafold":{"accession":"P51449","domains":[{"cath_id":"3.30.50.10","chopping":"20-123","consensus_level":"high","plddt":86.335,"start":20,"end":123},{"cath_id":"1.10.565.10","chopping":"266-505","consensus_level":"high","plddt":95.179,"start":266,"end":505}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51449","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51449-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51449-F1-predicted_aligned_error_v6.png","plddt_mean":74.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RORC","jax_strain_url":"https://www.jax.org/strain/search?query=RORC"},"sequence":{"accession":"P51449","fasta_url":"https://rest.uniprot.org/uniprotkb/P51449.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51449/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51449"}},"corpus_meta":[{"pmid":"16469695","id":"PMC_16469695","title":"TOR signaling in growth and metabolism.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16469695","citation_count":4640,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11057898","id":"PMC_11057898","title":"TOR, a central controller of cell growth.","date":"2000","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/11057898","citation_count":1628,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10995454","id":"PMC_10995454","title":"Tor-mediated induction of autophagy via an Apg1 protein kinase complex.","date":"2000","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10995454","citation_count":942,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22174183","id":"PMC_22174183","title":"Target of rapamycin (TOR) in nutrient signaling and growth control.","date":"2011","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22174183","citation_count":690,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23542588","id":"PMC_23542588","title":"Glucose-TOR signalling reprograms the transcriptome and activates meristems.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23542588","citation_count":614,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32130880","id":"PMC_32130880","title":"AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32130880","citation_count":602,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28096180","id":"PMC_28096180","title":"Nutrient sensing and TOR signaling in yeast and mammals.","date":"2017","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/28096180","citation_count":572,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20519118","id":"PMC_20519118","title":"With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging.","date":"2010","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/20519118","citation_count":504,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24828042","id":"PMC_24828042","title":"The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/24828042","citation_count":489,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11416184","id":"PMC_11416184","title":"The target of rapamycin (TOR) proteins.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11416184","citation_count":485,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12563289","id":"PMC_12563289","title":"Tor signalling in bugs, brain and brawn.","date":"2003","source":"Nature reviews. Molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12563289","citation_count":478,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9425342","id":"PMC_9425342","title":"TOR signalling and control of cell growth.","date":"1997","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9425342","citation_count":415,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15780592","id":"PMC_15780592","title":"The expanding TOR signaling network.","date":"2005","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15780592","citation_count":403,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14607085","id":"PMC_14607085","title":"Rheb fills a GAP between TSC and TOR.","date":"2003","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/14607085","citation_count":392,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18971624","id":"PMC_18971624","title":"Aging: ROS or TOR.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18971624","citation_count":310,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26905651","id":"PMC_26905651","title":"TOR Signaling and Nutrient Sensing.","date":"2016","source":"Annual review of plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/26905651","citation_count":309,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18670193","id":"PMC_18670193","title":"The role of TOR in autophagy regulation from yeast to plants and mammals.","date":"2008","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/18670193","citation_count":302,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18765678","id":"PMC_18765678","title":"Amino acid regulation of TOR complex 1.","date":"2008","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/18765678","citation_count":294,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12456783","id":"PMC_12456783","title":"Elucidating TOR signaling and rapamycin action: lessons from Saccharomyces cerevisiae.","date":"2002","source":"Microbiology and molecular biology reviews : MMBR","url":"https://pubmed.ncbi.nlm.nih.gov/12456783","citation_count":285,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11266435","id":"PMC_11266435","title":"The TOR kinases link nutrient sensing to cell growth.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11266435","citation_count":284,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19380822","id":"PMC_19380822","title":"IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19380822","citation_count":273,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9843498","id":"PMC_9843498","title":"The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9843498","citation_count":270,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15989961","id":"PMC_15989961","title":"The TOR and EGO protein complexes orchestrate microautophagy in yeast.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15989961","citation_count":267,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19539012","id":"PMC_19539012","title":"The TOR pathway comes of age.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19539012","citation_count":263,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14668532","id":"PMC_14668532","title":"TOR signaling.","date":"2003","source":"Science's STKE : signal transduction knowledge environment","url":"https://pubmed.ncbi.nlm.nih.gov/14668532","citation_count":249,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12654728","id":"PMC_12654728","title":"Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2.","date":"2003","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/12654728","citation_count":241,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10072357","id":"PMC_10072357","title":"Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation.","date":"1999","source":"Current opinion in genetics & development","url":"https://pubmed.ncbi.nlm.nih.gov/10072357","citation_count":236,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18992839","id":"PMC_18992839","title":"Insulin/TOR signaling in growth and homeostasis: a view from the fly world.","date":"2008","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18992839","citation_count":233,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22134914","id":"PMC_22134914","title":"Rapamycin and glucose-target of rapamycin (TOR) protein signaling in plants.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22134914","citation_count":219,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19875293","id":"PMC_19875293","title":"TOR complex 2: a signaling pathway of its own.","date":"2009","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19875293","citation_count":214,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21548787","id":"PMC_21548787","title":"Amino acid signaling in TOR activation.","date":"2011","source":"Annual review of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21548787","citation_count":181,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22305521","id":"PMC_22305521","title":"Sensing nutrient and energy status by SnRK1 and TOR kinases.","date":"2012","source":"Current opinion in plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/22305521","citation_count":163,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16684541","id":"PMC_16684541","title":"The amino acid sensitive TOR pathway from yeast to mammals.","date":"2006","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16684541","citation_count":162,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18215152","id":"PMC_18215152","title":"TOR regulation of AGC kinases in yeast and mammals.","date":"2008","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18215152","citation_count":159,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22575479","id":"PMC_22575479","title":"Organ size control by Hippo and TOR pathways.","date":"2012","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/22575479","citation_count":156,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29986898","id":"PMC_29986898","title":"TOR signaling in plants: conservation and innovation.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29986898","citation_count":155,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19494260","id":"PMC_19494260","title":"Regulation of T cell activation by Notch ligand, DLL4, promotes IL-17 production and Rorc activation.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19494260","citation_count":154,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24502334","id":"PMC_24502334","title":"Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc).","date":"2014","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24502334","citation_count":149,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14560952","id":"PMC_14560952","title":"Autophagy in yeast: a TOR-mediated response to nutrient starvation.","date":"2004","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14560952","citation_count":146,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28027512","id":"PMC_28027512","title":"Shaping plant development through the SnRK1-TOR metabolic regulators.","date":"2016","source":"Current opinion in plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/28027512","citation_count":138,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16516475","id":"PMC_16516475","title":"Complexity of the TOR signaling network.","date":"2006","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16516475","citation_count":138,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24684168","id":"PMC_24684168","title":"The TOR signaling pathway regulates vegetative development and virulence in Fusarium graminearum.","date":"2014","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/24684168","citation_count":125,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23246968","id":"PMC_23246968","title":"The evolution of the TOR pathway and its role in cancer.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23246968","citation_count":123,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30715492","id":"PMC_30715492","title":"Integration of nutrient, energy, light, and hormone signalling via TOR in plants.","date":"2019","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/30715492","citation_count":115,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33831352","id":"PMC_33831352","title":"Diverse nitrogen signals activate convergent ROP2-TOR signaling in Arabidopsis.","date":"2021","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/33831352","citation_count":114,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31594908","id":"PMC_31594908","title":"TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging.","date":"2019","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31594908","citation_count":110,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26476687","id":"PMC_26476687","title":"Novel links in the plant TOR kinase signaling network.","date":"2015","source":"Current opinion in plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/26476687","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22057117","id":"PMC_22057117","title":"Evolution of the TOR pathway.","date":"2011","source":"Journal of molecular evolution","url":"https://pubmed.ncbi.nlm.nih.gov/22057117","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17046229","id":"PMC_17046229","title":"Thinking globally and acting locally with TOR.","date":"2006","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17046229","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21428920","id":"PMC_21428920","title":"A longer and healthier life with TOR down-regulation: genetics and drugs.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21428920","citation_count":103,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16740339","id":"PMC_16740339","title":"Regulation of chemotaxis by the orchestrated activation of Ras, PI3K, and TOR.","date":"2006","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16740339","citation_count":103,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29104218","id":"PMC_29104218","title":"Evolutionary Conservation of the Components in the TOR Signaling Pathways.","date":"2017","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/29104218","citation_count":97,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15454083","id":"PMC_15454083","title":"Temporal control of differentiation by the insulin receptor/tor pathway in Drosophila.","date":"2004","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15454083","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18396450","id":"PMC_18396450","title":"Nutritional control via Tor signaling in Saccharomyces cerevisiae.","date":"2008","source":"Current opinion in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18396450","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28485389","id":"PMC_28485389","title":"EGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28485389","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20385253","id":"PMC_20385253","title":"TOR signaling never gets old: aging, longevity and TORC1 activity.","date":"2010","source":"Ageing research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/20385253","citation_count":92,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9037523","id":"PMC_9037523","title":"Identification and characterization of an endogenous ligand for opioid receptor homologue ROR-C: its involvement in allodynic response to innocuous stimulus.","date":"1996","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9037523","citation_count":91,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32051250","id":"PMC_32051250","title":"TOR dynamically regulates plant cell-cell transport.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32051250","citation_count":90,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17081107","id":"PMC_17081107","title":"Mitochondrial signaling, TOR, and life span.","date":"2006","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17081107","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22240970","id":"PMC_22240970","title":"Regulation of TOR by small GTPases.","date":"2012","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/22240970","citation_count":87,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21115526","id":"PMC_21115526","title":"TOR and ageing: a complex pathway for a complex process.","date":"2011","source":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21115526","citation_count":85,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36104568","id":"PMC_36104568","title":"Glucose-driven TOR-FIE-PRC2 signalling controls plant development.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/36104568","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20530756","id":"PMC_20530756","title":"The TOR pathway modulates the structure of cell walls in Arabidopsis.","date":"2010","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/20530756","citation_count":83,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11244074","id":"PMC_11244074","title":"TOR modulates GCN4-dependent expression of genes turned on by nitrogen limitation.","date":"2001","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/11244074","citation_count":80,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17698581","id":"PMC_17698581","title":"TOR signaling is a determinant of cell survival in response to DNA damage.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17698581","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36243007","id":"PMC_36243007","title":"Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element.","date":"2022","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/36243007","citation_count":73,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28888322","id":"PMC_28888322","title":"TOR, the Gateway to Cellular Metabolism, Cell Growth, and Disease.","date":"2017","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/28888322","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26195783","id":"PMC_26195783","title":"Regulation of ribosomal DNA amplification by the TOR pathway.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26195783","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17679098","id":"PMC_17679098","title":"Structure of TOR and its complex with KOG1.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/17679098","citation_count":66,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35787039","id":"PMC_35787039","title":"ABA represses TOR and root meristem activity through nuclear exit of the SnRK1 kinase.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35787039","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21210909","id":"PMC_21210909","title":"Activating mutations of TOR (target of rapamycin).","date":"2011","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/21210909","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21428923","id":"PMC_21428923","title":"Regulation of plant growth and metabolism by the TOR kinase.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21428923","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33309324","id":"PMC_33309324","title":"A Tour of TOR Complex Signaling in Plants.","date":"2020","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33309324","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24567496","id":"PMC_24567496","title":"Balancing act: matching growth with environment by the TOR signalling pathway.","date":"2014","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/24567496","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33495632","id":"PMC_33495632","title":"Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition.","date":"2021","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33495632","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31216485","id":"PMC_31216485","title":"Mutations of the AtYAK1 Kinase Suppress TOR Deficiency in Arabidopsis.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31216485","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26024507","id":"PMC_26024507","title":"Activation of the TOR Signalling Pathway by Glutamine Regulates Insect Fecundity.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26024507","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14560949","id":"PMC_14560949","title":"The role of phosphatases in TOR signaling in yeast.","date":"2004","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14560949","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14560955","id":"PMC_14560955","title":"TOR action in mammalian cells and in Caenorhabditis elegans.","date":"2004","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14560955","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23698095","id":"PMC_23698095","title":"Evolutionarily conserved regulation of TOR signalling.","date":"2013","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23698095","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32117365","id":"PMC_32117365","title":"The Importance of TOR Kinase in Plant Development.","date":"2020","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/32117365","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34496244","id":"PMC_34496244","title":"Light regulates alternative splicing outcomes via the TOR kinase pathway.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34496244","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26048793","id":"PMC_26048793","title":"Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists.","date":"2015","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/26048793","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35585790","id":"PMC_35585790","title":"The RALF1-FERONIA complex interacts with and activates TOR signaling in response to low nutrients.","date":"2022","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/35585790","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30098100","id":"PMC_30098100","title":"The Arabidopsis THADA homologue modulates TOR activity and cold acclimation.","date":"2018","source":"Plant biology (Stuttgart, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/30098100","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27763256","id":"PMC_27763256","title":"Target of Rapamycin (TOR) Regulates Growth in Response to Nutritional Signals.","date":"2016","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/27763256","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20689155","id":"PMC_20689155","title":"P66SHC and ageing: ROS and TOR?","date":"2010","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/20689155","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27902985","id":"PMC_27902985","title":"Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis.","date":"2016","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27902985","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33513917","id":"PMC_33513917","title":"TOR Signaling Pathway in Cardiac Aging and Heart Failure.","date":"2021","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/33513917","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20587805","id":"PMC_20587805","title":"Evolution of the TSC1/TSC2-TOR signaling pathway.","date":"2010","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/20587805","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24812667","id":"PMC_24812667","title":"Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24812667","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17245124","id":"PMC_17245124","title":"TOR-in(g) the nucleus.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/17245124","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18493947","id":"PMC_18493947","title":"What controls TOR?","date":"2008","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/18493947","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32759652","id":"PMC_32759652","title":"Structural Insights into TOR Signaling.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/32759652","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32393676","id":"PMC_32393676","title":"The flipside of the TOR coin - TORC2 and plasma membrane homeostasis at a glance.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/32393676","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31619674","id":"PMC_31619674","title":"NFAT primes the human RORC locus for RORγt expression in CD4+ T cells.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31619674","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17618850","id":"PMC_17618850","title":"TOR signaling and S6 kinase 1: Yeast catches up.","date":"2007","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17618850","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34996872","id":"PMC_34996872","title":"Photosynthetic assimilation of CO2 regulates TOR activity.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34996872","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36343753","id":"PMC_36343753","title":"α-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson's disease.","date":"2022","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/36343753","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31063760","id":"PMC_31063760","title":"ROS Inhibits Cell Growth by Regulating 4EBP and S6K, Independent of TOR, during Development.","date":"2019","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/31063760","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23128233","id":"PMC_23128233","title":"Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23128233","citation_count":3725,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18368049","id":"PMC_18368049","title":"TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18368049","citation_count":1563,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19274049","id":"PMC_19274049","title":"A census of human transcription factors: function, expression and evolution.","date":"2009","source":"Nature reviews. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19274049","citation_count":1191,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31776512","id":"PMC_31776512","title":"Bile acid metabolites control TH17 and Treg cell differentiation.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31776512","citation_count":1091,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28473536","id":"PMC_28473536","title":"Impact of cytosine methylation on DNA binding specificities of human transcription factors.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28473536","citation_count":934,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11076863","id":"PMC_11076863","title":"DNA cloning using in vitro site-specific recombination.","date":"2000","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/11076863","citation_count":815,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10875923","id":"PMC_10875923","title":"Requirement for RORgamma in thymocyte survival and lymphoid organ development.","date":"2000","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/10875923","citation_count":603,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8125298","id":"PMC_8125298","title":"Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8125298","citation_count":492,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19029904","id":"PMC_19029904","title":"Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin.","date":"2008","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19029904","citation_count":477,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22170608","id":"PMC_22170608","title":"Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22170608","citation_count":467,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18434325","id":"PMC_18434325","title":"Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18434325","citation_count":353,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26160376","id":"PMC_26160376","title":"IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.","date":"2015","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26160376","citation_count":336,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20106535","id":"PMC_20106535","title":"Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients.","date":"2010","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20106535","citation_count":288,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10963675","id":"PMC_10963675","title":"Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10963675","citation_count":266,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19439651","id":"PMC_19439651","title":"Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19439651","citation_count":251,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24668754","id":"PMC_24668754","title":"RORα and ROR γ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D.","date":"2014","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/24668754","citation_count":237,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26878233","id":"PMC_26878233","title":"Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells.","date":"2016","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26878233","citation_count":223,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7811290","id":"PMC_7811290","title":"ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle.","date":"1994","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7811290","citation_count":205,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11983153","id":"PMC_11983153","title":"Nuclear hormone receptors in T lymphocytes.","date":"2002","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/11983153","citation_count":204,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30602780","id":"PMC_30602780","title":"RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30602780","citation_count":198,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21566134","id":"PMC_21566134","title":"Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21566134","citation_count":191,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20203100","id":"PMC_20203100","title":"Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma.","date":"2010","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/20203100","citation_count":187,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34664,"output_tokens":2163,"usd":0.068219},"stage2":{"model":"claude-opus-4-6","input_tokens":5542,"output_tokens":2120,"usd":0.121065},"total_usd":0.48524,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":46834,"output_tokens":5917,"usd":0.114628},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8932,"output_tokens":3049,"usd":0.181328}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-27 inhibits RORγt (encoded by RORC) expression in a STAT1-dependent manner, suppressing Th17 differentiation. IL-27 blocks TGFβ plus IL-6- or IL-23-dependent Th17 development by repressing RORc transcription, and mice deficient for IL-27p28 show enhanced Th17 responses in vivo.\",\n      \"method\": \"Genetic knockout mice (IL-27p28-/-), in vitro T cell differentiation assays, gene expression analysis, in vivo models (DTH, EAE)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic and cellular experiments across mouse and human systems with multiple orthogonal methods\",\n      \"pmids\": [\"19380822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Notch ligand DLL4 upregulates Rorc expression in T cells and directly activates both the Rorc and Il17 gene promoters as transcriptional Notch targets, promoting Th17 differentiation in the presence of IL-6 and TGF-β.\",\n      \"method\": \"In vitro T cell differentiation, promoter-reporter assays, gene expression analysis, Notch inhibition experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding and functional differentiation assays in a single study\",\n      \"pmids\": [\"19494260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RORγt (encoded by RORC) directly binds to the Ptger2/PTGER2 (EP2 prostaglandin receptor) gene promoter in Th17 cells, silencing EP2 expression. Knockdown of RORC restored EP2 expression in human Th17 cells, and reduced RORC binding in MS patients led to elevated EP2 and pathogenic Th17 cytokine production.\",\n      \"method\": \"ChIP-seq, RORC knockdown, gene expression analysis, human patient samples\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq demonstrating direct binding combined with loss-of-function validation and human disease context\",\n      \"pmids\": [\"24812667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RORc (RORγ) is a nuclear receptor whose ligand-binding domain structure has been characterized, serving as a basis for development of inverse agonist modulators that suppress IL-17 production in human primary cells.\",\n      \"method\": \"Structural biology, medicinal chemistry, IL-17 suppression assays in human primary cells, cellular selectivity panels\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural biology with functional validation of ligand modulation, single study\",\n      \"pmids\": [\"24502334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NFAT proteins bind to regulatory elements at the human RORC locus and activate RORγt transcription in cooperation with NF-κB in activated CD4+ T cells. TCR stimulation induces cyclosporine A-sensitive histone modifications and P300/CBP acetylase recruitment at these elements, and CRISPR/Cas9 deletion of these regulatory elements reduces RORγt expression.\",\n      \"method\": \"CRISPR/Cas9 deletion of regulatory elements, ChIP, NFAT binding assays, histone modification analysis, reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR loss-of-function with multiple orthogonal epigenomic and mechanistic readouts\",\n      \"pmids\": [\"31619674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RORα cooperatively binds with RORγt (encoded by RORC) to a previously unidentified Rorc cis-regulatory element. This cooperative binding is essential for Th17 lineage maintenance in vivo; absence of RORα reduces RORγt expression and Th17 effector function in peripheral tissues.\",\n      \"method\": \"RORα conditional knockout in T cells, ChIP, identification of novel cis-regulatory element, in vivo Th17 response assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic loss-of-function combined with ChIP demonstrating cooperative binding at identified cis-regulatory element\",\n      \"pmids\": [\"36243007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RORc (RORγ) inverse agonists of the imidazo[1,5-a]pyridine/pyrimidine class potently and selectively suppress IL-17 production in human primary cells by acting on the RORc nuclear receptor ligand-binding domain, with >300-fold selectivity over other ROR family members.\",\n      \"method\": \"Cell-based potency and selectivity assays, IL-17 suppression in human primary cells, nuclear receptor selectivity panel\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional pharmacological characterization in human primary cells with selectivity profiling\",\n      \"pmids\": [\"26048793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"α-Synuclein promotes transcription of RORC (encoding RORγt) in circulating CD4+ T cells including Tregs and Th17 cells, leading to increased Th17 differentiation and loss of Treg function. RORγt inhibitor GSK805 attenuated DA neuron apoptosis and restored Th17/Treg balance in MPTP-treated mice.\",\n      \"method\": \"In vitro T cell stimulation with α-Syn, RORC gene expression analysis, RORγt inhibitor treatment in mouse PD models (MPTP and A53T transgenic), human patient correlation\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic link between α-Syn and RORC transcription with in vivo pharmacological rescue, but upstream mechanism of RORC induction not fully defined\",\n      \"pmids\": [\"36343753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"ROR-C (identified as an opioid receptor homologue from rat cerebrum) binds the endogenous heptadecapeptide nociceptin/orphanin FQ and mediates inhibition of forskolin-induced cAMP accumulation in ROR-C-expressing CHO cells.\",\n      \"method\": \"Peptide purification from bovine brain, cAMP accumulation assay in CHO cells expressing ROR-C, Northern blot, in situ hybridization, intrathecal administration\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — this paper describes a rat opioid receptor homologue sharing the symbol ROR-C but its function (GPCR/opioid receptor) is fundamentally incompatible with human RORC (nuclear receptor/Th17 transcription factor); likely symbol collision\",\n      \"pmids\": [\"9037523\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RORC encodes RORγt, a nuclear receptor transcription factor that is the master regulator of Th17 cell differentiation; it is transcriptionally activated at the RORC locus by NFAT/NF-κB-dependent regulatory elements following TCR stimulation, is stabilized by cooperative binding with RORα at a cis-regulatory element, directly silences EP2 (PTGER2) transcription in Th17 cells, and is suppressed by IL-27 in a STAT1-dependent manner, while its activity as a ligand-binding nuclear receptor can be modulated by small-molecule inverse agonists to block IL-17 production.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll first classify each paper, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\n- Papers [1]-[20] (main corpus) and [22]-[100] (main corpus): The vast majority are about TOR/mTOR signaling, completely unrelated to RORC. These are SYMBOL COLLISION / off-target papers (TOR ≠ RORC).\n\n**KEEP from main corpus:**\n- [21] PMID:19380822 — IL-27 blocks RORc expression → directly about RORC\n- [37] PMID:19494260 — DLL4/Notch regulation of Rorc expression → directly about RORC\n- [38] PMID:24502334 — Modulators of RORc (nuclear receptor biology) → directly about RORC\n- [57] PMID:9037523 — \"ROR-C\" as opioid receptor homologue — This is a SYMBOL COLLISION: describes a rat opioid receptor (nociceptin receptor, now known as ORL1/OPRL1), not the nuclear receptor RORC. EXCLUDE.\n- [66] PMID:36243007 — RORα binding to Rorc cis-regulatory element → directly about RORC\n- [83] PMID:26048793 — RORc inverse agonists → directly about RORC\n- [88] PMID:27902985 — RORC methylation in SSc → expression/epigenetic correlation, no mechanism. EXCLUDE.\n- [91] PMID:24812667 — RORC directly silences PTGER2 → directly about RORC mechanism. KEEP.\n- [96] PMID:31619674 — NFAT primes RORC locus → directly about RORC. KEEP.\n- [99] PMID:36343753 — α-Syn promotes RORC transcription → about RORC expression regulation. Minimal mechanism. KEEP (upstream regulation of RORC).\n\n**KEEP from gene2pubmed corpus:**\n- [2] PMID:18368049 — Foxp3 inhibits RORgammat function → directly about RORC product. KEEP.\n- [13] PMID:10875923 — RORgamma required for thymocyte survival, Bcl-xL regulation. KEEP.\n- [15] PMID:19029904 — RORgammat influence on NKp46+ cell populations. KEEP.\n- [18] PMID:18434325 — Foxp3 directly interacts with RORgammat. KEEP.\n- [19] PMID:26160376 — Bi-allelic RORC mutations, loss of IL-17A/F T cells. KEEP.\n- [21] PMID:10963675 — RORgamma KO mice, lymphoid organogenesis, apoptosis/Bcl-XL. KEEP.\n- [23] PMID:24668754 — Hydroxyvitamin D as RORγ antagonists. KEEP.\n- [24] PMID:26878233 — Transient ROR-γt inhibition, differential requirements in TH17 vs ILC3. KEEP.\n- [26] PMID:7811290 — Identification/cloning of ROR gamma. KEEP.\n- [27] PMID:11983153 — Nuclear hormone receptors in T lymphocytes, RORgamma review. KEEP (foundational).\n- [28] PMID:30602780 — RORγt inhibition targets IL-17 producing iNKT/γδ-T cells. KEEP.\n- [29] PMID:21566134 — Ursolic acid antagonizes RORγt function. KEEP.\n- [30] PMID:20203100 — Crystal structure of RORgamma LBD with hydroxycholesterols. KEEP.\n- [5] PMID:31776512 — Bile acid metabolites, 3-oxoLCA binds RORγt directly. KEEP.\n\nOthers in gene2pubmed are genomics/interactome/cDNA resources — EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"RORγ (encoded by RORC) was identified as a novel member of the nuclear receptor superfamily, belonging to the ROR/RZR orphan receptor subfamily. It encodes a 560-amino-acid protein (~63 kDa) with a DNA-binding domain highly homologous to RORα/RZRα and RZRβ, and is most highly expressed in skeletal muscle, with the gene localized to human chromosome 1.\",\n      \"method\": \"cDNA cloning, Northern blot analysis, chromosomal localization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original molecular identification with sequence and expression characterization\",\n      \"pmids\": [\"7811290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"RORγ is required for thymocyte survival: mice lacking RORγ show loss of thymic Bcl-xL expression, increased apoptosis of CD4+CD8+ thymocytes, and failure of positive selection. RORγ is also essential for lymph node and Peyer's patch organogenesis, associated with loss of a CD3-CD4+CD45+ lymphoid tissue-inducer progenitor population.\",\n      \"method\": \"Targeted gene disruption (knockout mice), flow cytometry, TUNEL staining, Bcl-xL expression analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotypes, replicated across two independent KO studies\",\n      \"pmids\": [\"10875923\", \"10963675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"RORγ knockout mice exhibit a 4-fold increase in thymocyte apoptosis associated with greatly reduced Bcl-XL expression, and a 6-fold rise in S-phase cells among thymocytes, establishing RORγ as a negative regulator of apoptosis in thymocytes, likely through transcriptional control of Bcl-XL.\",\n      \"method\": \"Targeted disruption of RORγ, TUNEL staining, annexin V staining, flow cytometry, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple orthogonal phenotypic readouts in independent study\",\n      \"pmids\": [\"10963675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RORγt (the T-cell-specific isoform encoded by RORC) drives Th17 cell differentiation and IL-17A transcription. Foxp3, induced by high concentrations of TGF-β, directly binds RORγt protein and inhibits its transcriptional activity, thereby suppressing IL-17 production and Th17 differentiation. IL-6 and IL-21 relieve Foxp3-mediated inhibition of RORγt to promote Th17 differentiation.\",\n      \"method\": \"Genetic mouse models, co-immunoprecipitation, reporter assays, cytokine measurement, in vitro differentiation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal protein interaction demonstrated with functional rescue, replicated by independent lab\",\n      \"pmids\": [\"18368049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Foxp3 directly interacts with RORγt through the exon 2 region of Foxp3 and inhibits RORγt-mediated IL-17A promoter activation. The exon 2 region and forkhead (FKH) domain of Foxp3 are both necessary for suppression of RORγt transcriptional activity on the IL-17A minimum promoter.\",\n      \"method\": \"Reporter gene assays (IL-17A promoter-luciferase), co-immunoprecipitation, domain mapping by deletion mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct protein interaction with domain mapping and functional promoter assays\",\n      \"pmids\": [\"18434325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RORγt expression defines a previously unrecognized NKp46+CD3- lymphocyte subset in the intestinal lamina propria that produces IL-22 but has diminished degranulation and IFN-γ capacity. RORγt, previously known for its role in lymphoid tissue-inducer cell development, is thus required for this innate lymphoid subset's identity and function.\",\n      \"method\": \"Flow cytometry, intracellular cytokine staining, RORγt-GFP reporter mice, functional cytotoxicity and cytokine assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic reporter system with multiple functional readouts\",\n      \"pmids\": [\"19029904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-27 suppresses Th17 development by inhibiting RORγt (RORc) expression in a STAT1-dependent manner. IL-27 acts upstream of RORγt transcription to block IL-17A and IL-17F production during TGF-β plus IL-6 or IL-23-driven Th17 differentiation in both mouse and human systems.\",\n      \"method\": \"Cytokine treatment, gene expression analysis, STAT1-deficient cells, in vivo EAE and DTH models with IL-27p28-deficient mice\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (STAT1 dependence) plus in vivo KO validation\",\n      \"pmids\": [\"19380822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Notch ligand DLL4, induced on dendritic cells by TLR activation, upregulates Rorc expression in T cells and directly promotes IL-17 production. Both the Rorc and Il17 gene promoters are direct transcriptional Notch targets, establishing a DLL4-Notch-RORγt-IL-17 axis in Th17 differentiation.\",\n      \"method\": \"In vitro T cell culture with DLL4, gene expression analysis, promoter reporter assays for Rorc and Il17, Notch inhibitor experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct promoter targeting shown by reporter assay, single lab\",\n      \"pmids\": [\"19494260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hydroxycholesterols function as natural ligands of RORγ by binding in the ligand-binding domain (LBD) and promoting coactivator recruitment. Crystal structures of the RORγ LBD bound to multiple hydroxycholesterols reveal binding modes in the canonical active conformation; mutations disrupting hydroxycholesterol binding abolish constitutive RORγ activity.\",\n      \"method\": \"Crystal structure determination of RORγ LBD, biochemical coactivator recruitment assays, site-directed mutagenesis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and biochemical validation\",\n      \"pmids\": [\"20203100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ursolic acid (UA), a natural small molecule, selectively inhibits RORγt transcriptional function, resulting in decreased IL-17 expression in developing and differentiated Th17 cells and amelioration of EAE in vivo. UA acts as a selective RORγt antagonist without broadly affecting other nuclear receptors.\",\n      \"method\": \"In vitro Th17 differentiation, reporter gene assays, IL-17 ELISA, EAE mouse model, selectivity profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cellular assays with in vivo validation, single lab\",\n      \"pmids\": [\"21566134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RORC (RORγt) directly silences PTGER2 (encoding prostaglandin receptor EP2) transcription in Th17 cells. Chromatin immunoprecipitation-sequencing (ChIP-seq) in mouse Th17 cells showed RORγt binds directly to the Ptger2 locus; RORC knockdown in human Th17 cells restored EP2 expression. In MS patients, reduced RORC binding to the PTGER2 promoter correlated with higher EP2 levels and a pathogenic Th17 phenotype (elevated IFN-γ and GM-CSF).\",\n      \"method\": \"ChIP-seq, RORC knockdown (siRNA), gene expression analysis, EP2 overexpression in primary human Th17 cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct ChIP-seq binding combined with loss-of-function and gain-of-function experiments in primary human cells\",\n      \"pmids\": [\"24812667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RORγ (RORc) and RORα expressed in human skin serve as receptors for endogenously produced noncalcemic vitamin D derivatives (20(OH)D3 and 20,23(OH)2D3), which act as antagonists/inverse agonists. This was demonstrated by ligand binding assays, ROR-responsive element luciferase reporter assays, and molecular docking to crystal structures of RORα and RORγ LBDs, with 20(OH)D3 inhibiting IL-17 promoter activity in cells overexpressing RORγ.\",\n      \"method\": \"Stable cell line reporter assays, mammalian 2-hybrid LBD interaction assay, molecular docking, IL-17 promoter-luciferase assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — structural modeling plus cell-based functional assays; binding not confirmed by direct crystallography\",\n      \"pmids\": [\"24668754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RORc (RORγ) structural biology and pharmacology: the LBD of RORc adopts an active conformation and is amenable to small-molecule modulation. Inverse agonists occupying the ligand-binding pocket suppress coactivator recruitment and IL-17 production, providing a structural basis for targeting RORc in autoimmune disease.\",\n      \"method\": \"Review integrating crystal structures, biochemical assays, medicinal chemistry SAR, cellular IL-17 inhibition assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — synthesizes multiple crystal structure and functional studies; review paper\",\n      \"pmids\": [\"24502334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Bi-allelic loss-of-function mutations in RORC in humans result in absence of IL-17A/F-producing T cells (explaining chronic mucocutaneous candidiasis) and unexpectedly impaired IFN-γ production, particularly by circulating γδ T cells and CD4+CCR6+CXCR3+ αβ T cells, demonstrating that both RORγ and RORγT isoforms are required for systemic immunity to Mycobacterium in humans.\",\n      \"method\": \"Human genetics (bi-allelic RORC mutations), immunophenotyping of patient cells, cytokine production assays, T cell subset analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — natural human loss-of-function with comprehensive immune characterization across multiple kindreds\",\n      \"pmids\": [\"26160376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Potent and selective imidazo[1,5-a]pyridine and -pyrimidine compounds were identified as RORc inverse agonists with >300-fold selectivity over other ROR family members and other nuclear receptors, demonstrating that inverse agonist occupancy of the RORc LBD suppresses IL-17 production in human primary cells.\",\n      \"method\": \"Biochemical binding assays, cellular selectivity profiling, IL-17 suppression in human primary cells\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — rigorous selectivity panel with primary human cell functional validation\",\n      \"pmids\": [\"26048793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Transient pharmacological inhibition of ROR-γt (encoded by Rorc) selectively reduces cytokine production from TH17 cells but not from group 3 ILCs (ILC3s) in vivo. Temporal deletion of Rorc in mature ILCs did not impair their cytokine response, revealing that ongoing ROR-γt activity is differentially required for TH17 maintenance versus ILC3 function.\",\n      \"method\": \"Pharmacological ROR-γt inhibition in mice, conditional/temporal Rorc deletion, infection models, cytokine assays, IBD patient tissue analysis\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological approaches combined with in vivo infection models and human tissue validation\",\n      \"pmids\": [\"26878233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The bile acid metabolite 3-oxoLCA inhibits TH17 cell differentiation by directly binding to RORγt (encoded by RORC) and blocking coactivator recruitment. Biochemical binding assays confirmed direct physical interaction between 3-oxoLCA and the RORγt LBD, establishing bile acid metabolites as endogenous RORγt ligands that modulate the TH17/Treg balance in the intestine.\",\n      \"method\": \"Bile acid metabolite library screen, direct binding assays (competitive binding to RORγt LBD), Th17 differentiation assays, in vivo intestinal lamina propria analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct ligand-binding demonstrated biochemically with functional cellular and in vivo validation\",\n      \"pmids\": [\"31776512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NFAT proteins bind to newly defined regulatory elements at the human RORC locus and activate RORγt transcription in cooperation with NF-κB in CD4+ T cells. T cell receptor stimulation induces cyclosporine A-sensitive (calcineurin/NFAT-dependent) histone modifications and P300/CBP acetylase recruitment at these RORC regulatory elements; CRISPR/Cas9-guided deletion of these elements reduced RORγt expression.\",\n      \"method\": \"CRISPR/Cas9 deletion of regulatory elements, ChIP assays, NFAT overexpression/inhibition (cyclosporine A), histone modification analysis, reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR deletion of cis-elements combined with ChIP and functional assays\",\n      \"pmids\": [\"31619674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RORγt+ iNKT and γδ-T cell subsets expressing a Th17-like profile are enriched in inflamed joints of spondyloarthritis patients and act as major IL-17 secretors. RORγt inhibition blocks IL-17 production by these innate-like T cells while selectively sparing IL-22-producing subsets, demonstrating that RORγt is required for the IL-17 effector program of both iNKT17 and γδ17 cells.\",\n      \"method\": \"Flow cytometry, gene expression profiling, RORγt pharmacological inhibition, cytokine production assays in patient cells and healthy donors\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition with comprehensive phenotyping in primary human patient cells\",\n      \"pmids\": [\"30602780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RORα cooperatively binds with RORγt to a previously unidentified Rorc cis-regulatory element and is required for maintenance of RORγt expression and Th17 effector function in peripheral tissues in vivo. RORα-deficient T cells show reduced RORγt expression and impaired Th17 responses, while cooperative RORα/RORγt binding to this element is essential for Th17 lineage stability.\",\n      \"method\": \"T cell-specific RORα conditional knockout mice, ChIP assays, CRISPR/Cas9 deletion of Rorc cis-regulatory element, flow cytometry, cytokine assays, in vivo tissue analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with ChIP and CRISPR deletion providing mechanistic and in vivo validation\",\n      \"pmids\": [\"36243007\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RORC encodes the nuclear receptor RORγ (and its T-cell-specific isoform RORγt), which drives Th17 cell differentiation by directly binding the IL-17A promoter and silencing PTGER2 (EP2 receptor); its LBD binds endogenous ligands including hydroxycholesterols and bile acid metabolites (3-oxoLCA) that modulate coactivator recruitment; Foxp3 and ursolic acid antagonize its transcriptional activity through direct protein-protein interaction or LBD occupancy, respectively; NFAT/NF-κB and Notch signaling regulate its own transcription at defined RORC cis-regulatory elements; and in vivo it is essential for thymocyte survival via Bcl-xL regulation, lymphoid organogenesis, ILC3 identity, and both mucocutaneous (Candida) and systemic (Mycobacterium) immunity in humans.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RORC encodes RORγt, a ligand-responsive nuclear receptor transcription factor that serves as the master regulator of Th17 cell differentiation and maintenance. Transcription of RORC is activated downstream of TCR signaling through NFAT and NF-κB binding at cis-regulatory elements, accompanied by P300/CBP-mediated histone acetylation, and is further stabilized by cooperative binding of RORα at a dedicated cis-regulatory element within the Rorc locus [PMID:31619674, PMID:36243007]. RORγt directly silences EP2 (PTGER2) in Th17 cells, and its expression is negatively regulated by IL-27 via STAT1 and positively regulated by Notch/DLL4 signaling [PMID:24812667, PMID:19380822, PMID:19494260]. The ligand-binding domain of RORγt is pharmacologically targetable by inverse agonists that suppress IL-17 production and modulate Th17/Treg balance in autoimmune and neuroinflammatory contexts [PMID:24502334, PMID:36343753].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that RORC/RORγt expression is under negative control by IL-27 via STAT1 resolved how anti-inflammatory cytokines limit Th17 commitment at the transcriptional level.\",\n      \"evidence\": \"IL-27p28 knockout mice, in vitro Th17 differentiation, EAE and DTH models\",\n      \"pmids\": [\"19380822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether STAT1 directly binds the RORC locus or acts indirectly was not determined\",\n        \"Relative contribution of IL-27 vs. other STAT1-activating cytokines to RORC repression in vivo remains undefined\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that Notch ligand DLL4 directly activates the Rorc and Il17 promoters placed RORC transcription downstream of the Notch pathway during Th17 polarization.\",\n      \"evidence\": \"Promoter-reporter assays, Notch inhibition, in vitro T cell differentiation with IL-6/TGFβ\",\n      \"pmids\": [\"19494260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct ChIP for Notch/RBPJ at the endogenous RORC locus was not shown\",\n        \"In vivo genetic validation (Notch-deficient T cells) was not performed\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"ChIP-seq identification of direct RORγt binding at the PTGER2 promoter, combined with knockdown rescue, established that RORγt acts as a transcriptional silencer of EP2 in Th17 cells, linking reduced RORγt occupancy to pathogenic cytokine production in multiple sclerosis.\",\n      \"evidence\": \"ChIP-seq in Th17 cells, RORC knockdown in human Th17 cells, MS patient samples\",\n      \"pmids\": [\"24812667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of RORγt-mediated silencing (co-repressor recruitment) was not defined\",\n        \"Whether EP2 de-repression is causal for disease pathology vs. correlative in MS patients\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Structural characterization of the RORγt ligand-binding domain and demonstration that inverse agonists suppress IL-17 production established RORγt as a druggable nuclear receptor.\",\n      \"evidence\": \"Structural biology (crystal structure), medicinal chemistry, IL-17 suppression in human primary cells\",\n      \"pmids\": [\"24502334\", \"26048793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of endogenous ligand(s) for RORγt remains incompletely resolved\",\n        \"In vivo efficacy and therapeutic window of inverse agonists in autoimmune disease models were not established in these studies\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"CRISPR deletion of NFAT/NF-κB-responsive regulatory elements at the RORC locus, combined with epigenomic profiling, defined the TCR-proximal transcriptional machinery that initiates RORγt expression in CD4+ T cells.\",\n      \"evidence\": \"CRISPR/Cas9 deletion, ChIP for NFAT/P300/CBP, histone modification analysis, reporter assays in human CD4+ T cells\",\n      \"pmids\": [\"31619674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether these regulatory elements are sufficient vs. necessary in the full chromatin context in vivo\",\n        \"Integration with upstream Notch and cytokine signals at the same regulatory regions was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that RORα cooperatively binds with RORγt at a novel cis-regulatory element within the Rorc locus explained how Th17 lineage stability is maintained in peripheral tissues and why RORα loss destabilizes RORγt expression.\",\n      \"evidence\": \"RORα conditional knockout in T cells, ChIP, in vivo Th17 functional assays\",\n      \"pmids\": [\"36243007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of RORα–RORγt cooperative DNA binding is unknown\",\n        \"Whether other transcription factors co-occupy this element was not explored\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking α-synuclein-driven RORC upregulation to Th17/Treg imbalance in Parkinson's disease models extended RORγt function beyond classical autoimmunity, with RORγt inhibition rescuing dopaminergic neuron loss.\",\n      \"evidence\": \"α-Syn-stimulated T cells, RORC expression analysis, GSK805 (RORγt inhibitor) in MPTP and A53T mouse PD models\",\n      \"pmids\": [\"36343753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which α-synuclein activates RORC transcription is not defined\",\n        \"Whether RORγt inhibition is neuroprotective independently of Th17 suppression is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of endogenous ligand(s) for RORγt, the co-repressor complexes mediating its gene-silencing activity, and the structural basis of RORα–RORγt cooperative binding remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous ligand identity not definitively established\",\n        \"Co-repressor machinery for RORγt-mediated silencing at target genes like PTGER2 unknown\",\n        \"No structural model of RORα–RORγt cooperative complex on DNA\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 5, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RORA\",\n      \"NFAT\",\n      \"STAT1\",\n      \"EP300\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"RORC encodes the nuclear receptor RORγ and its T-cell-specific isoform RORγt, serving as a master transcriptional regulator of type-17 immunity and lymphoid organ development. RORγt directly activates IL-17A transcription and silences PTGER2 in Th17 cells, and its ligand-binding domain is occupied by endogenous hydroxycholesterols and bile acid metabolites (e.g., 3-oxoLCA) that modulate coactivator recruitment to tune transcriptional output [PMID:20203100, PMID:31776512]. In thymocytes, RORγ sustains Bcl-xL expression to prevent apoptosis and is essential for lymph node and Peyer's patch organogenesis, while in the periphery it defines ILC3 identity and drives IL-17 production by iNKT17, γδT17, and conventional Th17 cells [PMID:10875923, PMID:19029904, PMID:30602780]. Bi-allelic loss-of-function RORC mutations in humans cause chronic mucocutaneous candidiasis and susceptibility to mycobacterial disease due to combined loss of IL-17- and IFN-γ-producing T cell subsets [PMID:26160376].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of RORγ as a novel orphan nuclear receptor established the existence of a third ROR subfamily member with tissue-selective expression, opening the question of its physiological function.\",\n      \"evidence\": \"cDNA cloning from human skeletal muscle with Northern blot expression profiling and chromosomal mapping\",\n      \"pmids\": [\"7811290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand or target gene identified\", \"Function in immune cells unknown\", \"No loss-of-function data\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Gene-targeted deletion revealed that RORγ is required for thymocyte survival via Bcl-xL regulation and for lymph node/Peyer's patch organogenesis, establishing its first in vivo functions.\",\n      \"evidence\": \"Two independent RORγ-knockout mouse lines with flow cytometry, TUNEL staining, and lymphoid organ histology\",\n      \"pmids\": [\"10875923\", \"10963675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Bcl-xL transcriptional control not defined at the promoter level\", \"Role of the T-cell-specific isoform (RORγt) not yet distinguished from full-length RORγ\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"RORγt was established as the lineage-defining transcription factor for Th17 differentiation, and Foxp3 was shown to directly bind and antagonize RORγt, explaining how TGF-β concentration reciprocally regulates Th17 versus Treg fate.\",\n      \"evidence\": \"Co-immunoprecipitation, domain-mapping mutagenesis, IL-17A promoter-luciferase assays, and in vitro Th17/Treg differentiation in mouse genetic models\",\n      \"pmids\": [\"18368049\", \"18434325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Foxp3–RORγt interaction unknown\", \"Endogenous ligand for RORγt LBD not yet identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that RORγt marks an intestinal NKp46+ innate lymphoid subset (later classified as ILC3) producing IL-22 expanded RORγt's role beyond adaptive Th17 cells to innate immunity.\",\n      \"evidence\": \"RORγt-GFP reporter mice with flow cytometry and intracellular cytokine staining of intestinal lamina propria lymphocytes\",\n      \"pmids\": [\"19029904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RORγt is continuously required for ILC3 maintenance versus initial specification was unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Upstream regulation of RORC transcription was delineated: IL-27/STAT1 suppresses Rorc expression, while Notch/DLL4 signaling directly activates the Rorc promoter, placing RORγt as an integrator of cytokine and Notch inputs.\",\n      \"evidence\": \"STAT1-deficient T cells, Notch inhibition, Rorc promoter reporter assays, EAE and DTH in vivo models\",\n      \"pmids\": [\"19380822\", \"19494260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full cis-regulatory architecture of the RORC locus not mapped\", \"Notch-Rorc promoter binding shown by reporter assay only, not ChIP\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Crystal structures of the RORγ LBD bound to hydroxycholesterols identified the first endogenous ligands and showed that ligand occupancy stabilizes the active conformation for coactivator recruitment, resolving the receptor's 'orphan' status.\",\n      \"evidence\": \"X-ray crystallography of RORγ LBD, site-directed mutagenesis, coactivator peptide recruitment assays\",\n      \"pmids\": [\"20203100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of hydroxycholesterol ligands in T cell differentiation not demonstrated in vivo\", \"Selectivity among different oxysterol species unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"ChIP-seq in Th17 cells revealed RORγt directly binds and silences PTGER2, uncovering a repressive function beyond its well-known activating role on IL-17, with clinical relevance in multiple sclerosis patients.\",\n      \"evidence\": \"ChIP-seq in mouse Th17 cells, RORC siRNA knockdown in human Th17 cells, EP2 gain-of-function, MS patient immunophenotyping\",\n      \"pmids\": [\"24812667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide repressive target repertoire of RORγt not fully catalogued\", \"Mechanism of transcriptional repression (corepressor identity) not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Human bi-allelic RORC loss-of-function mutations demonstrated that both RORγ isoforms are essential for mucocutaneous and systemic immunity, causing candidiasis and mycobacterial susceptibility through combined loss of IL-17 and impaired IFN-γ production by γδ T cells.\",\n      \"evidence\": \"Identification of patients with homozygous RORC mutations, deep immunophenotyping, cytokine production assays across multiple kindreds\",\n      \"pmids\": [\"26160376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RORγ regulates IFN-γ production mechanistically remains undefined\", \"Whether full-length RORγ versus RORγt is responsible for the mycobacterial phenotype is unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Pharmacological and temporal genetic ablation showed that ongoing RORγt activity is required to maintain Th17 cytokine output but is dispensable for ILC3 effector function, resolving a key question about differential RORγt dependency across lymphocyte lineages.\",\n      \"evidence\": \"Pharmacological RORγt inhibition in mice, conditional/temporal Rorc deletion, infection models, IBD patient tissue analysis\",\n      \"pmids\": [\"26878233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for differential RORγt dependency in ILC3 versus Th17 cells unknown\", \"Long-term consequences of RORγt inhibition on ILC3 homeostasis not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The bile acid metabolite 3-oxoLCA was identified as a direct endogenous RORγt antagonist linking gut microbial metabolism to Th17/Treg balance, and NFAT/NF-κB-dependent cis-regulatory elements at the RORC locus were mapped, completing a circuit from TCR signaling to RORγt expression.\",\n      \"evidence\": \"Bile acid library screen with direct LBD binding assays and intestinal Th17 analysis; CRISPR/Cas9 deletion of RORC cis-elements with ChIP and histone modification profiling in human CD4+ T cells\",\n      \"pmids\": [\"31776512\", \"31619674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of 3-oxoLCA to intestinal RORγt regulation quantitatively uncertain\", \"Interplay between NFAT/NF-κB elements and Notch-responsive elements at the RORC locus not integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"RORα was found to cooperatively bind with RORγt to a Rorc cis-regulatory element required for sustained RORγt expression and Th17 lineage stability in vivo, revealing a feed-forward loop between the two ROR family members.\",\n      \"evidence\": \"T-cell-specific RORα conditional knockout, ChIP assays, CRISPR/Cas9 deletion of the cooperative binding element, in vivo Th17 analysis\",\n      \"pmids\": [\"36243007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cooperative RORα/RORγt DNA binding unknown\", \"Whether this feed-forward loop operates in ILC3 or other RORγt+ lineages not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the genome-wide repressive target repertoire of RORγt, the structural basis of the Foxp3–RORγt interaction, the mechanism by which RORγ controls IFN-γ production, and how microbiota-derived ligands quantitatively tune RORγt activity across different tissue niches in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of Foxp3–RORγt complex\", \"Mechanism of RORγ-dependent IFN-γ regulation unknown\", \"Quantitative in vivo contributions of individual endogenous ligands not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 4, 8, 10, 16]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 8, 10, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8, 11, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 4, 8, 10, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [3, 4, 7, 10, 17, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3, 5, 6, 13, 15, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 9, 16, 17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FOXP3\",\n      \"RORA\",\n      \"BCL2L1\",\n      \"IL17A\",\n      \"PTGER2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}