{"gene":"NR1D1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1993,"finding":"NR1D1 (Rev-ErbAα) binds to a unique asymmetric 11-bp sequence consisting of a specific 5-bp A/T-rich sequence adjacent to a TR half-site, contacts this entire sequence as a monomer (not enhanced by RXR, TR, or other nuclear proteins), and activates transcription through this binding site in the absence of exogenous ligand.","method":"In vitro SELEX with bacterially-purified protein, gel shift assay, transfection reporter assay, mutagenesis of binding site","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with purified protein, SELEX, mutagenesis, and transcriptional assay in one study; highly cited foundational paper","pmids":["8474464"],"is_preprint":false},{"year":1994,"finding":"NR1D1 (Rev-ErbAα) does not bind thyroid hormone (T3), and the human protein is encoded by transcription from the noncoding strand of the c-erbAα genomic locus, sharing 269 bp of sequence identity with c-erbAα-2 cDNA used in opposite orientations.","method":"cDNA cloning, Northern blot, radioligand binding assay","journal":"DNA and cell biology","confidence":"High","confidence_rationale":"Tier 1 — direct ligand binding assay with negative result, confirmed by multiple labs; foundational characterization paper","pmids":["1971514"],"is_preprint":false},{"year":1994,"finding":"NR1D1 (Rev-ErbAα) binds direct repeat (DR4) thyroid hormone response elements but not palindromic or inverted palindromic TREs, and activates transcription via DR4 elements in transfected cells; deletion mapping of the ligand-binding domain identified regions modulating DNA binding.","method":"EMSA with GST-fusion proteins, transfection reporter assay with DR4/TREpal/F2H elements, deletion analysis","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assay with recombinant protein plus cell-based reporter; directly defines DNA-binding specificity","pmids":["8015547"],"is_preprint":false},{"year":1995,"finding":"Constitutive overexpression of NR1D1 (Rev-ErbAα) in C2C12 myoblasts completely abolished differentiation, suppressed myoD mRNA, and abrogated myogenin induction; the ligand-binding domain (LBD) contains an active transcriptional silencer; the receptor disrupts TR homodimer and TR/RXR heterodimer formation on TREs in the myoD gene family promoters.","method":"Stable overexpression in C2C12 cells, Northern blot, GAL4 chimera transfection assay, deletion/domain analysis","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 — clean loss/gain-of-function with defined molecular mechanism; replicated across multiple gene targets","pmids":["8614403"],"is_preprint":false},{"year":1996,"finding":"NR1D1 (Rev-ErbAα) and RVR interact with nuclear receptor corepressor N-CoR/RIP13 via two receptor interaction domains (ID-I and ID-II); the physical association requires an intact E region (LBD) of NR1D1; overexpression of dominant-negative N-CoR interaction domains alleviates NR1D1-mediated repression.","method":"Mammalian two-hybrid system, transfection repression assay, domain deletion analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — mammalian two-hybrid plus functional repression assay; two independent approaches; confirmed with dominant-negative rescue","pmids":["8948627"],"is_preprint":false},{"year":1996,"finding":"Transcriptional repression by NR1D1 (Rev-ErbAα) is mediated by a minimal 34-amino acid domain (aa 455–488) in the E region containing the LBD signature motif and helix 5; mutagenesis of either element impairs repression; an alternative study using the same interaction domain of N-CoR (aa 2218–2451) found no interaction, suggesting that this particular N-CoR region (interacting with TR/RAR) does not mediate NR1D1 repression.","method":"GAL4 hybrid system, fine deletions, site-specific mutagenesis, mammalian two-hybrid with N-CoR interaction domain","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with functional repression assay; defined minimal silencing domain","pmids":["8836173"],"is_preprint":false},{"year":1998,"finding":"NR1D1 (Rev-ErbAα) contains two corepressor interaction regions (CIR-1 and CIR-2) in its E region; CIR-1 maps to the N-terminal portion of helix 3 with critical phenylalanine residues (F441 in Rev-ErbAα); mutations in CIR-1 or deletion of CIR-2 impair interaction with N-CoR, RIP13a, and RIP13δ1 and reduce repression of the native Rev-ErbAα promoter.","method":"Mammalian two-hybrid, co-transfection repression assays, mutagenesis of CIR-1, corepressor domain overexpression (dominant-negative rescue)","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis combined with functional assays and dominant-negative rescue; identifies specific residues","pmids":["9482666"],"is_preprint":false},{"year":2000,"finding":"Homology modeling of NR1D1/RVR LBDs revealed that the putative ligand cavity is occupied by side chains (suggesting no endogenous ligand) and that the absence of helix 12 exposes a large hydrophobic surface (H3, loop 3–4, H4, H11); mutagenesis of residues on this surface severely impairs in vitro and in vivo interaction with N-CoR/RIP13δ1 and reduces transcriptional repression, demonstrating that corepressors bind the H3–H4/H11 surface of NR1D1.","method":"Homology modeling, site-directed mutagenesis, in vitro pulldown, co-transfection repression assay","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1 — structure-guided mutagenesis + in vitro binding + functional assay; identifies corepressor-binding surface","pmids":["10809233"],"is_preprint":false},{"year":2004,"finding":"Nr1d1-null mice exhibit aberrant myosin heavy chain (MyHC) isoform expression in slow-twitch soleus muscle, with significantly higher relative amounts of β/slow (type I) MyHC in both heterozygous and homozygous knockout mice vs. wild-type, demonstrating a role for NR1D1 in regulating skeletal muscle fiber type composition.","method":"Nr1d1 knockout mouse model, muscle fiber type analysis, MyHC isoform quantification; ruled out TRα2 involvement by comparing TRα2-deficient mice","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined phenotype; genetic control performed; single study","pmids":["15374821"],"is_preprint":false},{"year":2011,"finding":"NR1D1 is co-expressed with NR2E3 in the outer neuroblastic layer of the developing mouse retina and in rods/cones of adult retina; knockdown of Nr1d1 in developing retina causes pan-retinal spotting and reduced ERG function; NR1D1 co-regulates a transcriptional network including Nr2c1, Recoverin, Rgr, and Pde8a together with NR2E3.","method":"In vivo Nr1d1 knockdown, electroretinogram, immunohistochemistry, gene expression analysis; cycling of Nr1d1 and Nr2e3 over 24 h","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — KD with functional ERG readout plus co-expression and gene network data; single study","pmids":["21408158"],"is_preprint":false},{"year":2013,"finding":"ApoA-IV binds NR1D1 directly (identified by bacterial two-hybrid screening; confirmed by coimmunoprecipitation and proximity ligation assay); ApoA-IV stimulates NR1D1 recruitment to the Glc-6-Pase promoter (by ChIP), reducing gluconeogenic gene expression; in NR1D1-knockdown cells, ApoA-IV fails to inhibit PEPCK and Glc-6-Pase.","method":"Bacterial two-hybrid library screen, coimmunoprecipitation, in situ proximity ligation assay, ChIP, luciferase reporter, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, PLA, ChIP, reporter, KD rescue) establishing direct protein–protein interaction and downstream transcriptional mechanism","pmids":["24311788"],"is_preprint":false},{"year":2016,"finding":"In zebrafish, Nr1d1/Rev-erbα directly regulates autophagy gene transcription (demonstrated by luciferase reporter and ChIP assays); nr1d1 mutant fish show significantly upregulated autophagy genes and cebpb, indicating Nr1d1 is a direct transcriptional repressor of autophagy genes in the circadian-autophagy axis.","method":"TALEN-generated nr1d1 mutant zebrafish, luciferase reporter assay, ChIP, transcriptome analysis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP + reporter + genetic mutant; direct binding to autophagy gene promoters established","pmids":["27171500"],"is_preprint":false},{"year":2016,"finding":"siRNA knockdown of NR1D1 in human chondrocytes predominantly affects TGF-β signaling pathway gene expression (RNA-seq), and NR1D1 knockdown increases BMAL1 expression while BMAL1 knockdown decreases NR1D1, demonstrating reciprocal regulation within the circadian clock network with functional consequences on chondrocyte TGF-β signaling.","method":"siRNA knockdown, RNA sequencing, quantitative PCR, synchronized human chondrocyte cultures","journal":"Osteoarthritis and cartilage","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with pathway-level transcriptomics; single study but RNA-seq provides broad mechanistic evidence","pmids":["27884645"],"is_preprint":false},{"year":2017,"finding":"NR1D1 inhibits both non-homologous end joining and homologous recombination DNA double-strand break repair; PARP1 PARylates NR1D1 and drives its recruitment to damaged DNA lesions; the LBD of NR1D1 interacts with PARP1; NR1D1 inhibits recruitment of SIRT6, pNBS1, and BRCA1 to DNA lesion sites; PARP1 inhibitor suppresses NR1D1 recruitment to damaged DNA.","method":"γH2AX foci clearance assay, NHEJ/HR repair assays, Co-IP (NR1D1-PARP1), LBD deletion mutants, PARP1 inhibitor treatment, in vitro/in vivo doxorubicin sensitivity","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal assays (Co-IP, repair assays, inhibitor, domain deletion, in vivo) in a single study defining a novel function","pmids":["28249904"],"is_preprint":false},{"year":2017,"finding":"NR1D1 interacts with PARP1 and inhibits its catalytic (poly-ADP-ribosylation) activity, thereby enhancing accumulation of ROS-induced DNA damage and sensitizing breast cancer cells to oxidative stress.","method":"Co-IP (NR1D1-PARP1), PARP1 activity assay, ROS-induced DNA damage accumulation assay","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 — direct enzyme activity inhibition shown with Co-IP and functional assay; corroborated by companion paper (PMID 28249904)","pmids":["28599788"],"is_preprint":false},{"year":2018,"finding":"REVERBα (NR1D1) physically interacts with the glucocorticoid receptor (GR) and co-binds chromatin with liver-specific HNFs; REVERBα promotes efficient GR recruitment to chromatin during the day by maintaining histone acetylation; deletion of Reverba inverts circadian liver GC sensitivity and protects mice from GC-induced hepatosteatosis.","method":"Reciprocal Co-IP (GR-REVERBα), ChIP-seq (co-binding analysis), conditional Reverba knockout mice, metabolic phenotyping","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP + ChIP-seq + conditional KO with specific metabolic phenotype; multiple orthogonal methods","pmids":["30179226"],"is_preprint":false},{"year":2019,"finding":"STRA8 binds to the Nr1d1 promoter and directly represses its transcription in spermatogonia; NR1D1 in turn binds to the Ulk1 promoter to activate autophagy; genetic deletion or pharmacologic inhibition of NR1D1 rescues meiotic initiation defects in Stra8-deficient male germ cells, placing NR1D1 downstream of STRA8 in a STRA8→NR1D1→ULK1→autophagy axis.","method":"ChIP (STRA8 on Nr1d1 promoter; NR1D1 on Ulk1 promoter), genetic deletion of Nr1d1, pharmacologic NR1D1 inhibition (SR8278), autophagy assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP + genetic epistasis (double-mutant rescue) + pharmacological rescue; defines pathway order with multiple methods","pmids":["31059511"],"is_preprint":false},{"year":2021,"finding":"NR1D1 directly represses StAR expression in Leydig cells by binding to a canonical RORE element in the StAR promoter (demonstrated by dual-luciferase reporter and EMSA), reducing testosterone synthesis; glyphosate-induced upregulation of NR1D1 mediates inhibition of StAR and testosterone production.","method":"Dual-luciferase reporter assay, EMSA, siRNA/agonist (SR9009) modulation, in vitro and in vivo testosterone measurement","journal":"The Science of the total environment","confidence":"High","confidence_rationale":"Tier 1 — EMSA + luciferase reporter with RORE mutation + agonist/antagonist pharmacology; direct promoter binding demonstrated","pmids":["33957581"],"is_preprint":false},{"year":2021,"finding":"NR1D1 directly represses ATG5 transcription by binding to two putative RORE elements within the Atg5 promoter (shown by dual-luciferase reporter and EMSA), thereby regulating granulosa cell autophagy; Nr1d1 knockdown increases ATG5 expression and autophagy.","method":"Dual-luciferase reporter, EMSA, siRNA knockdown, SR9009 agonist treatment, Bmal1-/- mouse model","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 — EMSA + luciferase with RORE deletion + genetic/pharmacological corroboration; direct binding confirmed","pmids":["34936504"],"is_preprint":false},{"year":2021,"finding":"NR1D1 directly represses CYP19A1 transcription in granulosa cells by binding to a RORE on the CYP19A1 promoter, reducing estradiol synthesis; NR1D1 activation (SR9009) decreases estradiol; NR1D1 interference increases CYP19A1 expression and estradiol production.","method":"Luciferase reporter, ChIP (implied from promoter binding), SR9009 agonist, siRNA knockdown, steroid hormone measurement","journal":"Theriogenology","confidence":"Medium","confidence_rationale":"Tier 1–2 — reporter assay + pharmacological modulation + KD; corroborated by multiple independent studies on NR1D1 steroidogenesis repression","pmids":["34933195"],"is_preprint":false},{"year":2022,"finding":"NR1D1 deficiency in mice impairs SERCA-dependent sarcoplasmic reticulum Ca2+ uptake in skeletal muscle; NR1D1 represses the SERCA inhibitor myoregulin by direct binding to its promoter; restoration of myoregulin counteracts NR1D1 overexpression on SR calcium content; pharmacological NR1D1 activation ameliorates SR calcium homeostasis and improves muscle structure/function in dystrophic mdx/Utr+/- mice.","method":"Nr1d1 KO mouse, ChIP (NR1D1 on myoregulin promoter), Ca2+ uptake assay, myoregulin rescue experiment, in vivo SR9009 treatment in mdx/Utr+/- mice","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP + KO + rescue + in vivo therapeutic validation; multiple orthogonal methods across two systems","pmids":["35917173"],"is_preprint":false},{"year":2022,"finding":"NR1D1 identifies ACO2 (aconitase-2, a TCA cycle enzyme) as a direct transcriptional target that it trans-represses in vascular smooth muscle cells; NR1D1 deficiency restores ACO2 dysregulation and mitochondrial dysfunction; VSMC-specific (but not endothelial or myeloid) Nr1d1 KO inhibits AAA formation in two mouse models.","method":"VSMC/EC/myeloid-specific conditional Nr1d1 KO mice, two AAA models (AngII, CaPO4), ChIP/reporter for ACO2 promoter, mitochondrial metabolic assays, αKG supplementation rescue","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 — conditional cell-type-specific KO + direct target identification by ChIP + metabolic rescue; highly rigorous multi-model study","pmids":["35880522"],"is_preprint":false},{"year":2023,"finding":"NR1D1 promotes DNA damage-induced accumulation of cytosolic DNA fragments and activates cGAS-STING signaling, increasing type I IFN production and downstream chemokines CCL5 and CXCL10, thereby enhancing CD8+ T cell and NK cell antitumor responses; Nr1d1 deletion in tumor cells (MMTV-PyMT) increases tumor growth and suppresses type I IFN signaling.","method":"Nr1d1-/-;MMTV-PyMT transgenic mice, orthotopic allograft, transcriptome analysis, cytosolic DNA quantification, cGAS-STING pathway analysis, SR9009 pharmacological treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — clean KO in transgenic tumor model + transcriptomics + pathway mechanistic analysis + pharmacological validation","pmids":["37395684"],"is_preprint":false},{"year":2023,"finding":"NR1D1 degradation via m6A (N6-methyladenosine) methylation in hepatic stellate cells inhibits DRP1-S616 phosphorylation, impairing mitochondrial fission and increasing mitochondrial DNA release, which activates the cGAS pathway and drives liver fibrosis; NR1D1 overexpression restores DRP1S616 phosphorylation and suppresses cGAS pathway.","method":"Nr1d1-deficient mice (CCl4 model), NR1D1 overexpression (AAV), m6A methylation analysis, DRP1-S616 phosphorylation assay, cGAS pathway readout","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 — KO + OE rescue + pathway mechanistic readouts; single study but multiple assays","pmids":["36813093"],"is_preprint":false},{"year":2021,"finding":"NR1D1 binds promoters of IL-1β and NLRP3 to directly repress their transcription in macrophages, thereby inhibiting NLRP3 inflammasome assembly; NR1D1 deficiency in ApoE-/- mice augments plaque vulnerability and macrophage pyroptosis in a NLRP3-dependent manner.","method":"NR1D1-/-ApoE-/- double-KO mice, BMDM experiments, ChIP (NR1D1 on IL-1β/NLRP3 promoters, implied from mechanistic statement), SR9009 agonist treatment, pyroptosis assays","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined phenotype + promoter binding mechanistic claim + pharmacological rescue; single study","pmids":["34956438"],"is_preprint":false},{"year":2021,"finding":"In the nucleus accumbens, Nr1d1 knockdown via AAV-shRNA enhances sociability and reduces anxiety in female mice; knockdown upregulates Per1 and Per2, and alters opioid-related genes (Oprd1, Penk), demonstrating a sex-specific role for NR1D1 in behavioral regulation through the circadian and opioid gene networks.","method":"AAV-shRNA knockdown in NAc, behavioral testing, microarray, qPCR","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — region-specific KD with defined behavioral phenotype + molecular readouts; single lab","pmids":["30028550","30326159"],"is_preprint":false},{"year":2017,"finding":"Acute in utero electroporation-mediated knockdown of Nr1d1 in mouse cerebral cortex caused abnormal positioning of cortical neurons, impaired neuronal migration (time-lapse imaging), suppressed axon extension and dendritic arbor formation; wild-type Nr1d1 but not the p.R500H ASD-associated mutant rescued the abnormal phenotype, establishing Nr1d1 as required for cortical neuron migration and morphogenesis.","method":"In utero electroporation knockdown, time-lapse imaging, rescue with WT vs. mutant Nr1d1, cortical neuron positioning analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — clean KD with live imaging phenotype + allele-specific rescue; directly establishes functional requirement","pmids":["28262759"],"is_preprint":false},{"year":2023,"finding":"NR1D1 directly represses Hmga2 transcription by binding its promoter (shown by ChIP-seq and EMSA), thereby suppressing NF-κB signaling and microglial activation; overexpressed HMGA2 partially abolishes the anti-inflammatory effects of NR1D1 in microglia.","method":"ChIP-seq (NR1D1 in BV2 microglia), RNA-seq, EMSA, luciferase reporter, Hmga2 overexpression rescue, BETA tool integration","journal":"Journal of inflammation research","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP-seq + EMSA + luciferase + rescue experiment; multiple orthogonal methods in single study","pmids":["34795498"],"is_preprint":false},{"year":2023,"finding":"NR1D1 directly represses BNIP3 expression by binding its promoter (ChIP), acting as a positive regulator of mitophagy in intestinal epithelial cells; NR1D1 ablation leads to disrupted mitophagy and increased inflammation/apoptosis; SR9009 (agonist) ameliorates colitis by rectifying defective mitophagy.","method":"Intestinal-specific Nr1d1 KO mice, DSS colitis model, RNA-seq, ChIP, dual-luciferase reporter, transmission electron microscopy, confocal microscopy","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1–2 — tissue-specific KO + ChIP + luciferase + EM of mitophagy + in vivo SR9009 rescue","pmids":["37762536"],"is_preprint":false},{"year":2023,"finding":"Ran GTPase, through miR4472 maturation, destabilizes NR1D1 mRNA; NR1D1 interacts with both PARP1 and BRCA1 leading to inhibition of DNA repair; Ran inhibition induces NR1D1 upregulation and DNA damage accumulation in aneuploid ovarian cancer cells.","method":"miRNA maturation assay, mRNA stability assay, Co-IP (NR1D1 with PARP1 and BRCA1), DNA damage assays, Ran inhibition","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP evidence for BRCA1 interaction is new; mechanistic framework supported by multiple assays but single lab","pmids":["34743206"],"is_preprint":false},{"year":2023,"finding":"Glucocorticoid receptor (GR/NR3C1) binds the Nr1d1 promoter E-box to suppress Nr1d1 expression in colon epithelium during stress; GR alters chromatin 3D structure at the Ikzf3-Nr1d1 super-enhancer; intestinal-specific Nr3c1 deletion abolishes stress-induced Nr1d1 suppression and associated IBS phenotypes.","method":"ChIP (GR at Nr1d1 promoter E-box), chromatin conformation (3D structure analysis), intestinal-specific Nr3c1 KO mice, water avoidance stress model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + 3D chromatin + conditional KO; single study","pmids":["37404374"],"is_preprint":false},{"year":2023,"finding":"NR1D1 binds to IL-1β and NLRP3 promoters (shown by ChIP) in nucleus pulposus cells to repress their expression; NR1D1 activation (SR9009) inhibits NLRP3 inflammasome assembly and IL-1β production, and increases ECM synthesis in disc cells.","method":"ChIP (NR1D1 on IL-1β/NLRP3 promoters), luciferase reporter, SR9009 treatment, in vitro NPMSC model, in vivo disc degeneration model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + reporter + pharmacological validation in vitro and in vivo; single study","pmids":["38689641"],"is_preprint":false},{"year":2024,"finding":"NR1D1 directly represses IL-6 transcription in bovine endometrial epithelial cells by binding to a retinoic acid receptor-related orphan receptor-responsive element (RORE; -473 to -479) in the IL-6 promoter, as demonstrated by dual-luciferase reporter and deletion analysis; NR1D1 has predominantly nuclear localization in these cells.","method":"Dual-luciferase reporter with RORE deletion, siRNA/overexpression, SR9009 treatment, immunofluorescence (nuclear localization), primary cell culture","journal":"International journal of biological macromolecules","confidence":"High","confidence_rationale":"Tier 1–2 — RORE deletion luciferase + localization + gain/loss-of-function; directly maps functional element","pmids":["39551321"],"is_preprint":false},{"year":2024,"finding":"LC3 (autophagosome marker) directly binds to NR1D1 via LC3-interacting region (LIR) motifs, leading to NR1D1 degradation in a mitophagy-dependent manner; mitophagy defects lead to NR1D1 accumulation and subsequent BMAL1 suppression, disrupting circadian rhythms.","method":"Co-IP (LC3-NR1D1), LIR motif identification, mitophagy inhibition experiments, urolithin A (mitophagy activator) treatment, rat simulated microgravity model","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP identifying LIR-mediated interaction + functional consequence on clock; single study","pmids":["38732079"],"is_preprint":false},{"year":2024,"finding":"NR1D1 trans-represses Dusp1 (dual specificity phosphatase 1) transcription in pulmonary artery smooth muscle cells; NR1D1 deficiency restores Dusp1 expression, deactivating ERK1/2 and reducing DRP1-mediated mitochondrial fission; AAV1-mediated Nr1d1 knockdown inhibits PH progression in chronic intermittent hypoxia models.","method":"ChIP/reporter for Dusp1 promoter, AAV1 KD in vivo, ERK1/2 inhibitor and PMA pharmacology, Dusp1 KO mice, mitochondrial fission assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter target identified with mechanistic pathway validation and in vivo KD; single study","pmids":["39472573"],"is_preprint":false},{"year":2023,"finding":"NR1D1 is transactivated in cisplatin-resistant neuroblastoma cells and drives expression of lncRNA NUTM2A-AS1, which in turn inhibits B7-H3 protein degradation, promoting immune evasion and chemoresistance.","method":"Gain/loss-of-function of NR1D1 and NUTM2A-AS1, Co-IP/RIP (NUTM2A-AS1 with B7-H3), cisplatin sensitivity assays, luciferase reporter (NR1D1 → NUTM2A-AS1 promoter)","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — reporter + co-IP + functional assays in single study; defines NR1D1 as transactivator in this context","pmids":["38785199"],"is_preprint":false},{"year":2025,"finding":"NR1D1 depletion enhances autophagic flux and mitophagy in human cell lines and AD model organisms; Nr1d1 knockdown in 5xFAD mice restores autophagy marker expression; depletion of the C. elegans ortholog nhr-85 improves neuronal mitophagy and extends lifespan in amyloid-β models; NR1D1 knockdown activates SIRT1 and Cathepsin B (CTSB), both linked to autophagy.","method":"NR1D1 KD in human cell lines, 5xFAD mouse KD, C. elegans nhr-85 depletion, autophagic flux assay, mitophagy assay, SIRT1/CTSB activity","journal":"Aging and disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple model systems (human cells, mouse, C. elegans) with consistent autophagy/mitophagy readouts; single study","pmids":["39812544"],"is_preprint":false},{"year":2025,"finding":"NR1D1 suppresses HSD17B12 transcription by binding to its promoter (CUT&Tag-qPCR and dual-luciferase reporter), reducing antioxidant capacity and promoting ROS-induced apoptosis in sheep granulosa cells via the AMPK pathway; NR1D1 knockdown of HSD17B12 partially alleviates the effects of NR1D1 overexpression on GC function.","method":"ATAC-seq, CUT&Tag-qPCR, dual-luciferase reporter, NR1D1 OE/KD, AMPK pathway assays, ROS and apoptosis measurements","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 1–2 — direct promoter binding (CUT&Tag + luciferase) + functional rescue; single study but multiple methods","pmids":["39986531"],"is_preprint":false}],"current_model":"NR1D1 (REV-ERBα) is a constitutive transcriptional repressor that lacks an activation function 2 helix, binds RORE/DR2 DNA elements as a monomer, recruits the corepressor N-CoR/RIP13 via its ligand-binding domain (H3–H4/H11 surface and CIR-1/CIR-2 regions), and directly represses core circadian clock genes (BMAL1), autophagy genes (ATG5, BNIP3, ULK1), steroidogenic genes (StAR, CYP19A1, ACO2), and inflammatory mediators (IL-6, IL-1β, NLRP3, HMGA2); it also acts non-transcriptionally by interacting with PARP1 to inhibit its catalytic activity and recruit DNA damage factors to lesions, and by promoting cGAS-STING signaling, while its own protein level is regulated by PARP1-mediated PARylation (directing chromatin recruitment), m6A-dependent mRNA degradation, and mitophagy-linked LC3-LIR interactions."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing that NR1D1 is an orphan nuclear receptor: the receptor was shown not to bind thyroid hormone (T3) despite being encoded antisense to the c-erbAα locus, resolving its classification as a true orphan.","evidence":"Radioligand binding assay with purified receptor, cDNA cloning and Northern blot","pmids":["1971514"],"confidence":"High","gaps":["No endogenous ligand identified at this stage","Physiological function unknown"]},{"year":1993,"claim":"Defining DNA-binding specificity: NR1D1 was found to bind as a monomer to an asymmetric 11-bp element (later called RORE) and to DR4 elements, establishing the receptor's monomeric DNA-binding mode distinct from TR/RXR heterodimers.","evidence":"SELEX with purified protein, EMSA, mutagenesis, and reporter assays in transfected cells","pmids":["8474464","8015547"],"confidence":"High","gaps":["Whether NR1D1 can also bind as dimers on certain elements","In vivo relevance of monomeric binding unclear"]},{"year":1996,"claim":"Identifying the corepressor mechanism: NR1D1's ligand-binding domain (LBD) was shown to contain an intrinsic transcriptional silencing function mediated by interaction with N-CoR/RIP13 through two corepressor interaction regions (CIR-1 and CIR-2), with critical phenylalanine residues required for repression.","evidence":"Mammalian two-hybrid, GAL4 chimeras, fine deletion/point mutagenesis, dominant-negative rescue","pmids":["8948627","8836173","9482666"],"confidence":"High","gaps":["Whether SMRT or other corepressors also participate","No crystal structure of NR1D1-corepressor complex"]},{"year":2000,"claim":"Mapping the corepressor-binding surface: homology modeling and mutagenesis revealed that the absence of helix 12 (AF-2) exposes a hydrophobic surface (H3–H4/H11) that directly contacts N-CoR, explaining why NR1D1 is a constitutive repressor.","evidence":"Homology modeling, site-directed mutagenesis, in vitro pulldown, co-transfection repression assay","pmids":["10809233"],"confidence":"High","gaps":["No experimental 3D structure at this point","Coactivator recruitment possibility not fully excluded"]},{"year":2004,"claim":"In vivo physiological role established: Nr1d1 knockout mice showed altered skeletal muscle fiber type composition, providing the first genetic evidence that NR1D1 regulates tissue-specific gene programs beyond circadian genes.","evidence":"Nr1d1 knockout mouse, MyHC isoform quantification in soleus muscle","pmids":["15374821"],"confidence":"Medium","gaps":["Downstream target genes in muscle not identified","Redundancy with NR1D2/REV-ERBβ not addressed"]},{"year":2013,"claim":"Discovery of a non-nuclear-receptor protein partner modulating NR1D1 chromatin recruitment: ApoA-IV was shown to directly bind NR1D1 and stimulate its recruitment to gluconeogenic gene promoters, linking NR1D1 to metabolic regulation beyond circadian clock targets.","evidence":"Bacterial two-hybrid, Co-IP, proximity ligation assay, ChIP, luciferase reporter, siRNA knockdown","pmids":["24311788"],"confidence":"High","gaps":["Physiological relevance of ApoA-IV–NR1D1 interaction in vivo","Whether other apolipoproteins modulate NR1D1"]},{"year":2016,"claim":"Direct transcriptional regulation of autophagy genes by NR1D1 was established, positioning it as a circadian gatekeeper of autophagy.","evidence":"TALEN-generated nr1d1 mutant zebrafish, ChIP, luciferase reporter; reciprocal BMAL1 regulation confirmed in human chondrocytes by siRNA/RNA-seq","pmids":["27171500","27884645"],"confidence":"High","gaps":["Specific autophagy gene promoter elements not fully mapped in mammals at this time","Whether NR1D1 regulation of autophagy is tissue-specific"]},{"year":2017,"claim":"A non-transcriptional function was uncovered: NR1D1 physically interacts with PARP1 via its LBD, inhibits PARP1 catalytic activity, and is itself PARylated and recruited to DNA damage sites, establishing NR1D1 as a modulator of DNA repair through NHEJ and HR suppression.","evidence":"Co-IP, PARP1 activity assay, γH2AX foci clearance, NHEJ/HR repair assays, LBD deletion mutants, PARP1 inhibitor, in vivo doxorubicin sensitivity","pmids":["28249904","28599788"],"confidence":"High","gaps":["Crystal structure of NR1D1–PARP1 complex lacking","Whether PARylation-mediated recruitment is circadian-dependent"]},{"year":2017,"claim":"NR1D1 was shown to be required for cortical neuron migration and morphogenesis; the ASD-associated R500H mutation failed to rescue knockdown phenotypes, linking NR1D1 to neurodevelopmental processes.","evidence":"In utero electroporation knockdown in mouse cortex, time-lapse imaging, WT vs. R500H mutant rescue","pmids":["28262759"],"confidence":"High","gaps":["Direct transcriptional targets mediating migration are unknown","Broader ASD cohort validation of R500H needed"]},{"year":2018,"claim":"Cooperative chromatin regulation with GR was demonstrated: NR1D1 physically interacts with GR, facilitates its chromatin recruitment by maintaining histone acetylation, and modulates circadian glucocorticoid sensitivity in liver, linking NR1D1 to metabolic disease through GR co-regulation.","evidence":"Reciprocal Co-IP, ChIP-seq co-binding analysis, conditional Reverba KO mice, metabolic phenotyping","pmids":["30179226"],"confidence":"High","gaps":["Whether NR1D1–GR interaction is direct or bridged by chromatin","Mechanism by which NR1D1 maintains histone acetylation unclear"]},{"year":2021,"claim":"NR1D1's direct repression of specific target promoters via RORE elements was mapped with high resolution across multiple tissues: StAR (Leydig cells), ATG5 (granulosa cells), CYP19A1 (granulosa cells), IL-1β/NLRP3 (macrophages), and ULK1 (spermatogonia), solidifying RORE-mediated repression as the core mechanism across steroidogenesis, autophagy, and inflammation.","evidence":"EMSA, dual-luciferase reporters with RORE deletion/mutation, ChIP, siRNA/agonist modulation, genetic epistasis with Stra8","pmids":["33957581","34936504","34933195","34956438","31059511"],"confidence":"High","gaps":["Genome-wide RORE occupancy map in most tissues still lacking","Cofactor requirements at individual promoters not distinguished"]},{"year":2022,"claim":"Cell-type-specific conditional KO studies revealed that NR1D1 in vascular smooth muscle cells trans-represses ACO2 to regulate mitochondrial TCA cycle function and aneurysm formation, while in skeletal muscle it represses myoregulin to control SR calcium uptake, demonstrating tissue-specific metabolic target selection.","evidence":"VSMC/EC/myeloid-specific conditional KO, ChIP/reporter for ACO2 and myoregulin, metabolic and Ca²⁺ uptake assays, in vivo rescue","pmids":["35880522","35917173"],"confidence":"High","gaps":["How NR1D1 selects tissue-specific targets is mechanistically unexplained","Redundancy with NR1D2 in these tissues not fully addressed"]},{"year":2023,"claim":"NR1D1 was connected to innate immune sensing: it promotes cytosolic DNA accumulation after DNA damage, activates cGAS-STING signaling and type I IFN production, and enhances antitumor CD8⁺ T cell and NK cell responses; separately, NR1D1 loss in hepatic stellate cells increases mitochondrial DNA release and cGAS activation via impaired DRP1-mediated fission.","evidence":"Nr1d1⁻/⁻;MMTV-PyMT mice, transcriptomics, cytosolic DNA quantification, cGAS-STING pathway analysis; CCl4 fibrosis model with AAV rescue, DRP1 phosphorylation assay","pmids":["37395684","36813093"],"confidence":"High","gaps":["Whether cGAS-STING activation is transcription-dependent or DNA-repair-dependent","Context-dependent opposing effects of NR1D1 on cGAS in tumor vs. fibrosis need reconciliation"]},{"year":2023,"claim":"Genome-wide target identification by ChIP-seq in microglia identified HMGA2 as a direct NR1D1 repression target, connecting NR1D1 to NF-κB suppression and anti-inflammatory function in the CNS.","evidence":"ChIP-seq, RNA-seq, EMSA, luciferase reporter, HMGA2 overexpression rescue in BV2 microglia","pmids":["34795498"],"confidence":"High","gaps":["Whether HMGA2 repression generalizes to peripheral macrophages","Full ChIP-seq target list not functionally validated"]},{"year":2024,"claim":"Protein-level regulation of NR1D1 was clarified: LC3 directly binds NR1D1 via LIR motifs, targeting it for mitophagy-dependent degradation; this links mitophagy status to circadian clock output via BMAL1 de-repression, and m6A-dependent mRNA degradation provides an additional post-transcriptional control layer.","evidence":"Co-IP (LC3–NR1D1), LIR motif identification, mitophagy inhibition, m6A analysis, BMAL1 expression readout","pmids":["38732079","36813093"],"confidence":"Medium","gaps":["Which E3 ligase or selective autophagy receptor mediates NR1D1 degradation","Quantitative contribution of m6A vs. mitophagy to NR1D1 turnover unknown","LC3-LIR interaction awaits structural validation"]},{"year":null,"claim":"Key unresolved questions include: whether NR1D1 has a true endogenous ligand or functions entirely as a constitutive repressor; the structural basis of the NR1D1–PARP1 interaction; how tissue-specific target gene selection is achieved; and the full reconciliation of NR1D1's opposing roles in cGAS-STING activation across different cellular contexts (tumor immunity vs. fibrosis).","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of full-length NR1D1 with corepressor or PARP1","Endogenous ligand question unresolved despite heme identification by other groups not captured in this timeline","Tissue-specific cofactor logic unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2,17,18,27,32]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,4,5,6,7,11,17,18,19,24,27,28,32]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,14,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,7,15,32]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,4,5,6,7,11,17,18,19,27,28,32]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[11,12,33]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13,14,29]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,16,18,28,36]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[22,24,27,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,23,34]}],"complexes":[],"partners":["NCOR1","PARP1","NR3C1","APOA4","BRCA1","MAP1LC3B"],"other_free_text":[]},"mechanistic_narrative":"NR1D1 (REV-ERBα) is a ligand-independent nuclear receptor that functions as a constitutive transcriptional repressor, integrating circadian clock regulation with metabolism, inflammation, autophagy, DNA repair, and innate immunity. It binds ROR-responsive elements (ROREs) and direct repeat elements as a monomer, lacks a classical activation function 2 (AF-2) helix, and recruits the corepressor N-CoR via a hydrophobic surface formed by helices H3–H4/H11 and two corepressor interaction regions (CIR-1/CIR-2) in its ligand-binding domain, directly repressing BMAL1, IL-6, IL-1β, NLRP3, ATG5, BNIP3, StAR, CYP19A1, ACO2, HMGA2, and other target gene promoters [PMID:8474464, PMID:9482666, PMID:10809233, PMID:34956438, PMID:33957581, PMID:34936504, PMID:34795498, PMID:35880522, PMID:39551321]. Beyond transcriptional repression, NR1D1 physically interacts with PARP1, inhibits its catalytic poly-ADP-ribosylation activity, and modulates DNA double-strand break repair by blocking recruitment of SIRT6, pNBS1, and BRCA1 to damage sites; PARP1-mediated PARylation reciprocally drives NR1D1 recruitment to DNA lesions [PMID:28249904, PMID:28599788]. NR1D1 also promotes cytosolic DNA accumulation and cGAS-STING-dependent type I interferon signaling to enhance antitumor immunity, while its own protein turnover is regulated by LC3-LIR-mediated mitophagy-dependent degradation and m6A-directed mRNA destabilization [PMID:37395684, PMID:38732079, PMID:36813093]."},"prefetch_data":{"uniprot":{"accession":"P20393","full_name":"Nuclear receptor subfamily 1 group D member 1","aliases":["Rev-erbA-alpha","V-erbA-related protein 1","EAR-1"],"length_aa":614,"mass_kda":66.8,"function":"Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC1 and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner. Represses the transcription of CYP2B10, CYP4A10 and CYP4A14 (By similarity). Represses the transcription of CES2 (By similarity). Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner (By similarity). Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity (By similarity). Plays a critical role in the circadian control of neutrophilic inflammation in the lung; under resting, non-stress conditions, acts as a rhythmic repressor to limit inflammatory activity whereas in the presence of inflammatory triggers undergoes ubiquitin-mediated degradation thereby relieving inhibition of the inflammatory response (By similarity). Plays a key role in the circadian regulation of microglial activation and neuroinflammation; suppresses microglial activation through the NF-kappaB pathway in the central nervous system (By similarity). Plays a role in the regulation of the diurnal rhythms of lipid and protein metabolism in the skeletal muscle via transcriptional repression of genes controlling lipid and amino acid metabolism in the muscle (By similarity)","subcellular_location":"Nucleus; Cytoplasm; Cell projection, dendrite; Cell projection, dendritic spine","url":"https://www.uniprot.org/uniprotkb/P20393/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR1D1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NR1D1","total_profiled":1310},"omim":[{"mim_id":"609987","title":"STIMULATED BY RETINOIC ACID 8; STRA8","url":"https://www.omim.org/entry/609987"},{"mim_id":"607735","title":"PROGESTERONE RECEPTOR MEMBRANE COMPONENT 2; PGRMC2","url":"https://www.omim.org/entry/607735"},{"mim_id":"606200","title":"BASIC HELIX-LOOP-HELIX FAMILY, MEMBER E41; BHLHE41","url":"https://www.omim.org/entry/606200"},{"mim_id":"605327","title":"NUCLEAR FACTOR, INTERLEUKIN 3-REGULATED; NFIL3","url":"https://www.omim.org/entry/605327"},{"mim_id":"604517","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR 1, ALPHA; PPARGC1A","url":"https://www.omim.org/entry/604517"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skin 1","ntpm":329.3}],"url":"https://www.proteinatlas.org/search/NR1D1"},"hgnc":{"alias_symbol":["ear-1","hRev","Rev-ErbAalpha","THRA1","REVERBA","REVERBalpha"],"prev_symbol":["THRAL"]},"alphafold":{"accession":"P20393","domains":[{"cath_id":"3.30.50.10","chopping":"140-207","consensus_level":"high","plddt":91.6765,"start":140,"end":207},{"cath_id":"1.10.565.10","chopping":"431-611","consensus_level":"high","plddt":87.6687,"start":431,"end":611}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20393","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20393-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20393-F1-predicted_aligned_error_v6.png","plddt_mean":62.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR1D1","jax_strain_url":"https://www.jax.org/strain/search?query=NR1D1"},"sequence":{"accession":"P20393","fasta_url":"https://rest.uniprot.org/uniprotkb/P20393.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20393/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20393"}},"corpus_meta":[{"pmid":"8474464","id":"PMC_8474464","title":"The orphan receptor Rev-ErbA alpha activates transcription via a novel response element.","date":"1993","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8474464","citation_count":208,"is_preprint":false},{"pmid":"8344913","id":"PMC_8344913","title":"Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8344913","citation_count":172,"is_preprint":false},{"pmid":"6490539","id":"PMC_6490539","title":"Growth of a fish ear: 1. 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reporter assay, mutagenesis of binding site\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with purified protein, SELEX, mutagenesis, and transcriptional assay in one study; highly cited foundational paper\",\n      \"pmids\": [\"8474464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"NR1D1 (Rev-ErbAα) does not bind thyroid hormone (T3), and the human protein is encoded by transcription from the noncoding strand of the c-erbAα genomic locus, sharing 269 bp of sequence identity with c-erbAα-2 cDNA used in opposite orientations.\",\n      \"method\": \"cDNA cloning, Northern blot, radioligand binding assay\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct ligand binding assay with negative result, confirmed by multiple labs; foundational characterization paper\",\n      \"pmids\": [\"1971514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"NR1D1 (Rev-ErbAα) binds direct repeat (DR4) thyroid hormone response elements but not palindromic or inverted palindromic TREs, and activates transcription via DR4 elements in transfected cells; deletion mapping of the ligand-binding domain identified regions modulating DNA binding.\",\n      \"method\": \"EMSA with GST-fusion proteins, transfection reporter assay with DR4/TREpal/F2H elements, deletion analysis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assay with recombinant protein plus cell-based reporter; directly defines DNA-binding specificity\",\n      \"pmids\": [\"8015547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Constitutive overexpression of NR1D1 (Rev-ErbAα) in C2C12 myoblasts completely abolished differentiation, suppressed myoD mRNA, and abrogated myogenin induction; the ligand-binding domain (LBD) contains an active transcriptional silencer; the receptor disrupts TR homodimer and TR/RXR heterodimer formation on TREs in the myoD gene family promoters.\",\n      \"method\": \"Stable overexpression in C2C12 cells, Northern blot, GAL4 chimera transfection assay, deletion/domain analysis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss/gain-of-function with defined molecular mechanism; replicated across multiple gene targets\",\n      \"pmids\": [\"8614403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NR1D1 (Rev-ErbAα) and RVR interact with nuclear receptor corepressor N-CoR/RIP13 via two receptor interaction domains (ID-I and ID-II); the physical association requires an intact E region (LBD) of NR1D1; overexpression of dominant-negative N-CoR interaction domains alleviates NR1D1-mediated repression.\",\n      \"method\": \"Mammalian two-hybrid system, transfection repression assay, domain deletion analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mammalian two-hybrid plus functional repression assay; two independent approaches; confirmed with dominant-negative rescue\",\n      \"pmids\": [\"8948627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Transcriptional repression by NR1D1 (Rev-ErbAα) is mediated by a minimal 34-amino acid domain (aa 455–488) in the E region containing the LBD signature motif and helix 5; mutagenesis of either element impairs repression; an alternative study using the same interaction domain of N-CoR (aa 2218–2451) found no interaction, suggesting that this particular N-CoR region (interacting with TR/RAR) does not mediate NR1D1 repression.\",\n      \"method\": \"GAL4 hybrid system, fine deletions, site-specific mutagenesis, mammalian two-hybrid with N-CoR interaction domain\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with functional repression assay; defined minimal silencing domain\",\n      \"pmids\": [\"8836173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"NR1D1 (Rev-ErbAα) contains two corepressor interaction regions (CIR-1 and CIR-2) in its E region; CIR-1 maps to the N-terminal portion of helix 3 with critical phenylalanine residues (F441 in Rev-ErbAα); mutations in CIR-1 or deletion of CIR-2 impair interaction with N-CoR, RIP13a, and RIP13δ1 and reduce repression of the native Rev-ErbAα promoter.\",\n      \"method\": \"Mammalian two-hybrid, co-transfection repression assays, mutagenesis of CIR-1, corepressor domain overexpression (dominant-negative rescue)\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis combined with functional assays and dominant-negative rescue; identifies specific residues\",\n      \"pmids\": [\"9482666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Homology modeling of NR1D1/RVR LBDs revealed that the putative ligand cavity is occupied by side chains (suggesting no endogenous ligand) and that the absence of helix 12 exposes a large hydrophobic surface (H3, loop 3–4, H4, H11); mutagenesis of residues on this surface severely impairs in vitro and in vivo interaction with N-CoR/RIP13δ1 and reduces transcriptional repression, demonstrating that corepressors bind the H3–H4/H11 surface of NR1D1.\",\n      \"method\": \"Homology modeling, site-directed mutagenesis, in vitro pulldown, co-transfection repression assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-guided mutagenesis + in vitro binding + functional assay; identifies corepressor-binding surface\",\n      \"pmids\": [\"10809233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nr1d1-null mice exhibit aberrant myosin heavy chain (MyHC) isoform expression in slow-twitch soleus muscle, with significantly higher relative amounts of β/slow (type I) MyHC in both heterozygous and homozygous knockout mice vs. wild-type, demonstrating a role for NR1D1 in regulating skeletal muscle fiber type composition.\",\n      \"method\": \"Nr1d1 knockout mouse model, muscle fiber type analysis, MyHC isoform quantification; ruled out TRα2 involvement by comparing TRα2-deficient mice\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined phenotype; genetic control performed; single study\",\n      \"pmids\": [\"15374821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NR1D1 is co-expressed with NR2E3 in the outer neuroblastic layer of the developing mouse retina and in rods/cones of adult retina; knockdown of Nr1d1 in developing retina causes pan-retinal spotting and reduced ERG function; NR1D1 co-regulates a transcriptional network including Nr2c1, Recoverin, Rgr, and Pde8a together with NR2E3.\",\n      \"method\": \"In vivo Nr1d1 knockdown, electroretinogram, immunohistochemistry, gene expression analysis; cycling of Nr1d1 and Nr2e3 over 24 h\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with functional ERG readout plus co-expression and gene network data; single study\",\n      \"pmids\": [\"21408158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ApoA-IV binds NR1D1 directly (identified by bacterial two-hybrid screening; confirmed by coimmunoprecipitation and proximity ligation assay); ApoA-IV stimulates NR1D1 recruitment to the Glc-6-Pase promoter (by ChIP), reducing gluconeogenic gene expression; in NR1D1-knockdown cells, ApoA-IV fails to inhibit PEPCK and Glc-6-Pase.\",\n      \"method\": \"Bacterial two-hybrid library screen, coimmunoprecipitation, in situ proximity ligation assay, ChIP, luciferase reporter, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, PLA, ChIP, reporter, KD rescue) establishing direct protein–protein interaction and downstream transcriptional mechanism\",\n      \"pmids\": [\"24311788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In zebrafish, Nr1d1/Rev-erbα directly regulates autophagy gene transcription (demonstrated by luciferase reporter and ChIP assays); nr1d1 mutant fish show significantly upregulated autophagy genes and cebpb, indicating Nr1d1 is a direct transcriptional repressor of autophagy genes in the circadian-autophagy axis.\",\n      \"method\": \"TALEN-generated nr1d1 mutant zebrafish, luciferase reporter assay, ChIP, transcriptome analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP + reporter + genetic mutant; direct binding to autophagy gene promoters established\",\n      \"pmids\": [\"27171500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"siRNA knockdown of NR1D1 in human chondrocytes predominantly affects TGF-β signaling pathway gene expression (RNA-seq), and NR1D1 knockdown increases BMAL1 expression while BMAL1 knockdown decreases NR1D1, demonstrating reciprocal regulation within the circadian clock network with functional consequences on chondrocyte TGF-β signaling.\",\n      \"method\": \"siRNA knockdown, RNA sequencing, quantitative PCR, synchronized human chondrocyte cultures\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with pathway-level transcriptomics; single study but RNA-seq provides broad mechanistic evidence\",\n      \"pmids\": [\"27884645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NR1D1 inhibits both non-homologous end joining and homologous recombination DNA double-strand break repair; PARP1 PARylates NR1D1 and drives its recruitment to damaged DNA lesions; the LBD of NR1D1 interacts with PARP1; NR1D1 inhibits recruitment of SIRT6, pNBS1, and BRCA1 to DNA lesion sites; PARP1 inhibitor suppresses NR1D1 recruitment to damaged DNA.\",\n      \"method\": \"γH2AX foci clearance assay, NHEJ/HR repair assays, Co-IP (NR1D1-PARP1), LBD deletion mutants, PARP1 inhibitor treatment, in vitro/in vivo doxorubicin sensitivity\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal assays (Co-IP, repair assays, inhibitor, domain deletion, in vivo) in a single study defining a novel function\",\n      \"pmids\": [\"28249904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NR1D1 interacts with PARP1 and inhibits its catalytic (poly-ADP-ribosylation) activity, thereby enhancing accumulation of ROS-induced DNA damage and sensitizing breast cancer cells to oxidative stress.\",\n      \"method\": \"Co-IP (NR1D1-PARP1), PARP1 activity assay, ROS-induced DNA damage accumulation assay\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct enzyme activity inhibition shown with Co-IP and functional assay; corroborated by companion paper (PMID 28249904)\",\n      \"pmids\": [\"28599788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"REVERBα (NR1D1) physically interacts with the glucocorticoid receptor (GR) and co-binds chromatin with liver-specific HNFs; REVERBα promotes efficient GR recruitment to chromatin during the day by maintaining histone acetylation; deletion of Reverba inverts circadian liver GC sensitivity and protects mice from GC-induced hepatosteatosis.\",\n      \"method\": \"Reciprocal Co-IP (GR-REVERBα), ChIP-seq (co-binding analysis), conditional Reverba knockout mice, metabolic phenotyping\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP + ChIP-seq + conditional KO with specific metabolic phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"30179226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STRA8 binds to the Nr1d1 promoter and directly represses its transcription in spermatogonia; NR1D1 in turn binds to the Ulk1 promoter to activate autophagy; genetic deletion or pharmacologic inhibition of NR1D1 rescues meiotic initiation defects in Stra8-deficient male germ cells, placing NR1D1 downstream of STRA8 in a STRA8→NR1D1→ULK1→autophagy axis.\",\n      \"method\": \"ChIP (STRA8 on Nr1d1 promoter; NR1D1 on Ulk1 promoter), genetic deletion of Nr1d1, pharmacologic NR1D1 inhibition (SR8278), autophagy assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP + genetic epistasis (double-mutant rescue) + pharmacological rescue; defines pathway order with multiple methods\",\n      \"pmids\": [\"31059511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NR1D1 directly represses StAR expression in Leydig cells by binding to a canonical RORE element in the StAR promoter (demonstrated by dual-luciferase reporter and EMSA), reducing testosterone synthesis; glyphosate-induced upregulation of NR1D1 mediates inhibition of StAR and testosterone production.\",\n      \"method\": \"Dual-luciferase reporter assay, EMSA, siRNA/agonist (SR9009) modulation, in vitro and in vivo testosterone measurement\",\n      \"journal\": \"The Science of the total environment\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — EMSA + luciferase reporter with RORE mutation + agonist/antagonist pharmacology; direct promoter binding demonstrated\",\n      \"pmids\": [\"33957581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NR1D1 directly represses ATG5 transcription by binding to two putative RORE elements within the Atg5 promoter (shown by dual-luciferase reporter and EMSA), thereby regulating granulosa cell autophagy; Nr1d1 knockdown increases ATG5 expression and autophagy.\",\n      \"method\": \"Dual-luciferase reporter, EMSA, siRNA knockdown, SR9009 agonist treatment, Bmal1-/- mouse model\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — EMSA + luciferase with RORE deletion + genetic/pharmacological corroboration; direct binding confirmed\",\n      \"pmids\": [\"34936504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NR1D1 directly represses CYP19A1 transcription in granulosa cells by binding to a RORE on the CYP19A1 promoter, reducing estradiol synthesis; NR1D1 activation (SR9009) decreases estradiol; NR1D1 interference increases CYP19A1 expression and estradiol production.\",\n      \"method\": \"Luciferase reporter, ChIP (implied from promoter binding), SR9009 agonist, siRNA knockdown, steroid hormone measurement\",\n      \"journal\": \"Theriogenology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — reporter assay + pharmacological modulation + KD; corroborated by multiple independent studies on NR1D1 steroidogenesis repression\",\n      \"pmids\": [\"34933195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR1D1 deficiency in mice impairs SERCA-dependent sarcoplasmic reticulum Ca2+ uptake in skeletal muscle; NR1D1 represses the SERCA inhibitor myoregulin by direct binding to its promoter; restoration of myoregulin counteracts NR1D1 overexpression on SR calcium content; pharmacological NR1D1 activation ameliorates SR calcium homeostasis and improves muscle structure/function in dystrophic mdx/Utr+/- mice.\",\n      \"method\": \"Nr1d1 KO mouse, ChIP (NR1D1 on myoregulin promoter), Ca2+ uptake assay, myoregulin rescue experiment, in vivo SR9009 treatment in mdx/Utr+/- mice\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP + KO + rescue + in vivo therapeutic validation; multiple orthogonal methods across two systems\",\n      \"pmids\": [\"35917173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR1D1 identifies ACO2 (aconitase-2, a TCA cycle enzyme) as a direct transcriptional target that it trans-represses in vascular smooth muscle cells; NR1D1 deficiency restores ACO2 dysregulation and mitochondrial dysfunction; VSMC-specific (but not endothelial or myeloid) Nr1d1 KO inhibits AAA formation in two mouse models.\",\n      \"method\": \"VSMC/EC/myeloid-specific conditional Nr1d1 KO mice, two AAA models (AngII, CaPO4), ChIP/reporter for ACO2 promoter, mitochondrial metabolic assays, αKG supplementation rescue\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — conditional cell-type-specific KO + direct target identification by ChIP + metabolic rescue; highly rigorous multi-model study\",\n      \"pmids\": [\"35880522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR1D1 promotes DNA damage-induced accumulation of cytosolic DNA fragments and activates cGAS-STING signaling, increasing type I IFN production and downstream chemokines CCL5 and CXCL10, thereby enhancing CD8+ T cell and NK cell antitumor responses; Nr1d1 deletion in tumor cells (MMTV-PyMT) increases tumor growth and suppresses type I IFN signaling.\",\n      \"method\": \"Nr1d1-/-;MMTV-PyMT transgenic mice, orthotopic allograft, transcriptome analysis, cytosolic DNA quantification, cGAS-STING pathway analysis, SR9009 pharmacological treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO in transgenic tumor model + transcriptomics + pathway mechanistic analysis + pharmacological validation\",\n      \"pmids\": [\"37395684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR1D1 degradation via m6A (N6-methyladenosine) methylation in hepatic stellate cells inhibits DRP1-S616 phosphorylation, impairing mitochondrial fission and increasing mitochondrial DNA release, which activates the cGAS pathway and drives liver fibrosis; NR1D1 overexpression restores DRP1S616 phosphorylation and suppresses cGAS pathway.\",\n      \"method\": \"Nr1d1-deficient mice (CCl4 model), NR1D1 overexpression (AAV), m6A methylation analysis, DRP1-S616 phosphorylation assay, cGAS pathway readout\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO + OE rescue + pathway mechanistic readouts; single study but multiple assays\",\n      \"pmids\": [\"36813093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NR1D1 binds promoters of IL-1β and NLRP3 to directly repress their transcription in macrophages, thereby inhibiting NLRP3 inflammasome assembly; NR1D1 deficiency in ApoE-/- mice augments plaque vulnerability and macrophage pyroptosis in a NLRP3-dependent manner.\",\n      \"method\": \"NR1D1-/-ApoE-/- double-KO mice, BMDM experiments, ChIP (NR1D1 on IL-1β/NLRP3 promoters, implied from mechanistic statement), SR9009 agonist treatment, pyroptosis assays\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined phenotype + promoter binding mechanistic claim + pharmacological rescue; single study\",\n      \"pmids\": [\"34956438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In the nucleus accumbens, Nr1d1 knockdown via AAV-shRNA enhances sociability and reduces anxiety in female mice; knockdown upregulates Per1 and Per2, and alters opioid-related genes (Oprd1, Penk), demonstrating a sex-specific role for NR1D1 in behavioral regulation through the circadian and opioid gene networks.\",\n      \"method\": \"AAV-shRNA knockdown in NAc, behavioral testing, microarray, qPCR\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — region-specific KD with defined behavioral phenotype + molecular readouts; single lab\",\n      \"pmids\": [\"30028550\", \"30326159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Acute in utero electroporation-mediated knockdown of Nr1d1 in mouse cerebral cortex caused abnormal positioning of cortical neurons, impaired neuronal migration (time-lapse imaging), suppressed axon extension and dendritic arbor formation; wild-type Nr1d1 but not the p.R500H ASD-associated mutant rescued the abnormal phenotype, establishing Nr1d1 as required for cortical neuron migration and morphogenesis.\",\n      \"method\": \"In utero electroporation knockdown, time-lapse imaging, rescue with WT vs. mutant Nr1d1, cortical neuron positioning analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with live imaging phenotype + allele-specific rescue; directly establishes functional requirement\",\n      \"pmids\": [\"28262759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR1D1 directly represses Hmga2 transcription by binding its promoter (shown by ChIP-seq and EMSA), thereby suppressing NF-κB signaling and microglial activation; overexpressed HMGA2 partially abolishes the anti-inflammatory effects of NR1D1 in microglia.\",\n      \"method\": \"ChIP-seq (NR1D1 in BV2 microglia), RNA-seq, EMSA, luciferase reporter, Hmga2 overexpression rescue, BETA tool integration\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP-seq + EMSA + luciferase + rescue experiment; multiple orthogonal methods in single study\",\n      \"pmids\": [\"34795498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR1D1 directly represses BNIP3 expression by binding its promoter (ChIP), acting as a positive regulator of mitophagy in intestinal epithelial cells; NR1D1 ablation leads to disrupted mitophagy and increased inflammation/apoptosis; SR9009 (agonist) ameliorates colitis by rectifying defective mitophagy.\",\n      \"method\": \"Intestinal-specific Nr1d1 KO mice, DSS colitis model, RNA-seq, ChIP, dual-luciferase reporter, transmission electron microscopy, confocal microscopy\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — tissue-specific KO + ChIP + luciferase + EM of mitophagy + in vivo SR9009 rescue\",\n      \"pmids\": [\"37762536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ran GTPase, through miR4472 maturation, destabilizes NR1D1 mRNA; NR1D1 interacts with both PARP1 and BRCA1 leading to inhibition of DNA repair; Ran inhibition induces NR1D1 upregulation and DNA damage accumulation in aneuploid ovarian cancer cells.\",\n      \"method\": \"miRNA maturation assay, mRNA stability assay, Co-IP (NR1D1 with PARP1 and BRCA1), DNA damage assays, Ran inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP evidence for BRCA1 interaction is new; mechanistic framework supported by multiple assays but single lab\",\n      \"pmids\": [\"34743206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Glucocorticoid receptor (GR/NR3C1) binds the Nr1d1 promoter E-box to suppress Nr1d1 expression in colon epithelium during stress; GR alters chromatin 3D structure at the Ikzf3-Nr1d1 super-enhancer; intestinal-specific Nr3c1 deletion abolishes stress-induced Nr1d1 suppression and associated IBS phenotypes.\",\n      \"method\": \"ChIP (GR at Nr1d1 promoter E-box), chromatin conformation (3D structure analysis), intestinal-specific Nr3c1 KO mice, water avoidance stress model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + 3D chromatin + conditional KO; single study\",\n      \"pmids\": [\"37404374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR1D1 binds to IL-1β and NLRP3 promoters (shown by ChIP) in nucleus pulposus cells to repress their expression; NR1D1 activation (SR9009) inhibits NLRP3 inflammasome assembly and IL-1β production, and increases ECM synthesis in disc cells.\",\n      \"method\": \"ChIP (NR1D1 on IL-1β/NLRP3 promoters), luciferase reporter, SR9009 treatment, in vitro NPMSC model, in vivo disc degeneration model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + reporter + pharmacological validation in vitro and in vivo; single study\",\n      \"pmids\": [\"38689641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR1D1 directly represses IL-6 transcription in bovine endometrial epithelial cells by binding to a retinoic acid receptor-related orphan receptor-responsive element (RORE; -473 to -479) in the IL-6 promoter, as demonstrated by dual-luciferase reporter and deletion analysis; NR1D1 has predominantly nuclear localization in these cells.\",\n      \"method\": \"Dual-luciferase reporter with RORE deletion, siRNA/overexpression, SR9009 treatment, immunofluorescence (nuclear localization), primary cell culture\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — RORE deletion luciferase + localization + gain/loss-of-function; directly maps functional element\",\n      \"pmids\": [\"39551321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LC3 (autophagosome marker) directly binds to NR1D1 via LC3-interacting region (LIR) motifs, leading to NR1D1 degradation in a mitophagy-dependent manner; mitophagy defects lead to NR1D1 accumulation and subsequent BMAL1 suppression, disrupting circadian rhythms.\",\n      \"method\": \"Co-IP (LC3-NR1D1), LIR motif identification, mitophagy inhibition experiments, urolithin A (mitophagy activator) treatment, rat simulated microgravity model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP identifying LIR-mediated interaction + functional consequence on clock; single study\",\n      \"pmids\": [\"38732079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR1D1 trans-represses Dusp1 (dual specificity phosphatase 1) transcription in pulmonary artery smooth muscle cells; NR1D1 deficiency restores Dusp1 expression, deactivating ERK1/2 and reducing DRP1-mediated mitochondrial fission; AAV1-mediated Nr1d1 knockdown inhibits PH progression in chronic intermittent hypoxia models.\",\n      \"method\": \"ChIP/reporter for Dusp1 promoter, AAV1 KD in vivo, ERK1/2 inhibitor and PMA pharmacology, Dusp1 KO mice, mitochondrial fission assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter target identified with mechanistic pathway validation and in vivo KD; single study\",\n      \"pmids\": [\"39472573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR1D1 is transactivated in cisplatin-resistant neuroblastoma cells and drives expression of lncRNA NUTM2A-AS1, which in turn inhibits B7-H3 protein degradation, promoting immune evasion and chemoresistance.\",\n      \"method\": \"Gain/loss-of-function of NR1D1 and NUTM2A-AS1, Co-IP/RIP (NUTM2A-AS1 with B7-H3), cisplatin sensitivity assays, luciferase reporter (NR1D1 → NUTM2A-AS1 promoter)\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reporter + co-IP + functional assays in single study; defines NR1D1 as transactivator in this context\",\n      \"pmids\": [\"38785199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NR1D1 depletion enhances autophagic flux and mitophagy in human cell lines and AD model organisms; Nr1d1 knockdown in 5xFAD mice restores autophagy marker expression; depletion of the C. elegans ortholog nhr-85 improves neuronal mitophagy and extends lifespan in amyloid-β models; NR1D1 knockdown activates SIRT1 and Cathepsin B (CTSB), both linked to autophagy.\",\n      \"method\": \"NR1D1 KD in human cell lines, 5xFAD mouse KD, C. elegans nhr-85 depletion, autophagic flux assay, mitophagy assay, SIRT1/CTSB activity\",\n      \"journal\": \"Aging and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple model systems (human cells, mouse, C. elegans) with consistent autophagy/mitophagy readouts; single study\",\n      \"pmids\": [\"39812544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NR1D1 suppresses HSD17B12 transcription by binding to its promoter (CUT&Tag-qPCR and dual-luciferase reporter), reducing antioxidant capacity and promoting ROS-induced apoptosis in sheep granulosa cells via the AMPK pathway; NR1D1 knockdown of HSD17B12 partially alleviates the effects of NR1D1 overexpression on GC function.\",\n      \"method\": \"ATAC-seq, CUT&Tag-qPCR, dual-luciferase reporter, NR1D1 OE/KD, AMPK pathway assays, ROS and apoptosis measurements\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — direct promoter binding (CUT&Tag + luciferase) + functional rescue; single study but multiple methods\",\n      \"pmids\": [\"39986531\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR1D1 (REV-ERBα) is a constitutive transcriptional repressor that lacks an activation function 2 helix, binds RORE/DR2 DNA elements as a monomer, recruits the corepressor N-CoR/RIP13 via its ligand-binding domain (H3–H4/H11 surface and CIR-1/CIR-2 regions), and directly represses core circadian clock genes (BMAL1), autophagy genes (ATG5, BNIP3, ULK1), steroidogenic genes (StAR, CYP19A1, ACO2), and inflammatory mediators (IL-6, IL-1β, NLRP3, HMGA2); it also acts non-transcriptionally by interacting with PARP1 to inhibit its catalytic activity and recruit DNA damage factors to lesions, and by promoting cGAS-STING signaling, while its own protein level is regulated by PARP1-mediated PARylation (directing chromatin recruitment), m6A-dependent mRNA degradation, and mitophagy-linked LC3-LIR interactions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NR1D1 (REV-ERBα) is a ligand-independent nuclear receptor that functions as a constitutive transcriptional repressor, integrating circadian clock regulation with metabolism, inflammation, autophagy, DNA repair, and innate immunity. It binds ROR-responsive elements (ROREs) and direct repeat elements as a monomer, lacks a classical activation function 2 (AF-2) helix, and recruits the corepressor N-CoR via a hydrophobic surface formed by helices H3–H4/H11 and two corepressor interaction regions (CIR-1/CIR-2) in its ligand-binding domain, directly repressing BMAL1, IL-6, IL-1β, NLRP3, ATG5, BNIP3, StAR, CYP19A1, ACO2, HMGA2, and other target gene promoters [PMID:8474464, PMID:9482666, PMID:10809233, PMID:34956438, PMID:33957581, PMID:34936504, PMID:34795498, PMID:35880522, PMID:39551321]. Beyond transcriptional repression, NR1D1 physically interacts with PARP1, inhibits its catalytic poly-ADP-ribosylation activity, and modulates DNA double-strand break repair by blocking recruitment of SIRT6, pNBS1, and BRCA1 to damage sites; PARP1-mediated PARylation reciprocally drives NR1D1 recruitment to DNA lesions [PMID:28249904, PMID:28599788]. NR1D1 also promotes cytosolic DNA accumulation and cGAS-STING-dependent type I interferon signaling to enhance antitumor immunity, while its own protein turnover is regulated by LC3-LIR-mediated mitophagy-dependent degradation and m6A-directed mRNA destabilization [PMID:37395684, PMID:38732079, PMID:36813093].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that NR1D1 is an orphan nuclear receptor: the receptor was shown not to bind thyroid hormone (T3) despite being encoded antisense to the c-erbAα locus, resolving its classification as a true orphan.\",\n      \"evidence\": \"Radioligand binding assay with purified receptor, cDNA cloning and Northern blot\",\n      \"pmids\": [\"1971514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No endogenous ligand identified at this stage\", \"Physiological function unknown\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Defining DNA-binding specificity: NR1D1 was found to bind as a monomer to an asymmetric 11-bp element (later called RORE) and to DR4 elements, establishing the receptor's monomeric DNA-binding mode distinct from TR/RXR heterodimers.\",\n      \"evidence\": \"SELEX with purified protein, EMSA, mutagenesis, and reporter assays in transfected cells\",\n      \"pmids\": [\"8474464\", \"8015547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NR1D1 can also bind as dimers on certain elements\", \"In vivo relevance of monomeric binding unclear\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identifying the corepressor mechanism: NR1D1's ligand-binding domain (LBD) was shown to contain an intrinsic transcriptional silencing function mediated by interaction with N-CoR/RIP13 through two corepressor interaction regions (CIR-1 and CIR-2), with critical phenylalanine residues required for repression.\",\n      \"evidence\": \"Mammalian two-hybrid, GAL4 chimeras, fine deletion/point mutagenesis, dominant-negative rescue\",\n      \"pmids\": [\"8948627\", \"8836173\", \"9482666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SMRT or other corepressors also participate\", \"No crystal structure of NR1D1-corepressor complex\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapping the corepressor-binding surface: homology modeling and mutagenesis revealed that the absence of helix 12 (AF-2) exposes a hydrophobic surface (H3–H4/H11) that directly contacts N-CoR, explaining why NR1D1 is a constitutive repressor.\",\n      \"evidence\": \"Homology modeling, site-directed mutagenesis, in vitro pulldown, co-transfection repression assay\",\n      \"pmids\": [\"10809233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental 3D structure at this point\", \"Coactivator recruitment possibility not fully excluded\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"In vivo physiological role established: Nr1d1 knockout mice showed altered skeletal muscle fiber type composition, providing the first genetic evidence that NR1D1 regulates tissue-specific gene programs beyond circadian genes.\",\n      \"evidence\": \"Nr1d1 knockout mouse, MyHC isoform quantification in soleus muscle\",\n      \"pmids\": [\"15374821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream target genes in muscle not identified\", \"Redundancy with NR1D2/REV-ERBβ not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of a non-nuclear-receptor protein partner modulating NR1D1 chromatin recruitment: ApoA-IV was shown to directly bind NR1D1 and stimulate its recruitment to gluconeogenic gene promoters, linking NR1D1 to metabolic regulation beyond circadian clock targets.\",\n      \"evidence\": \"Bacterial two-hybrid, Co-IP, proximity ligation assay, ChIP, luciferase reporter, siRNA knockdown\",\n      \"pmids\": [\"24311788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of ApoA-IV–NR1D1 interaction in vivo\", \"Whether other apolipoproteins modulate NR1D1\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Direct transcriptional regulation of autophagy genes by NR1D1 was established, positioning it as a circadian gatekeeper of autophagy.\",\n      \"evidence\": \"TALEN-generated nr1d1 mutant zebrafish, ChIP, luciferase reporter; reciprocal BMAL1 regulation confirmed in human chondrocytes by siRNA/RNA-seq\",\n      \"pmids\": [\"27171500\", \"27884645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific autophagy gene promoter elements not fully mapped in mammals at this time\", \"Whether NR1D1 regulation of autophagy is tissue-specific\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A non-transcriptional function was uncovered: NR1D1 physically interacts with PARP1 via its LBD, inhibits PARP1 catalytic activity, and is itself PARylated and recruited to DNA damage sites, establishing NR1D1 as a modulator of DNA repair through NHEJ and HR suppression.\",\n      \"evidence\": \"Co-IP, PARP1 activity assay, γH2AX foci clearance, NHEJ/HR repair assays, LBD deletion mutants, PARP1 inhibitor, in vivo doxorubicin sensitivity\",\n      \"pmids\": [\"28249904\", \"28599788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of NR1D1–PARP1 complex lacking\", \"Whether PARylation-mediated recruitment is circadian-dependent\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"NR1D1 was shown to be required for cortical neuron migration and morphogenesis; the ASD-associated R500H mutation failed to rescue knockdown phenotypes, linking NR1D1 to neurodevelopmental processes.\",\n      \"evidence\": \"In utero electroporation knockdown in mouse cortex, time-lapse imaging, WT vs. R500H mutant rescue\",\n      \"pmids\": [\"28262759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating migration are unknown\", \"Broader ASD cohort validation of R500H needed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cooperative chromatin regulation with GR was demonstrated: NR1D1 physically interacts with GR, facilitates its chromatin recruitment by maintaining histone acetylation, and modulates circadian glucocorticoid sensitivity in liver, linking NR1D1 to metabolic disease through GR co-regulation.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP-seq co-binding analysis, conditional Reverba KO mice, metabolic phenotyping\",\n      \"pmids\": [\"30179226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NR1D1–GR interaction is direct or bridged by chromatin\", \"Mechanism by which NR1D1 maintains histone acetylation unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"NR1D1's direct repression of specific target promoters via RORE elements was mapped with high resolution across multiple tissues: StAR (Leydig cells), ATG5 (granulosa cells), CYP19A1 (granulosa cells), IL-1β/NLRP3 (macrophages), and ULK1 (spermatogonia), solidifying RORE-mediated repression as the core mechanism across steroidogenesis, autophagy, and inflammation.\",\n      \"evidence\": \"EMSA, dual-luciferase reporters with RORE deletion/mutation, ChIP, siRNA/agonist modulation, genetic epistasis with Stra8\",\n      \"pmids\": [\"33957581\", \"34936504\", \"34933195\", \"34956438\", \"31059511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide RORE occupancy map in most tissues still lacking\", \"Cofactor requirements at individual promoters not distinguished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cell-type-specific conditional KO studies revealed that NR1D1 in vascular smooth muscle cells trans-represses ACO2 to regulate mitochondrial TCA cycle function and aneurysm formation, while in skeletal muscle it represses myoregulin to control SR calcium uptake, demonstrating tissue-specific metabolic target selection.\",\n      \"evidence\": \"VSMC/EC/myeloid-specific conditional KO, ChIP/reporter for ACO2 and myoregulin, metabolic and Ca²⁺ uptake assays, in vivo rescue\",\n      \"pmids\": [\"35880522\", \"35917173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NR1D1 selects tissue-specific targets is mechanistically unexplained\", \"Redundancy with NR1D2 in these tissues not fully addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"NR1D1 was connected to innate immune sensing: it promotes cytosolic DNA accumulation after DNA damage, activates cGAS-STING signaling and type I IFN production, and enhances antitumor CD8⁺ T cell and NK cell responses; separately, NR1D1 loss in hepatic stellate cells increases mitochondrial DNA release and cGAS activation via impaired DRP1-mediated fission.\",\n      \"evidence\": \"Nr1d1⁻/⁻;MMTV-PyMT mice, transcriptomics, cytosolic DNA quantification, cGAS-STING pathway analysis; CCl4 fibrosis model with AAV rescue, DRP1 phosphorylation assay\",\n      \"pmids\": [\"37395684\", \"36813093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cGAS-STING activation is transcription-dependent or DNA-repair-dependent\", \"Context-dependent opposing effects of NR1D1 on cGAS in tumor vs. fibrosis need reconciliation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Genome-wide target identification by ChIP-seq in microglia identified HMGA2 as a direct NR1D1 repression target, connecting NR1D1 to NF-κB suppression and anti-inflammatory function in the CNS.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, EMSA, luciferase reporter, HMGA2 overexpression rescue in BV2 microglia\",\n      \"pmids\": [\"34795498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HMGA2 repression generalizes to peripheral macrophages\", \"Full ChIP-seq target list not functionally validated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Protein-level regulation of NR1D1 was clarified: LC3 directly binds NR1D1 via LIR motifs, targeting it for mitophagy-dependent degradation; this links mitophagy status to circadian clock output via BMAL1 de-repression, and m6A-dependent mRNA degradation provides an additional post-transcriptional control layer.\",\n      \"evidence\": \"Co-IP (LC3–NR1D1), LIR motif identification, mitophagy inhibition, m6A analysis, BMAL1 expression readout\",\n      \"pmids\": [\"38732079\", \"36813093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which E3 ligase or selective autophagy receptor mediates NR1D1 degradation\", \"Quantitative contribution of m6A vs. mitophagy to NR1D1 turnover unknown\", \"LC3-LIR interaction awaits structural validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: whether NR1D1 has a true endogenous ligand or functions entirely as a constitutive repressor; the structural basis of the NR1D1–PARP1 interaction; how tissue-specific target gene selection is achieved; and the full reconciliation of NR1D1's opposing roles in cGAS-STING activation across different cellular contexts (tumor immunity vs. fibrosis).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of full-length NR1D1 with corepressor or PARP1\", \"Endogenous ligand question unresolved despite heme identification by other groups not captured in this timeline\", \"Tissue-specific cofactor logic unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 17, 18, 27, 32]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 4, 5, 6, 7, 11, 17, 18, 19, 24, 27, 28, 32]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 14, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7, 15, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 4, 5, 6, 7, 11, 17, 18, 19, 27, 28, 32]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [11, 12, 33]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13, 14, 29]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 16, 18, 28, 36]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [22, 24, 27, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 23, 34]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NCOR1\",\n      \"PARP1\",\n      \"NR3C1\",\n      \"APOA4\",\n      \"BRCA1\",\n      \"MAP1LC3B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}