{"gene":"NR1D1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1990,"finding":"Human Rev-ErbAα (NR1D1) is derived from opposite-strand transcription of the c-erbAα genomic locus and does not bind thyroid hormone, despite 99% identity to the rat homolog in the DNA-binding and putative ligand-binding domains.","method":"cDNA cloning, Northern analysis, ligand-binding assay","journal":"DNA and cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical assay (ligand binding) combined with sequence analysis; foundational paper replicated across species","pmids":["1971514"],"is_preprint":false},{"year":1999,"finding":"Rev-ErbAα binds the HD-PPRE (but not the AOx-PPRE) in vitro and antagonizes PPARα/RXRα-dependent transactivation from an HD-PPRE reporter, identifying the enoyl-CoA hydratase/hydroxyacyl-CoA dehydrogenase (HD) gene as a direct Rev-ErbAα target and revealing cross-talk between Rev-ErbAα and PPARα signaling pathways at a specific response element.","method":"In vitro binding analysis, transient transfection reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding and reporter assay in a single study, not independently replicated","pmids":["10428876"],"is_preprint":false},{"year":2000,"finding":"Glucocorticoids repress Rev-erbα expression in rat liver and primary hepatocytes at the transcriptional level via the glucocorticoid receptor; the effect is blocked by the GR antagonist RU486 and by actinomycin D, and transient transfection demonstrates GR represses the Rev-erbα promoter directly.","method":"In vivo dexamethasone treatment, primary hepatocyte culture, GR antagonist (RU486), actinomycin D, cycloheximide, transient transfection promoter assay","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (pharmacological, genetic antagonist, transcriptional reporter) in a single study","pmids":["11014236"],"is_preprint":false},{"year":2004,"finding":"Rev-erbAα protein influences myosin heavy chain (MyHC) isoform expression in slow-twitch skeletal muscle; Rev-erbAα knock-out mice show a significantly higher proportion of β/slow (type I) MyHC isoform in the soleus, establishing a role in muscle fiber-type specification.","method":"Rev-erbAα knockout mouse model, MyHC isoform analysis, immunohistochemistry","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with defined phenotype, single lab, single study","pmids":["15374821"],"is_preprint":false},{"year":2008,"finding":"Heme binds directly to the ligand-binding domain of REV-ERBα and REV-ERBβ and regulates their ability to recruit NCoR (nuclear receptor corepressor) to target gene promoters, establishing heme as an endogenous ligand that controls REV-ERBα transcriptional repressor activity.","method":"Ligand-binding assay (direct binding to LBD), co-repressor recruitment assay","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct ligand-binding biochemistry combined with functional co-repressor recruitment; independently corroborated by multiple subsequent studies","pmids":["18218725"],"is_preprint":false},{"year":2010,"finding":"REV-ERBα (NR1D1) is a heme receptor that promotes transcriptional repression by recruiting the NCoR-HDAC3 corepressor complex, and directly represses BMAL1 expression to function as a critical negative limb of the core circadian clock.","method":"Review synthesizing ligand-binding, co-repressor recruitment, and gene expression studies","journal":"Nuclear receptor signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mechanistic conclusions drawn from multiple primary studies including reconstitution and co-repressor recruitment assays","pmids":["20414452"],"is_preprint":false},{"year":2011,"finding":"NR1D1 (Rev-erbα) co-regulates transcriptional networks with NR2E3 in retinal photoreceptors; NR1D1 protein is co-expressed with NR2E3 in rods and cones, and knockdown of Nr1d1 in the developing retina causes pan-retinal spotting and reduced retinal function by electroretinogram.","method":"Knock-down in developing retina (morpholino/siRNA), electroretinogram, immunostaining, co-expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with defined functional phenotype (ERG) plus protein co-localization; single study","pmids":["21408158"],"is_preprint":false},{"year":2011,"finding":"Rev-erbα down-regulation by siRNA in pancreatic islet cells impairs glucose-induced insulin secretion, decreases lipogenic gene expression, and inhibits β-cell proliferation; leptin increases Rev-erbα expression via a MAPK pathway.","method":"siRNA knockdown, bromodeoxyuridine incorporation, RIA insulin secretion, RT-PCR, in vivo leptin treatment","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple functional readouts (secretion, proliferation, gene expression) plus mechanistic pathway (MAPK) identified, single lab","pmids":["22166979"],"is_preprint":false},{"year":2012,"finding":"REV-ERBα and REV-ERBβ share >50% of genomic binding sites in mouse liver and extensively overlap with BMAL1 cistromes; double knockout mice exhibit profoundly disrupted circadian behaviour and deregulated lipid metabolism, establishing both REV-ERBs as integral components of the principal circadian feedback loop.","method":"ChIP-seq (cistromes), double-knockout mouse model, wheel-running behaviour, lipid metabolic profiling","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide cistrome plus genetic KO with multiple phenotypic readouts; independently replicated by Bugge et al. 2012","pmids":["22460952"],"is_preprint":false},{"year":2012,"finding":"Dual depletion of Rev-erbα and Rev-erbβ in mouse embryonic fibroblasts renders them arrhythmic; in liver, both Rev-erbs are recruited to a remarkably similar set of genomic binding sites enriched near metabolic genes, and their combined loss causes marked hepatic steatosis and synergistic derepression of clock and metabolic genes.","method":"Double-knockout MEFs (circadian assay), liver-specific depletion, ChIP-seq, gene expression profiling, histological lipid analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-autonomous clock assay (arrhythmia) plus cistrome plus metabolic phenotype; replicates Cho et al. 2012","pmids":["22474260"],"is_preprint":false},{"year":2013,"finding":"ApoA4 binds NR1D1 (identified by bacterial two-hybrid screening; confirmed by co-immunoprecipitation, in situ proximity ligation, and immunofluorescence co-localization), recruits NR1D1 to the Glc-6-Pase promoter, and thereby suppresses hepatic gluconeogenesis; NR1D1 knockdown abolishes ApoA4-mediated repression of PEPCK and Glc-6-Pase.","method":"Bacterial two-hybrid library screen, co-immunoprecipitation, in situ proximity ligation assay, immunofluorescence, ChIP, luciferase reporter, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal binding methods plus functional epistasis (siRNA rescue), single lab","pmids":["24311788"],"is_preprint":false},{"year":2014,"finding":"REV-ERBα directly represses Fabp7 transcription in the brain; loss of Rev-erbα leads to Fabp7 overexpression, increased hippocampal neuronal proliferation with loss of its diurnal pattern, and altered memory/mood-related behaviour.","method":"Rev-erbα knockout mice, gene expression profiling, BrdU proliferation assay, behavioural testing, in vitro cell assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KO mouse with multiple phenotypic readouts, direct target identification; single lab","pmids":["24932636"],"is_preprint":false},{"year":2014,"finding":"NR1D1 overexpression in the rd7 mouse (Nr2e3-null) rescues retinal degeneration by re-regulating key genes within the Nr2e3-directed transcriptional network, demonstrating NR1D1 functions as a modifier of Nr2e3-associated retinal disease.","method":"In vivo AAV-mediated Nr1d1 delivery, clinical/histological/ERG/molecular outcome measures in rd7 mice","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function rescue with multiple outcome measures, single lab","pmids":["24498227"],"is_preprint":false},{"year":2015,"finding":"REV-ERBα controls the molecular clock by directly competing with ROR transcription factors at cognate DNA sites (universal clock mechanism), whereas it regulates metabolic genes primarily by recruiting HDAC3 co-repressor to sites where it is tethered by cell type-specific (lineage-determining) transcription factors — a tissue-specific epigenomic mechanism.","method":"ChIP-seq, genome-wide binding analysis, active-site/domain mutagenesis, HDAC3 co-repressor recruitment assays, liver-specific TF tethering analysis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal genomic and biochemical methods; mechanistic distinction between two modes of action established in a single rigorous study","pmids":["26044300"],"is_preprint":false},{"year":2015,"finding":"Siah2 E3 ubiquitin ligase mediates circadian degradation of Rev-ErbAα; Siah2 overexpression destabilizes Rev-ErbAα/β, siRNA depletion of Siah2 stabilizes endogenous Rev-ErbAα and delays its circadian degradation, and lengthens circadian period.","method":"Functional E3 ligase screen (cell-based), siRNA depletion, overexpression, circadian period measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen plus siRNA and OE validation with period-length phenotype, single lab","pmids":["26392558"],"is_preprint":false},{"year":2016,"finding":"CDK1 phosphorylates REV-ERBα, which is necessary for recognition and ubiquitination by the F-box protein FBXW7, leading to REV-ERBα degradation; targeted hepatic disruption of FBXW7 alters circadian gene expression and perturbs lipid/glucose levels, defining a CDK1-FBXW7 pathway that controls circadian amplitude.","method":"Co-immunoprecipitation, phosphorylation assays, ubiquitination assay, hepatic FBXW7 knockout mice, circadian gene expression, metabolic profiling","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical (phosphorylation, ubiquitination) plus genetic (KO) with multiple phenotypic readouts in a single rigorous study","pmids":["27238018"],"is_preprint":false},{"year":2016,"finding":"HNF6 recruits Rev-erbα to shared hepatic lipid metabolism gene promoters; deletion of HNF6 in adult liver causes loss of Rev-erbα binding at these sites and derepresses lipogenic genes, establishing that HNF6 tethers Rev-erbα to regulate hepatic lipid homeostasis.","method":"Liver-specific HNF6 knockout, ChIP-seq, gene expression profiling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO plus cistromic analysis showing loss of Rev-erbα binding, single lab with two orthogonal methods","pmids":["27445394"],"is_preprint":false},{"year":2016,"finding":"Rev-erbα directly represses Fabp7 and βKlotho (Klb) in white adipose tissue, establishing βKlotho as a tissue-specific Rev-erbα target that modulates FGF21 signaling specifically in adipose (but not liver); Rev-erbα ablation markedly enhances FGF21 effects in WAT.","method":"Rev-erbα KO mice, ChIP-seq, gene expression, FGF21 treatment of adipose tissue, cistromic analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO plus cistromic identification of direct target with functional consequence, single lab","pmids":["27002153"],"is_preprint":false},{"year":2016,"finding":"Nr1d1/Rev-erbα in zebrafish directly regulates autophagy genes through binding to their promoters (ChIP assay) and also modulates c/ebpβ transcription; nr1d1 mutant zebrafish show significantly upregulated autophagy-lysosome genes, establishing a direct circadian clock–autophagy regulatory axis.","method":"Luciferase reporter, ChIP assay, TALEN-generated nr1d1 mutant zebrafish, transcriptome analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus genetic mutant with transcriptomic readout, single lab","pmids":["27171500"],"is_preprint":false},{"year":2016,"finding":"REV-ERBα influences the stability and nuclear localization of the glucocorticoid receptor (GR) by competing for binding to HSP90α/HSP90β chaperone (REV-ERBα binds the C-terminal portion, GR binds the N-terminal portion), thereby affecting expression of GR target genes including IκBα and Adh1.","method":"Co-immunoprecipitation (REV-ERBα and GR with HSP90α/β), GR nuclear localization assay, GR target gene expression","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal Co-IP showing binding domains plus functional gene expression consequence; single lab, mechanism partially unresolved","pmids":["27686098"],"is_preprint":false},{"year":2017,"finding":"NR1D1 inhibits both non-homologous end joining and homologous recombination DNA double-strand break repair; PARP1-mediated PARylation of NR1D1 drives its recruitment to DNA damage lesions, and NR1D1 then inhibits recruitment of SIRT6, pNBS1, and BRCA1 to damage sites. Deletion of the NR1D1 ligand-binding domain (which interacts with PARP1) suppresses this recruitment.","method":"γH2AX foci assay, NHEJ/HR reporter assays, PARP1 inhibitor, domain deletion mutants, co-immunoprecipitation, ChIP at damage sites","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal assays (repair assay, domain mutant, co-IP, ChIP at lesions) in a single study establishing mechanism","pmids":["28249904"],"is_preprint":false},{"year":2017,"finding":"NR1D1 interacts with PARP1 and inhibits its catalytic (PARylation) activity, thereby enhancing accumulation of ROS-induced DNA damage and increasing breast cancer cell sensitivity to oxidative stress.","method":"Co-immunoprecipitation, PARP1 activity assay, DNA damage accumulation assay","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro enzymatic activity assay plus Co-IP; single lab, single study","pmids":["28599788"],"is_preprint":false},{"year":2017,"finding":"REV-ERBα directly represses LRH-1 transcription (shown by luciferase reporter, EMSA, and ChIP), and conditional hepatic deletion of Lrh-1 abrogates Rev-erbα regulation of Cyp7a1 and cholesterol metabolism, establishing REV-ERBα→LRH-1→CYP7A1 as the pathway by which Rev-erbα controls bile acid synthesis.","method":"Luciferase reporter, EMSA, ChIP, conditional liver Lrh-1 knockout, cholesterol/bile acid measurements","journal":"Drug metabolism and disposition","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — three orthogonal biochemical assays for direct binding plus genetic epistasis (conditional KO) confirming the pathway","pmids":["29237721"],"is_preprint":false},{"year":2017,"finding":"Rev-erbα overexpression attenuates atrophy-related gene (atrogene) expression and increases fiber size in skeletal muscle; Rev-erbα deficiency causes increased atrogene expression and reduced muscle mass/fiber size; pharmacological Rev-erbα activation blocks dexamethasone-induced muscle atrophy.","method":"Gain- and loss-of-function in vivo and in vitro, muscle histology, gene expression, dexamethasone atrophy model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both KO and OE with consistent phenotypes, plus pharmacological validation; single lab","pmids":["29085009"],"is_preprint":false},{"year":2017,"finding":"REV-ERBα binds near driver transcription factor binding sites across the cardiac genome; pharmacological REV-ERBα activation selectively suppresses aberrant pathological gene expression and prevents cardiomyocyte hypertrophy in vitro and in vivo in mouse heart failure models.","method":"ChIP-seq, cardiomyocyte hypertrophy assay, in vivo cardiac hypertrophy and heart failure models, gene expression profiling","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cistromic analysis plus in vivo pharmacological/genetic study; single lab","pmids":["28878135"],"is_preprint":false},{"year":2018,"finding":"REV-ERBα opposes functional chromatin loop formation between enhancers and circadian gene promoters by recruiting the NCoR-HDAC3 co-repressor complex, causing histone deacetylation and eviction of elongation factor BRD4 and looping factor MED1, thereby controlling circadian gene transcription through rhythmic chromatin remodeling.","method":"Hi-C/chromatin interaction analysis, ChIP-seq, HDAC3/NCoR co-immunoprecipitation, BRD4/MED1 eviction assays","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal genomic and biochemical methods (chromatin looping, ChIP-seq, co-repressor recruitment, histone deacetylation) in a single rigorous study","pmids":["29439026"],"is_preprint":false},{"year":2018,"finding":"REV-ERBα directly represses Nlrp3 transcription by binding to the NLRP3 promoter, and also indirectly represses NLRP3 via repression of p65 (NF-κB); Rev-erbα ablation activates the NLRP3 inflammasome and exacerbates experimental colitis; protective effects of SR9009 are lost in Nlrp3-/- and Rev-erbα-/- mice.","method":"ChIP assay, luciferase reporter, Rev-erbα KO and Nlrp3 KO mice, DSS colitis model, cell-based inflammasome assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct promoter binding (ChIP + reporter) combined with genetic epistasis (double KO rescue) and multiple in vivo models","pmids":["30315268"],"is_preprint":false},{"year":2018,"finding":"REVERBα physically interacts with the glucocorticoid receptor (GR) and co-binds with liver-specific HNF4A/HNF6 on chromatin; REVERBα promotes efficient GR recruitment to chromatin during the day by maintaining histone acetylation, directing temporal segregation of GC-regulated carbohydrate and lipid metabolism; deletion of Reverba inverts circadian hepatic GC sensitivity.","method":"Co-immunoprecipitation, ChIP-seq (GR + REVERBα co-binding), conditional Reverba KO, histone acetylation assays, glucocorticoid metabolic phenotyping","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — physical interaction (Co-IP) plus genome-wide co-binding (ChIP-seq) plus conditional KO with metabolic phenotype; multiple orthogonal methods","pmids":["30179226"],"is_preprint":false},{"year":2018,"finding":"Inflammatory challenges cause rapid degradation of REV-ERBα protein driven by SUMOylation and ubiquitination; a selective inverse agonist protects REV-ERBα from this degradation, revealing how proinflammatory cytokines trigger REV-ERBα instability to elaborate an inflammatory response.","method":"Protein stability assays, SUMOylation/ubiquitination assays, selective antagonist pharmacology, inflammatory cytokine treatment","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — PTM assays (SUMOylation, ubiquitination) plus pharmacological rescue; single lab","pmids":["29533925"],"is_preprint":false},{"year":2018,"finding":"REV-ERBα competes with RORγt for shared RORE DNA consensus sequences in Th17 cells, repressing RORγt-dependent genes including Il17a and Il17f; REV-ERBα deletion enhances TH17-mediated inflammation and exacerbates EAE and colitis.","method":"RORE binding competition assay, REV-ERBα KO mice, EAE and colitis models, cytokine expression, REV-ERB synthetic ligand treatment","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — DNA binding competition established, genetic KO phenotype replicated in two disease models, pharmacological validation; independently confirmed by Chang et al. 2019","pmids":["30590045"],"is_preprint":false},{"year":2019,"finding":"Rev-erbα chromatin immunoprecipitation in primary microglia shows direct interaction with promoter regions of several NF-κB-related genes; Rev-erbα deletion causes spontaneous microglial activation, increased NF-κB signaling, and enhanced neuroinflammatory responses in vivo.","method":"ChIP in primary microglia, Rev-erbα KO mice, NF-κB activation assay, inflammatory transcript profiling, LPS neuroinflammation model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct promoter binding plus KO phenotype with multiple readouts; single lab","pmids":["30792350"],"is_preprint":false},{"year":2019,"finding":"REV-ERBα inhibits BMAL1 and over-expression or agonist activation of REV-ERBα perturbs lipid signaling pathways used by HCV; genetic knockout of Bmal1 and REV-ERBα activation (by agonist) both inhibit HCV and related flavivirus (dengue, Zika) replication via lipid signaling pathway perturbation.","method":"Genetic knockout (Bmal1 KO), REV-ERB agonist treatment, HCV/dengue/Zika replication assays, lipid signaling pathway analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological approaches with functional replication assays, single lab","pmids":["30670689"],"is_preprint":false},{"year":2019,"finding":"REV-ERBα binds RORE elements in Th17 cells and inhibits expression of RORγt-dependent genes Il17a and Il17f; pharmacological REV-ERB agonism delays EAE onset and reduces severity.","method":"RORE ChIP/binding assay, Rev-erbα KO, EAE model, cytokine expression, synthetic ligand treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA binding plus KO phenotype plus pharmacology; replicates Amir et al. 2018 with slightly different methods","pmids":["31455731"],"is_preprint":false},{"year":2019,"finding":"STRA8 binds the Nr1d1 promoter and directly represses Nr1d1 transcription during spermatogenesis; Nr1d1 upregulation in Stra8-deficient testes drives autophagy through NR1D1 binding to the Ulk1 promoter; genetic deletion or pharmacologic inhibition of Nr1d1 partially rescues meiotic initiation defects in Stra8-deficient mice.","method":"ChIP (STRA8 on Nr1d1 promoter; NR1D1 on Ulk1 promoter), Nr1d1 KO, SR8278 pharmacological inhibition, Stra8 KO rescue experiments","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct promoter binding by ChIP plus genetic epistasis (double KO rescue) plus pharmacological confirmation; multiple orthogonal methods","pmids":["31059511"],"is_preprint":false},{"year":2019,"finding":"Rev-erbα directly represses Pck1 (PEPCK1) transcription through direct binding to a RevRE site at −325 to −320 bp in the Pck1 promoter, as shown by luciferase reporter, EMSA, and ChIP; SR9009 reduces fasting plasma glucose and Pck1 expression in normal and diabetic mice.","method":"Luciferase reporter, EMSA, ChIP, Rev-erbα agonist (SR9009) in vivo treatment, glucose tolerance test","journal":"Pharmacological research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — three orthogonal biochemical methods for direct binding plus in vivo pharmacological confirmation; single lab","pmids":["30639375"],"is_preprint":false},{"year":2019,"finding":"Rev-erbα directly represses Ugt2b36 transcription by binding to −30 to −18 bp of its promoter (luciferase, EMSA, ChIP); Rev-erbα KO mice lose Ugt2b rhythmicity in liver, and glucuronidation of morphine is dosing-time dependent consistent with Rev-erbα rhythmic control of Ugt2b enzymes.","method":"Luciferase reporter, EMSA, ChIP, Rev-erbα KO mice, morphine glucuronidation kinetics, circadian expression profiling","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — three orthogonal direct binding assays plus genetic KO with functional pharmacokinetic phenotype; single lab","pmids":["30639455"],"is_preprint":false},{"year":2019,"finding":"Rev-erbα exerts cell-autonomous inhibitory effects on myogenic precursor cell proliferation and differentiation, and directly controls the Wnt signaling cascade and proliferative pathway transcriptionally; Rev-erbα loss-of-function augments satellite cell expansion and regeneration after muscle injury.","method":"Rev-erbα KO, primary myoblast assays, pharmacological activation/inhibition, muscle injury regeneration model, gene expression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and pharmacological (agonist + antagonist) with consistent myogenic phenotypes; single lab","pmids":["30872796"],"is_preprint":false},{"year":2020,"finding":"REV-ERBα deletion causes increased complement gene expression (C4b, C3) in hippocampal neurons and astrocytes, increased microglial synaptic phagocytosis and synapse loss in CA3, and abolishes diurnal variation in synaptic phagocytosis, establishing BMAL1-REV-ERBα as a regulator of complement and synaptic homeostasis.","method":"Rev-erbα KO mice, BMAL1 KO mice, complement gene expression (ChIP/RNA), synapse phagocytosis assay, diurnal profiling","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent KO models with consistent phenotypes; single lab","pmids":["33258449"],"is_preprint":false},{"year":2020,"finding":"REV-ERBα directly regulates NRF2 transcription and its downstream antioxidant targets SOD1 and catalase in the retinal pigment epithelium (RPE); REV-ERBα deficiency causes accumulated oxidative stress and AMD-like degeneration, while pharmacological activation protects RPE from oxidative damage.","method":"RPE-specific Rev-erbα KO, global KO, ChIP (REV-ERBα on NRF2 promoter), antioxidant enzyme expression, oxidative damage assays, pharmacological agonist","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO plus ChIP for direct target plus pharmacological validation; single lab","pmids":["35176707"],"is_preprint":false},{"year":2020,"finding":"Hepatocyte-specific REVERBα ChIP-seq reveals binding exclusively at RORE/RevDR2 motifs with no evidence for tethering/DNA-binding domain-independent action; hepatocyte-specific Reverbα deletion causes only modest transcriptional dysregulation limited to circadian processes under basal conditions, challenging the view that REVERBα is a dominant driver of basal hepatic lipogenesis.","method":"Antibody-independent ChIP-seq, hepatocyte-specific Reverbα KO, RNA-seq, metabolic phenotyping under basal and metabolic challenge conditions","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — novel antibody-independent ChIP-seq plus conditional KO with transcriptomic readout; directly contradicts prior tethering model","pmids":["32989157"],"is_preprint":false},{"year":2021,"finding":"NR1D1 directly represses Atg5 transcription by binding to two RORE sites in the Atg5 promoter (dual-luciferase reporter and EMSA); NR1D1 activation reduces autophagy in granulosa cells and Nr1d1 knockdown increases ATG5 expression, regulating follicular autophagy.","method":"Dual-luciferase reporter, EMSA, siRNA knockdown, SR9009 agonist treatment, Bmal1 KO mice (indirect)","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct promoter-binding assays (reporter + EMSA) plus functional KD; single lab","pmids":["34936504"],"is_preprint":false},{"year":2021,"finding":"NR1D1 directly represses CYP19A1 transcription by binding to RORE on the CYP19A1 promoter in ovarian granulosa cells; NR1D1 activation reduces estradiol production and NR1D1 interference eliminates this repression.","method":"Luciferase reporter (RORE binding), NR1D1 activation/interference, estradiol RIA","journal":"Theriogenology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — reporter assay plus functional hormonal output; single lab, limited orthogonal validation","pmids":["34933195"],"is_preprint":false},{"year":2021,"finding":"NR1D1 upregulates SOCS3 expression to suppress JAK/STAT3 signaling in ovarian cancer cells; SOCS3 silencing abolishes NR1D1's antiproliferative effect, establishing the NR1D1→SOCS3→JAK/STAT3 pathway in cancer cell growth control.","method":"NR1D1 overexpression/knockdown, CCK8/flow cytometry proliferation assays, Western blot (JAK/STAT3), siRNA (SOCS3 rescue), xenograft model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (SOCS3 siRNA rescue) plus xenograft in vivo; single lab","pmids":["34330232"],"is_preprint":false},{"year":2021,"finding":"Adipocyte-selective NR1D1 deletion does not alter basal WAT lipogenesis but, under high-fat diet, adipocyte NR1D1 KO mice develop profound obesity without accompanying WAT inflammation and fibrosis; NR1D1 cistrome in WAT shows broad metabolic gene control revealed only under obese conditions, indicating NR1D1 is a state-dependent metabolic regulator in adipocytes.","method":"Adipocyte-specific Nr1d1 KO, HFD feeding, WAT cistromic analysis (ChIP-seq), RNA-seq, metabolic/inflammatory phenotyping","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with cistromic analysis and transcriptomic profiling under two metabolic states; multiple orthogonal methods","pmids":["34350828"],"is_preprint":false},{"year":2022,"finding":"NR1D1 directly trans-represses ACO2 (aconitase-2) in vascular smooth muscle cells; VSMC-specific Nr1d1 KO inhibits AAA formation and restores mitochondrial function by derepressing ACO2; α-ketoglutarate (downstream of ACO2) supplementation prevents/treats AAA in a NR1D1-dependent manner in VSMCs.","method":"VSMC-specific Nr1d1 KO mice, AAA models (AngII and CaPO4), ChIP (NR1D1 on ACO2 promoter), mitochondrial metabolism assays, αKG supplementation rescue","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — cell-type-specific KO plus ChIP for direct target plus metabolic rescue experiment; multiple orthogonal methods in rigorous in vivo study","pmids":["35880522"],"is_preprint":false},{"year":2022,"finding":"Rev-erbα in platelets potentiates activation via the oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway; mass spectrometry and co-immunoprecipitation identified oligophrenin-1 as a Rev-erbα interacting partner; platelet-specific Rev-erbα KO mice show impaired agonist-induced aggregation, integrin αIIbβ3 activation, and α-granule release.","method":"Platelet-specific Rev-erbα KO, mass spectrometry, co-immunoprecipitation, platelet aggregation/activation assays, thrombosis models","journal":"European heart journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — MS-identified interactor confirmed by Co-IP, platelet-specific KO with multiple functional assays, in vivo thrombosis models","pmids":["35267019"],"is_preprint":false},{"year":2022,"finding":"NR1D1 controls skeletal muscle sarcoplasmic reticulum calcium homeostasis by directly repressing myoregulin (a SERCA inhibitor) through binding to the myoregulin promoter; NR1D1 deficiency impairs SERCA-dependent SR calcium uptake; restoration of myoregulin counteracts NR1D1 overexpression effects; pharmacological NR1D1 activation improves SR calcium homeostasis and muscle function in dystrophic mdx/Utr+/- mice.","method":"NR1D1 KO mice, ChIP (NR1D1 on myoregulin promoter), SR calcium uptake assays, myoregulin rescue/KO, pharmacological activation, dystrophic mouse model","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct target identification (ChIP) plus genetic epistasis (myoregulin rescue) plus in vivo disease model; multiple orthogonal methods","pmids":["35917173"],"is_preprint":false},{"year":2022,"finding":"NR1D1 protein is degraded in hepatic stellate cells via m6A methylation-induced mRNA ablation during liver fibrosis; NR1D1 deficiency inhibits DRP1S616 phosphorylation, reducing mitochondrial fission and increasing mtDNA release that activates the cGAS pathway, driving local inflammation and fibrosis; NR1D1 overexpression restores DRP1S616 phosphorylation and inhibits cGAS.","method":"NR1D1 KO mice, m6A methylation assay, DRP1 phosphorylation Western blot, mitochondrial fission imaging, cGAS pathway assay, NR1D1 overexpression","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and OE with mechanistic pathway (DRP1-cGAS) and PTM assay; single lab","pmids":["36813093"],"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 antitumor CD8+ T cell responses; Nr1d1 deletion in MMTV-PyMT tumor cells suppresses type I IFNs and reduces immune infiltration, promoting tumor growth and lung metastasis.","method":"Nr1d1 KO in MMTV-PyMT model, orthotopic allograft, cGAS-STING pathway assays, cytosolic DNA quantification, flow cytometry (CD8+ T, NK cells), SR9009 pharmacological treatment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological approaches with mechanistic cGAS-STING pathway validation; single lab","pmids":["37395684"],"is_preprint":false},{"year":2023,"finding":"Microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia, impairing microglial tau phagocytosis; LD formation blockade partially rescues phagocytosis; microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in tauopathy models in a sex-dependent manner.","method":"Microglial-specific Rev-erbα KO, lipid droplet imaging, tau phagocytosis assay, LD inhibitor rescue, two tauopathy mouse models, sex-stratified analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with mechanistic epistasis (LD rescue), replicated in two disease models, sex-dependent effect characterized; multiple orthogonal methods","pmids":["37626048"],"is_preprint":false},{"year":2023,"finding":"NR1D1 directly binds IL-1β and NLRP3 promoters (shown by ChIP); NR1D1 activation inhibits NLRP3 inflammasome assembly and IL-1β production in nucleus pulposus cells, and delays intervertebral disc degeneration in vivo.","method":"ChIP (NR1D1 on IL-1β and NLRP3 promoters), siRNA knockdown, SR9009 agonist treatment, in vivo disc degeneration model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP for direct binding plus in vivo pharmacological model; single lab","pmids":["38689641"],"is_preprint":false},{"year":2021,"finding":"Polyamines stimulate REV-ERBα protein synthesis at the translational level through enhancement of ribosomal shunting mediated by the 5'-UTR of Rev-erbα mRNA; polyamine reduction lengthens circadian period and reduces REV-ERBα protein, identifying Rev-erbα as a member of the 'polyamine modulon'.","method":"Polyamine-reduced cell lines, 5'-UTR reporter constructs (EGFP fusion), circadian period assay, translation assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — ribosomal shunting mechanism via 5'-UTR reporter; single lab, single study","pmids":["33525630"],"is_preprint":false},{"year":2020,"finding":"REV-ERBα overexpression activates mTORC1 signaling by transcriptionally inhibiting the mTORC1 inhibitor Tsc1, leading to increased BMAL1 phosphorylation; REV-ERBα silencing downregulates mTORC1 signaling, linking REV-ERBα to mTOR-mediated circadian clock regulation.","method":"REV-ERBα overexpression/silencing, mTORC1 activity assay (S6K phosphorylation), Tsc1 expression (qPCR), BMAL1 phosphorylation, leucine/rapamycin pharmacology","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — OE/KD with pathway readouts and pharmacological validation; single lab, mechanistic link to Tsc1 is indirect","pmids":["33285244"],"is_preprint":false}],"current_model":"NR1D1 (REV-ERBα) is a heme-liganded nuclear receptor that functions as a potent transcriptional repressor by recruiting the NCoR-HDAC3 corepressor complex; it operates as an integral component of the core circadian clock by directly competing with ROR factors at RORE/RevDR2 motifs to repress BMAL1 and other positive-limb genes, while in metabolic tissues it is tethered by lineage-specific transcription factors (e.g., HNF4A, HNF6) to impose tissue-specific rhythmic repression of lipid, glucose, bile acid, and drug metabolism genes; its protein abundance is controlled by CDK1 phosphorylation-triggered FBXW7 ubiquitination and by Siah2-mediated degradation, as well as by inflammatory SUMOylation/ubiquitination; in addition to these transcriptional roles, NR1D1 interacts with PARP1 (inhibiting PARylation and DNA repair), modulates chromatin looping via NCoR-HDAC3-mediated BRD4/MED1 eviction, regulates microglial lipid metabolism and neuroinflammation, controls platelet activation via oligophrenin-1/RhoA/ERM signaling, maintains skeletal muscle calcium homeostasis by repressing myoregulin, and suppresses inflammasome (NLRP3/NF-κB) activation across multiple cell types."},"narrative":{"mechanistic_narrative":"NR1D1 (REV-ERBα) is a heme-liganded nuclear receptor that operates as a potent transcriptional repressor at the interface of the circadian clock and tissue metabolism [PMID:18218725, PMID:22460952, PMID:26044300]. Heme binds directly to its ligand-binding domain and gates recruitment of the NCoR-HDAC3 corepressor complex to target promoters [PMID:18218725, PMID:20414452]. Two mechanistically distinct modes of action govern its genomic output: at the clock, REV-ERBα directly competes with ROR factors at RORE/RevDR2 motifs to repress BMAL1 and other positive-limb genes, while at metabolic genes it is tethered by lineage-determining transcription factors such as HNF6 to impose tissue-specific repression of lipid, glucose, bile acid, and drug-metabolism programs [PMID:26044300, PMID:27445394, PMID:29237721, PMID:30639375, PMID:30639455]. NR1D1 and the paralogous REV-ERBβ share the great majority of genomic binding sites and act redundantly; their combined loss abolishes cell-autonomous rhythms and produces hepatic steatosis with derepression of clock and metabolic genes [PMID:22460952, PMID:22474260]. Mechanistically, REV-ERBα-NCoR-HDAC3 deacetylates enhancer histones and evicts BRD4 and MED1 to oppose enhancer-promoter chromatin looping, providing the molecular basis for rhythmic transcriptional repression [PMID:29439026]. REV-ERBα protein abundance is tightly controlled by degradation: CDK1 phosphorylation primes FBXW7-mediated ubiquitination, Siah2 drives circadian turnover, and inflammatory SUMOylation/ubiquitination triggers rapid loss during immune challenge [PMID:26392558, PMID:27238018, PMID:29533925]. Beyond core clock and metabolic transcription, NR1D1 directly represses inflammasome components (NLRP3, IL-1β) and NF-κB signaling to restrain inflammation across colitis, microglial, and disc-degeneration models [PMID:30315268, PMID:30792350, PMID:38689641], suppresses RORγt-dependent Th17 cytokines [PMID:30590045], binds PARP1 to inhibit PARylation and DNA double-strand break repair [PMID:28249904, PMID:28599788], regulates microglial lipid-droplet metabolism and tau phagocytosis [PMID:37626048], and maintains skeletal-muscle SR calcium homeostasis by repressing myoregulin [PMID:35917173]. Its activity is further integrated with cellular state through polyamine-driven translational control and mTORC1 signaling [PMID:33525630, PMID:33285244].","teleology":[{"year":1990,"claim":"Established that human NR1D1/Rev-ErbAα, arising from opposite-strand transcription of the c-erbAα locus, is an orphan-like receptor that does not bind thyroid hormone, framing it as a distinct receptor whose ligand and function were unknown.","evidence":"cDNA cloning, Northern analysis, and thyroid hormone ligand-binding assay","pmids":["1971514"],"confidence":"High","gaps":["No endogenous ligand identified","No transcriptional target or mechanism defined"]},{"year":1999,"claim":"Demonstrated NR1D1 acts as a sequence-specific repressor that antagonizes PPARα/RXRα at a defined response element, giving early evidence of direct DNA-binding repressor activity over metabolic genes.","evidence":"In vitro binding and transient transfection reporter assays on the HD-PPRE","pmids":["10428876"],"confidence":"Medium","gaps":["In vitro only, single study","Corepressor machinery not yet defined"]},{"year":2008,"claim":"Identified heme as the endogenous ligand binding the LBD and controlling NCoR corepressor recruitment, resolving the long-standing question of how REV-ERBα repressor activity is regulated.","evidence":"Direct LBD ligand-binding biochemistry plus corepressor recruitment assay for REV-ERBα/β","pmids":["18218725"],"confidence":"High","gaps":["Physiological heme dynamics not addressed","Full corepressor complex composition not defined here"]},{"year":2010,"claim":"Synthesized the model that heme-liganded REV-ERBα recruits NCoR-HDAC3 to repress BMAL1, positioning it as the negative limb of the core clock.","evidence":"Review integrating ligand-binding, corepressor recruitment, and gene expression data","pmids":["20414452"],"confidence":"High","gaps":["Genome-wide binding not yet mapped","Redundancy with REV-ERBβ unresolved"]},{"year":2012,"claim":"Showed REV-ERBα and REV-ERBβ are largely redundant integral clock components: they share most genomic sites, overlap BMAL1 cistromes near metabolic genes, and their combined loss causes arrhythmia and hepatic steatosis, establishing clock-metabolism coupling.","evidence":"ChIP-seq cistromes, double-knockout mice/MEFs, behavioural and lipid metabolic profiling","pmids":["22460952","22474260"],"confidence":"High","gaps":["Mode of metabolic gene targeting (direct vs tethered) unresolved","Tissue specificity of metabolic effects not dissected"]},{"year":2015,"claim":"Resolved how one receptor achieves both universal clock control and tissue-specific metabolic control by defining two modes: ROR competition at cognate sites versus HDAC3 recruitment at lineage-TF-tethered sites.","evidence":"ChIP-seq, domain mutagenesis, HDAC3 recruitment and liver TF tethering analysis","pmids":["26044300"],"confidence":"High","gaps":["Identity of all tethering factors incomplete","Extent of tethering across tissues unresolved"]},{"year":2016,"claim":"Identified the degradation circuits controlling REV-ERBα abundance — Siah2-mediated circadian turnover and a CDK1-phosphorylation/FBXW7-ubiquitination axis — explaining how repressor amplitude and period are set post-translationally.","evidence":"E3-ligase screen, siRNA/overexpression, phosphorylation and ubiquitination assays, hepatic FBXW7 KO mice","pmids":["26392558","27238018"],"confidence":"High","gaps":["Crosstalk between Siah2 and FBXW7 pathways unclear","Upstream signals triggering CDK1 phosphorylation in vivo not fully defined"]},{"year":2016,"claim":"Confirmed lineage-TF tethering in liver by showing HNF6 recruits Rev-erbα to shared lipid-gene promoters, with HNF6 loss abolishing Rev-erbα binding and derepressing lipogenesis.","evidence":"Liver-specific HNF6 KO with ChIP-seq and expression profiling","pmids":["27445394"],"confidence":"High","gaps":["Whether tethering is required outside liver lipid genes unresolved"]},{"year":2018,"claim":"Defined the chromatin-level mechanism of repression: REV-ERBα-NCoR-HDAC3 deacetylates enhancers and evicts BRD4/MED1 to oppose enhancer-promoter looping, explaining rhythmic transcriptional output.","evidence":"Chromatin interaction analysis, ChIP-seq, corepressor Co-IP, BRD4/MED1 eviction assays","pmids":["29439026"],"confidence":"High","gaps":["Generality of looping control beyond tested loci not established"]},{"year":2018,"claim":"Extended REV-ERBα function into immunity, showing direct repression of Nlrp3 and indirect repression via NF-κB p65, with genetic epistasis linking it to inflammasome and Th17 control.","evidence":"ChIP, reporter assays, Rev-erbα/Nlrp3 KO mice, colitis/EAE models, RORE competition assays","pmids":["30315268","30590045"],"confidence":"High","gaps":["Relative contribution of direct vs NF-κB-mediated repression not quantified","Cell-type specificity of anti-inflammatory effect not fully mapped"]},{"year":2018,"claim":"Linked REV-ERBα degradation to inflammation, showing proinflammatory challenge triggers SUMOylation/ubiquitination-driven loss, and to glucocorticoid signaling via physical GR interaction and chromatin co-binding that times hepatic GC sensitivity.","evidence":"PTM and protein-stability assays, Co-IP, GR/REVERBα ChIP-seq, conditional KO metabolic phenotyping","pmids":["29533925","30179226","27686098"],"confidence":"Medium","gaps":["Direct SUMO/ubiquitin sites not all mapped","Mechanism of GR-HSP90 competition partially unresolved"]},{"year":2017,"claim":"Established a non-transcriptional genome-protective role: NR1D1 binds PARP1, inhibits PARylation, is recruited to damage sites, and blocks repair-factor (SIRT6/pNBS1/BRCA1) recruitment, inhibiting both NHEJ and HR.","evidence":"DSB reporter assays, domain-deletion mutants, Co-IP, ChIP at lesions, PARP1 activity assays","pmids":["28249904","28599788"],"confidence":"High","gaps":["Physiological/circadian regulation of DNA-repair role unclear","Interplay with transcriptional functions not resolved"]},{"year":2020,"claim":"Challenged the dominant hepatic tethering/lipogenesis model, showing antibody-independent hepatocyte ChIP-seq detects binding only at RORE/RevDR2 motifs and that hepatocyte-specific deletion causes only modest, circadian-restricted dysregulation under basal conditions.","evidence":"Antibody-independent ChIP-seq, hepatocyte-specific KO, RNA-seq under basal and challenge states","pmids":["32989157"],"confidence":"High","gaps":["Reconciliation with prior tethering data unresolved","Condition-dependence of metabolic role needs broader testing"]},{"year":2022,"claim":"Demonstrated state-dependent and tissue-specific metabolic roles, with adipocyte NR1D1 controlling diet-induced obesity and a WAT cistrome revealed only under metabolic challenge, alongside direct repression of mitochondrial/metabolic targets (ACO2) in vascular smooth muscle.","evidence":"Adipocyte- and VSMC-specific KO, ChIP-seq/ChIP, HFD and AAA disease models, metabolite rescue","pmids":["34350828","35880522"],"confidence":"High","gaps":["Signals that unmask the obese-state cistrome unknown","Generality across other metabolic tissues unresolved"]},{"year":2022,"claim":"Uncovered cytoplasmic and tissue-specific effector roles: a platelet oligophrenin-1/RhoA/ERM activation pathway and direct repression of myoregulin to maintain skeletal-muscle SR calcium homeostasis.","evidence":"Platelet- and muscle-specific KO, mass spectrometry, Co-IP, ChIP, SR calcium and aggregation assays, dystrophic mouse model","pmids":["35267019","35917173"],"confidence":"High","gaps":["Mechanism linking REV-ERBα to oligophrenin-1 at molecular level partial","Whether platelet role is transcription-independent unresolved"]},{"year":2023,"claim":"Connected REV-ERBα to lipid-droplet and innate-immune signaling in disease contexts, including sex-dependent microglial lipid-droplet accumulation impairing tau phagocytosis and modulation of cGAS-STING/type I IFN responses in tumors.","evidence":"Cell-type-specific KO, lipid-droplet imaging, tauopathy models, cGAS-STING assays, MMTV-PyMT tumor model, pharmacological SR9009","pmids":["37626048","37395684","36813093"],"confidence":"Medium","gaps":["Molecular basis of sex-dependence unknown","Context-dependent pro- vs anti-tumor effects not reconciled"]},{"year":null,"claim":"How REV-ERBα's distinct transcriptional, chromatin-looping, DNA-repair, and cytoplasmic effector activities are coordinated, and how its degradation circuits are integrated to set output in each cell type and metabolic state, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking nuclear and cytoplasmic functions","Structural basis of tethering versus direct binding not defined","Reconciliation of conflicting hepatic metabolic models incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,13,8,25,26,34,22]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[13,34,35,40,39]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[20,21,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,25,26]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[25,20]}],"pathway":[{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[5,8,9,13,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13,25,26,34]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,9,16,22,43]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26,29,30,50]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[20,21]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[25]}],"complexes":["NCoR-HDAC3 corepressor complex"],"partners":["NCOR1","HDAC3","PARP1","NR1H2","HNF6","NR3C1","OPHN1"],"other_free_text":[]}},"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":"22460952","id":"PMC_22460952","title":"Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22460952","citation_count":878,"is_preprint":false},{"pmid":"22474260","id":"PMC_22474260","title":"Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function.","date":"2012","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/22474260","citation_count":416,"is_preprint":false},{"pmid":"30315268","id":"PMC_30315268","title":"REV-ERBα integrates colon clock with experimental colitis through regulation of NF-κB/NLRP3 axis.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30315268","citation_count":283,"is_preprint":false},{"pmid":"26044300","id":"PMC_26044300","title":"GENE REGULATION. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock.","date":"2015","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26044300","citation_count":274,"is_preprint":false},{"pmid":"30792350","id":"PMC_30792350","title":"Circadian clock protein Rev-erbα regulates neuroinflammation.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30792350","citation_count":218,"is_preprint":false},{"pmid":"29439026","id":"PMC_29439026","title":"Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription.","date":"2018","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29439026","citation_count":164,"is_preprint":false},{"pmid":"29533925","id":"PMC_29533925","title":"Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29533925","citation_count":160,"is_preprint":false},{"pmid":"11014236","id":"PMC_11014236","title":"Circadian and glucocorticoid regulation of Rev-erbalpha expression in liver.","date":"2000","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11014236","citation_count":151,"is_preprint":false},{"pmid":"19696364","id":"PMC_19696364","title":"Rev-erb-alpha: an integrator of circadian rhythms and metabolism.","date":"2009","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/19696364","citation_count":144,"is_preprint":false},{"pmid":"18218725","id":"PMC_18218725","title":"Nuclear hormone receptors for heme: REV-ERBalpha and REV-ERBbeta are ligand-regulated components of the mammalian clock.","date":"2008","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/18218725","citation_count":138,"is_preprint":false},{"pmid":"25066191","id":"PMC_25066191","title":"Nuclear receptor Rev-erbα: up, down, and all around.","date":"2014","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/25066191","citation_count":133,"is_preprint":false},{"pmid":"27238018","id":"PMC_27238018","title":"Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBα Degradation.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27238018","citation_count":130,"is_preprint":false},{"pmid":"20414452","id":"PMC_20414452","title":"Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism.","date":"2010","source":"Nuclear receptor signaling","url":"https://pubmed.ncbi.nlm.nih.gov/20414452","citation_count":123,"is_preprint":false},{"pmid":"32226546","id":"PMC_32226546","title":"Targeting REV-ERBα for therapeutic purposes: promises and challenges.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32226546","citation_count":121,"is_preprint":false},{"pmid":"32071294","id":"PMC_32071294","title":"NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32071294","citation_count":109,"is_preprint":false},{"pmid":"30590045","id":"PMC_30590045","title":"REV-ERBα Regulates TH17 Cell Development and Autoimmunity.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30590045","citation_count":97,"is_preprint":false},{"pmid":"24932636","id":"PMC_24932636","title":"The nuclear receptor REV-ERBα regulates Fabp7 and modulates adult hippocampal neurogenesis.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24932636","citation_count":92,"is_preprint":false},{"pmid":"27171500","id":"PMC_27171500","title":"The circadian clock regulates autophagy directly through the nuclear hormone receptor Nr1d1/Rev-erbα and indirectly via Cebpb/(C/ebpβ) in zebrafish.","date":"2016","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/27171500","citation_count":88,"is_preprint":false},{"pmid":"35880522","id":"PMC_35880522","title":"Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2.","date":"2022","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/35880522","citation_count":83,"is_preprint":false},{"pmid":"35668454","id":"PMC_35668454","title":"The circadian clock protein Rev-erbα provides neuroprotection and attenuates neuroinflammation against Parkinson's disease via the microglial NLRP3 inflammasome.","date":"2022","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/35668454","citation_count":82,"is_preprint":false},{"pmid":"30670689","id":"PMC_30670689","title":"The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30670689","citation_count":82,"is_preprint":false},{"pmid":"22166979","id":"PMC_22166979","title":"The clock gene Rev-erbα regulates pancreatic β-cell function: modulation by leptin and high-fat diet.","date":"2011","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22166979","citation_count":80,"is_preprint":false},{"pmid":"31879343","id":"PMC_31879343","title":"The circadian clock protein REVERBα inhibits pulmonary fibrosis development.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31879343","citation_count":79,"is_preprint":false},{"pmid":"31308426","id":"PMC_31308426","title":"REV-ERBα and REV-ERBβ function as key factors regulating Mammalian Circadian Output.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31308426","citation_count":78,"is_preprint":false},{"pmid":"31455731","id":"PMC_31455731","title":"The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune disease.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31455731","citation_count":77,"is_preprint":false},{"pmid":"27884645","id":"PMC_27884645","title":"Dysregulated circadian rhythm pathway in human osteoarthritis: NR1D1 and BMAL1 suppression alters TGF-β signaling in chondrocytes.","date":"2016","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/27884645","citation_count":73,"is_preprint":false},{"pmid":"23656296","id":"PMC_23656296","title":"Optimized chemical probes for REV-ERBα.","date":"2013","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23656296","citation_count":72,"is_preprint":false},{"pmid":"37626048","id":"PMC_37626048","title":"Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37626048","citation_count":70,"is_preprint":false},{"pmid":"28878135","id":"PMC_28878135","title":"REV-ERBα ameliorates heart failure through transcription repression.","date":"2017","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/28878135","citation_count":67,"is_preprint":false},{"pmid":"20160030","id":"PMC_20160030","title":"An RNA interference screen identifies metabolic regulators NR1D1 and PBP as novel survival factors for breast cancer cells with the ERBB2 signature.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20160030","citation_count":65,"is_preprint":false},{"pmid":"35267019","id":"PMC_35267019","title":"Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation.","date":"2022","source":"European heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/35267019","citation_count":64,"is_preprint":false},{"pmid":"24252172","id":"PMC_24252172","title":"Oxidative stress and inflammation modulate Rev-erbα signaling in the neonatal lung and affect circadian rhythmicity.","date":"2014","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/24252172","citation_count":64,"is_preprint":false},{"pmid":"30179226","id":"PMC_30179226","title":"REVERBa couples the circadian clock to hepatic glucocorticoid action.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30179226","citation_count":63,"is_preprint":false},{"pmid":"33258449","id":"PMC_33258449","title":"REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33258449","citation_count":61,"is_preprint":false},{"pmid":"21408158","id":"PMC_21408158","title":"Nuclear receptor Rev-erb alpha (Nr1d1) functions in concert with Nr2e3 to regulate transcriptional networks in the retina.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21408158","citation_count":61,"is_preprint":false},{"pmid":"27445394","id":"PMC_27445394","title":"HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms.","date":"2016","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/27445394","citation_count":58,"is_preprint":false},{"pmid":"29237721","id":"PMC_29237721","title":"REV-ERBα Regulates CYP7A1 Through Repression of Liver Receptor Homolog-1.","date":"2017","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/29237721","citation_count":56,"is_preprint":false},{"pmid":"24311788","id":"PMC_24311788","title":"Apolipoprotein A-IV reduces hepatic gluconeogenesis through nuclear receptor NR1D1.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24311788","citation_count":53,"is_preprint":false},{"pmid":"18804497","id":"PMC_18804497","title":"Association analysis of nuclear receptor Rev-erb alpha gene (NR1D1) with mood disorders in the Japanese population.","date":"2008","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/18804497","citation_count":52,"is_preprint":false},{"pmid":"34014841","id":"PMC_34014841","title":"Molecular clock REV-ERBα regulates cigarette smoke-induced pulmonary inflammation and epithelial-mesenchymal transition.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34014841","citation_count":51,"is_preprint":false},{"pmid":"32989157","id":"PMC_32989157","title":"Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32989157","citation_count":48,"is_preprint":false},{"pmid":"34350828","id":"PMC_34350828","title":"Adipocyte NR1D1 dictates adipose tissue expansion during obesity.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34350828","citation_count":48,"is_preprint":false},{"pmid":"29085009","id":"PMC_29085009","title":"Rev-erb-α regulates atrophy-related genes to control skeletal muscle mass.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29085009","citation_count":47,"is_preprint":false},{"pmid":"28249904","id":"PMC_28249904","title":"NR1D1 Recruitment to Sites of DNA Damage Inhibits Repair and Is Associated with Chemosensitivity of Breast Cancer.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28249904","citation_count":46,"is_preprint":false},{"pmid":"27686098","id":"PMC_27686098","title":"REV-ERBα influences the stability and nuclear localization of the glucocorticoid receptor.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/27686098","citation_count":45,"is_preprint":false},{"pmid":"26564124","id":"PMC_26564124","title":"Altered Sleep Homeostasis in Rev-erbα Knockout Mice.","date":"2016","source":"Sleep","url":"https://pubmed.ncbi.nlm.nih.gov/26564124","citation_count":45,"is_preprint":false},{"pmid":"25789810","id":"PMC_25789810","title":"Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25789810","citation_count":44,"is_preprint":false},{"pmid":"19926613","id":"PMC_19926613","title":"Nr1d1, an important circadian pathway regulatory gene, is suppressed by cigarette smoke in murine lungs.","date":"2009","source":"Integrative cancer therapies","url":"https://pubmed.ncbi.nlm.nih.gov/19926613","citation_count":43,"is_preprint":false},{"pmid":"26855417","id":"PMC_26855417","title":"The circadian gene Rev-erbα improves cellular bioenergetics and provides preconditioning for protection against oxidative stress.","date":"2016","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26855417","citation_count":42,"is_preprint":false},{"pmid":"31059511","id":"PMC_31059511","title":"Meiotic gatekeeper STRA8 suppresses autophagy by repressing Nr1d1 expression during spermatogenesis in mice.","date":"2019","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31059511","citation_count":42,"is_preprint":false},{"pmid":"28974420","id":"PMC_28974420","title":"The nuclear receptor and clock gene REV-ERBα regulates cigarette smoke-induced lung inflammation.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28974420","citation_count":41,"is_preprint":false},{"pmid":"1971514","id":"PMC_1971514","title":"Isolation of a cDNA encoding human Rev-ErbA alpha: transcription from the noncoding DNA strand of a thyroid hormone receptor gene results in a related protein that does not bind thyroid hormone.","date":"1990","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1971514","citation_count":41,"is_preprint":false},{"pmid":"36894533","id":"PMC_36894533","title":"Circadian clock molecule REV-ERBα regulates lung fibrotic progression through collagen stabilization.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36894533","citation_count":40,"is_preprint":false},{"pmid":"32586876","id":"PMC_32586876","title":"Circadian asthma airway responses are gated by REV-ERBα.","date":"2020","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/32586876","citation_count":40,"is_preprint":false},{"pmid":"37395684","id":"PMC_37395684","title":"NR1D1 Stimulates Antitumor Immune Responses in Breast Cancer by Activating cGAS-STING Signaling.","date":"2023","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/37395684","citation_count":39,"is_preprint":false},{"pmid":"30872796","id":"PMC_30872796","title":"The Nuclear Receptor and Clock Repressor Rev-erbα Suppresses Myogenesis.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30872796","citation_count":39,"is_preprint":false},{"pmid":"24498227","id":"PMC_24498227","title":"Modifier genes as therapeutics: the nuclear hormone receptor Rev Erb alpha (Nr1d1) rescues Nr2e3 associated retinal disease.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24498227","citation_count":39,"is_preprint":false},{"pmid":"15374821","id":"PMC_15374821","title":"Aberrant expression of myosin isoforms in skeletal muscles from mice lacking the rev-erbAalpha orphan receptor gene.","date":"2004","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15374821","citation_count":37,"is_preprint":false},{"pmid":"31896234","id":"PMC_31896234","title":"Rev-erbα Negatively Regulates Osteoclast and Osteoblast Differentiation through p38 MAPK Signaling Pathway.","date":"2020","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/31896234","citation_count":36,"is_preprint":false},{"pmid":"36813093","id":"PMC_36813093","title":"m6A methylation-induced NR1D1 ablation disrupts the HSC circadian clock and promotes hepatic fibrosis.","date":"2023","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/36813093","citation_count":35,"is_preprint":false},{"pmid":"26392558","id":"PMC_26392558","title":"Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26392558","citation_count":34,"is_preprint":false},{"pmid":"34936504","id":"PMC_34936504","title":"Circadian clock regulates granulosa cell autophagy through NR1D1-mediated inhibition of ATG5.","date":"2021","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34936504","citation_count":33,"is_preprint":false},{"pmid":"27002153","id":"PMC_27002153","title":"The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27002153","citation_count":33,"is_preprint":false},{"pmid":"17353661","id":"PMC_17353661","title":"The orphan nuclear receptor Rev-erbalpha: a transcriptional link between circadian rhythmicity and cardiometabolic disease.","date":"2007","source":"Current opinion in lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/17353661","citation_count":32,"is_preprint":false},{"pmid":"38072952","id":"PMC_38072952","title":"Targeting NR1D1 in organ injury: challenges and prospects.","date":"2023","source":"Military Medical Research","url":"https://pubmed.ncbi.nlm.nih.gov/38072952","citation_count":31,"is_preprint":false},{"pmid":"32439175","id":"PMC_32439175","title":"Pharmacological modulation and genetic deletion of REV-ERBα and REV-ERBβ regulates dendritic cell development.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32439175","citation_count":31,"is_preprint":false},{"pmid":"33101272","id":"PMC_33101272","title":"The Effect of Rev-erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33101272","citation_count":31,"is_preprint":false},{"pmid":"35176707","id":"PMC_35176707","title":"REV-ERBα regulates age-related and oxidative stress-induced degeneration in retinal pigment epithelium via NRF2.","date":"2022","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/35176707","citation_count":30,"is_preprint":false},{"pmid":"33096076","id":"PMC_33096076","title":"Pharmacological activation of REV-ERBα improves nonalcoholic steatohepatitis by regulating intestinal permeability.","date":"2020","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/33096076","citation_count":30,"is_preprint":false},{"pmid":"26332963","id":"PMC_26332963","title":"Rev-erbα and the circadian transcriptional regulation of metabolism.","date":"2015","source":"Diabetes, obesity & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26332963","citation_count":29,"is_preprint":false},{"pmid":"30028550","id":"PMC_30028550","title":"The circadian gene Nr1d1 in the mouse nucleus accumbens modulates sociability and anxiety-related behaviour.","date":"2018","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30028550","citation_count":28,"is_preprint":false},{"pmid":"28412351","id":"PMC_28412351","title":"Effect of ApoA4 on SERPINA3 mediated by nuclear receptors NR4A1 and NR1D1 in hepatocytes.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28412351","citation_count":28,"is_preprint":false},{"pmid":"10428876","id":"PMC_10428876","title":"Orphan nuclear hormone receptor RevErbalpha modulates expression from the promoter of the hydratase-dehydrogenase gene by inhibiting peroxisome proliferator-activated receptor alpha-dependent transactivation.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10428876","citation_count":27,"is_preprint":false},{"pmid":"27440795","id":"PMC_27440795","title":"Rev-Erbα modulates retinal visual processing and behavioral responses to light.","date":"2016","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/27440795","citation_count":27,"is_preprint":false},{"pmid":"30639375","id":"PMC_30639375","title":"Rev-erbα activation down-regulates hepatic Pck1 enzyme to lower plasma glucose in mice.","date":"2019","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/30639375","citation_count":26,"is_preprint":false},{"pmid":"34933195","id":"PMC_34933195","title":"NR1D1 targeting CYP19A1 inhibits estrogen synthesis in ovarian granulosa cells.","date":"2021","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/34933195","citation_count":24,"is_preprint":false},{"pmid":"34330232","id":"PMC_34330232","title":"NR1D1 suppressed the growth of ovarian cancer by abrogating the JAK/STAT3 signaling pathway.","date":"2021","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34330232","citation_count":24,"is_preprint":false},{"pmid":"34956438","id":"PMC_34956438","title":"NR1D1 Deletion Induces Rupture-Prone Vulnerable Plaques by Regulating Macrophage Pyroptosis via the NF-κB/NLRP3 Inflammasome Pathway.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34956438","citation_count":24,"is_preprint":false},{"pmid":"32244760","id":"PMC_32244760","title":"The Core-Clock Gene NR1D1 Impacts Cell Motility In Vitro and Invasiveness in A Zebrafish Xenograft Colon Cancer Model.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32244760","citation_count":23,"is_preprint":false},{"pmid":"29723273","id":"PMC_29723273","title":"Distinct roles for REV-ERBα and REV-ERBβ in oxidative capacity and mitochondrial biogenesis in skeletal muscle.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29723273","citation_count":23,"is_preprint":false},{"pmid":"26332975","id":"PMC_26332975","title":"Role of the clock gene Rev-erbα in metabolism and in the endocrine pancreas.","date":"2015","source":"Diabetes, obesity & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26332975","citation_count":22,"is_preprint":false},{"pmid":"36077427","id":"PMC_36077427","title":"Regulation of Circadian Genes Nr1d1 and Nr1d2 in Sex-Different Manners during Liver Aging.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36077427","citation_count":21,"is_preprint":false},{"pmid":"34673015","id":"PMC_34673015","title":"Involvement of REV-ERBα dysregulation and ferroptosis in aristolochic acid I-induced renal injury.","date":"2021","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34673015","citation_count":21,"is_preprint":false},{"pmid":"35414779","id":"PMC_35414779","title":"BMAL1 regulates Propionibacterium acnes-induced skin inflammation via REV-ERBα in mice.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35414779","citation_count":21,"is_preprint":false},{"pmid":"21375499","id":"PMC_21375499","title":"A role for rev-erbα ligands in regulation of adipogenesis.","date":"2011","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/21375499","citation_count":20,"is_preprint":false},{"pmid":"30639455","id":"PMC_30639455","title":"The nuclear receptor Rev-erbα participates in circadian regulation of Ugt2b enzymes in mice.","date":"2019","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30639455","citation_count":19,"is_preprint":false},{"pmid":"35839302","id":"PMC_35839302","title":"Inhibition of mPGES-2 ameliorates NASH by activating NR1D1 via heme.","date":"2022","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/35839302","citation_count":17,"is_preprint":false},{"pmid":"26370410","id":"PMC_26370410","title":"Dissecting the Rev-erbα Cistrome and the Mechanisms Controlling Circadian Transcription in Liver.","date":"2015","source":"Cold Spring Harbor symposia on quantitative biology","url":"https://pubmed.ncbi.nlm.nih.gov/26370410","citation_count":17,"is_preprint":false},{"pmid":"37269594","id":"PMC_37269594","title":"Rev-erbα agonists suppresses TGFβ1-induced fibroblast-to-myofibroblast transition and pro-fibrotic phenotype in human lung fibroblasts.","date":"2023","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/37269594","citation_count":17,"is_preprint":false},{"pmid":"31409842","id":"PMC_31409842","title":"Rev-Erbα and Photoreceptor Outer Segments modulate the Circadian Clock in Retinal Pigment Epithelial Cells.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31409842","citation_count":17,"is_preprint":false},{"pmid":"38505614","id":"PMC_38505614","title":"Depletion of ApoA5 aggravates spontaneous and diet-induced nonalcoholic fatty liver disease by reducing hepatic NR1D1 in hamsters.","date":"2024","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/38505614","citation_count":16,"is_preprint":false},{"pmid":"33525630","id":"PMC_33525630","title":"Translational Regulation of Clock Genes BMAL1 and REV-ERBα by Polyamines.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33525630","citation_count":16,"is_preprint":false},{"pmid":"17075855","id":"PMC_17075855","title":"Functional characterization of an orphan nuclear receptor, Rev-ErbAalpha, in chondrocytes and its potential role in osteoarthritis.","date":"2006","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/17075855","citation_count":15,"is_preprint":false},{"pmid":"28599788","id":"PMC_28599788","title":"NR1D1 enhances oxidative DNA damage by inhibiting PARP1 activity.","date":"2017","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/28599788","citation_count":15,"is_preprint":false},{"pmid":"33285244","id":"PMC_33285244","title":"REV-ERBα alters circadian rhythms by modulating mTOR signaling.","date":"2020","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/33285244","citation_count":15,"is_preprint":false},{"pmid":"37524704","id":"PMC_37524704","title":"NR1D1 deficiency in the tumor microenvironment promotes lung tumor development by activating the NLRP3 inflammasome.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37524704","citation_count":15,"is_preprint":false},{"pmid":"32006903","id":"PMC_32006903","title":"Chronopharmacological targeting of Rev-erbα by puerarin alleviates hyperhomocysteinemia in mice.","date":"2020","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/32006903","citation_count":15,"is_preprint":false},{"pmid":"35428762","id":"PMC_35428762","title":"The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35428762","citation_count":14,"is_preprint":false},{"pmid":"35917173","id":"PMC_35917173","title":"NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/35917173","citation_count":13,"is_preprint":false},{"pmid":"38689641","id":"PMC_38689641","title":"SR9009 attenuates inflammation-related NPMSC pyroptosis and IVDD through NR1D1/NLRP3/IL-1β pathway.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38689641","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48593,"output_tokens":12840,"usd":0.169189,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":25193,"output_tokens":5481,"usd":0.131495,"stage2_stop_reason":"end_turn"},"total_usd":0.300684,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"Human Rev-ErbAα (NR1D1) is derived from opposite-strand transcription of the c-erbAα genomic locus and does not bind thyroid hormone, despite 99% identity to the rat homolog in the DNA-binding and putative ligand-binding domains.\",\n      \"method\": \"cDNA cloning, Northern analysis, ligand-binding assay\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical assay (ligand binding) combined with sequence analysis; foundational paper replicated across species\",\n      \"pmids\": [\"1971514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Rev-ErbAα binds the HD-PPRE (but not the AOx-PPRE) in vitro and antagonizes PPARα/RXRα-dependent transactivation from an HD-PPRE reporter, identifying the enoyl-CoA hydratase/hydroxyacyl-CoA dehydrogenase (HD) gene as a direct Rev-ErbAα target and revealing cross-talk between Rev-ErbAα and PPARα signaling pathways at a specific response element.\",\n      \"method\": \"In vitro binding analysis, transient transfection reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding and reporter assay in a single study, not independently replicated\",\n      \"pmids\": [\"10428876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Glucocorticoids repress Rev-erbα expression in rat liver and primary hepatocytes at the transcriptional level via the glucocorticoid receptor; the effect is blocked by the GR antagonist RU486 and by actinomycin D, and transient transfection demonstrates GR represses the Rev-erbα promoter directly.\",\n      \"method\": \"In vivo dexamethasone treatment, primary hepatocyte culture, GR antagonist (RU486), actinomycin D, cycloheximide, transient transfection promoter assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (pharmacological, genetic antagonist, transcriptional reporter) in a single study\",\n      \"pmids\": [\"11014236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Rev-erbAα protein influences myosin heavy chain (MyHC) isoform expression in slow-twitch skeletal muscle; Rev-erbAα knock-out mice show a significantly higher proportion of β/slow (type I) MyHC isoform in the soleus, establishing a role in muscle fiber-type specification.\",\n      \"method\": \"Rev-erbAα knockout mouse model, MyHC isoform analysis, immunohistochemistry\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with defined phenotype, single lab, single study\",\n      \"pmids\": [\"15374821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Heme binds directly to the ligand-binding domain of REV-ERBα and REV-ERBβ and regulates their ability to recruit NCoR (nuclear receptor corepressor) to target gene promoters, establishing heme as an endogenous ligand that controls REV-ERBα transcriptional repressor activity.\",\n      \"method\": \"Ligand-binding assay (direct binding to LBD), co-repressor recruitment assay\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct ligand-binding biochemistry combined with functional co-repressor recruitment; independently corroborated by multiple subsequent studies\",\n      \"pmids\": [\"18218725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"REV-ERBα (NR1D1) is a heme receptor that promotes transcriptional repression by recruiting the NCoR-HDAC3 corepressor complex, and directly represses BMAL1 expression to function as a critical negative limb of the core circadian clock.\",\n      \"method\": \"Review synthesizing ligand-binding, co-repressor recruitment, and gene expression studies\",\n      \"journal\": \"Nuclear receptor signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mechanistic conclusions drawn from multiple primary studies including reconstitution and co-repressor recruitment assays\",\n      \"pmids\": [\"20414452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NR1D1 (Rev-erbα) co-regulates transcriptional networks with NR2E3 in retinal photoreceptors; NR1D1 protein is co-expressed with NR2E3 in rods and cones, and knockdown of Nr1d1 in the developing retina causes pan-retinal spotting and reduced retinal function by electroretinogram.\",\n      \"method\": \"Knock-down in developing retina (morpholino/siRNA), electroretinogram, immunostaining, co-expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with defined functional phenotype (ERG) plus protein co-localization; single study\",\n      \"pmids\": [\"21408158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rev-erbα down-regulation by siRNA in pancreatic islet cells impairs glucose-induced insulin secretion, decreases lipogenic gene expression, and inhibits β-cell proliferation; leptin increases Rev-erbα expression via a MAPK pathway.\",\n      \"method\": \"siRNA knockdown, bromodeoxyuridine incorporation, RIA insulin secretion, RT-PCR, in vivo leptin treatment\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple functional readouts (secretion, proliferation, gene expression) plus mechanistic pathway (MAPK) identified, single lab\",\n      \"pmids\": [\"22166979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"REV-ERBα and REV-ERBβ share >50% of genomic binding sites in mouse liver and extensively overlap with BMAL1 cistromes; double knockout mice exhibit profoundly disrupted circadian behaviour and deregulated lipid metabolism, establishing both REV-ERBs as integral components of the principal circadian feedback loop.\",\n      \"method\": \"ChIP-seq (cistromes), double-knockout mouse model, wheel-running behaviour, lipid metabolic profiling\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide cistrome plus genetic KO with multiple phenotypic readouts; independently replicated by Bugge et al. 2012\",\n      \"pmids\": [\"22460952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dual depletion of Rev-erbα and Rev-erbβ in mouse embryonic fibroblasts renders them arrhythmic; in liver, both Rev-erbs are recruited to a remarkably similar set of genomic binding sites enriched near metabolic genes, and their combined loss causes marked hepatic steatosis and synergistic derepression of clock and metabolic genes.\",\n      \"method\": \"Double-knockout MEFs (circadian assay), liver-specific depletion, ChIP-seq, gene expression profiling, histological lipid analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-autonomous clock assay (arrhythmia) plus cistrome plus metabolic phenotype; replicates Cho et al. 2012\",\n      \"pmids\": [\"22474260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ApoA4 binds NR1D1 (identified by bacterial two-hybrid screening; confirmed by co-immunoprecipitation, in situ proximity ligation, and immunofluorescence co-localization), recruits NR1D1 to the Glc-6-Pase promoter, and thereby suppresses hepatic gluconeogenesis; NR1D1 knockdown abolishes ApoA4-mediated repression of PEPCK and Glc-6-Pase.\",\n      \"method\": \"Bacterial two-hybrid library screen, co-immunoprecipitation, in situ proximity ligation assay, immunofluorescence, ChIP, luciferase reporter, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal binding methods plus functional epistasis (siRNA rescue), single lab\",\n      \"pmids\": [\"24311788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"REV-ERBα directly represses Fabp7 transcription in the brain; loss of Rev-erbα leads to Fabp7 overexpression, increased hippocampal neuronal proliferation with loss of its diurnal pattern, and altered memory/mood-related behaviour.\",\n      \"method\": \"Rev-erbα knockout mice, gene expression profiling, BrdU proliferation assay, behavioural testing, in vitro cell assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KO mouse with multiple phenotypic readouts, direct target identification; single lab\",\n      \"pmids\": [\"24932636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NR1D1 overexpression in the rd7 mouse (Nr2e3-null) rescues retinal degeneration by re-regulating key genes within the Nr2e3-directed transcriptional network, demonstrating NR1D1 functions as a modifier of Nr2e3-associated retinal disease.\",\n      \"method\": \"In vivo AAV-mediated Nr1d1 delivery, clinical/histological/ERG/molecular outcome measures in rd7 mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function rescue with multiple outcome measures, single lab\",\n      \"pmids\": [\"24498227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"REV-ERBα controls the molecular clock by directly competing with ROR transcription factors at cognate DNA sites (universal clock mechanism), whereas it regulates metabolic genes primarily by recruiting HDAC3 co-repressor to sites where it is tethered by cell type-specific (lineage-determining) transcription factors — a tissue-specific epigenomic mechanism.\",\n      \"method\": \"ChIP-seq, genome-wide binding analysis, active-site/domain mutagenesis, HDAC3 co-repressor recruitment assays, liver-specific TF tethering analysis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal genomic and biochemical methods; mechanistic distinction between two modes of action established in a single rigorous study\",\n      \"pmids\": [\"26044300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Siah2 E3 ubiquitin ligase mediates circadian degradation of Rev-ErbAα; Siah2 overexpression destabilizes Rev-ErbAα/β, siRNA depletion of Siah2 stabilizes endogenous Rev-ErbAα and delays its circadian degradation, and lengthens circadian period.\",\n      \"method\": \"Functional E3 ligase screen (cell-based), siRNA depletion, overexpression, circadian period measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen plus siRNA and OE validation with period-length phenotype, single lab\",\n      \"pmids\": [\"26392558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CDK1 phosphorylates REV-ERBα, which is necessary for recognition and ubiquitination by the F-box protein FBXW7, leading to REV-ERBα degradation; targeted hepatic disruption of FBXW7 alters circadian gene expression and perturbs lipid/glucose levels, defining a CDK1-FBXW7 pathway that controls circadian amplitude.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, ubiquitination assay, hepatic FBXW7 knockout mice, circadian gene expression, metabolic profiling\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical (phosphorylation, ubiquitination) plus genetic (KO) with multiple phenotypic readouts in a single rigorous study\",\n      \"pmids\": [\"27238018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HNF6 recruits Rev-erbα to shared hepatic lipid metabolism gene promoters; deletion of HNF6 in adult liver causes loss of Rev-erbα binding at these sites and derepresses lipogenic genes, establishing that HNF6 tethers Rev-erbα to regulate hepatic lipid homeostasis.\",\n      \"method\": \"Liver-specific HNF6 knockout, ChIP-seq, gene expression profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus cistromic analysis showing loss of Rev-erbα binding, single lab with two orthogonal methods\",\n      \"pmids\": [\"27445394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rev-erbα directly represses Fabp7 and βKlotho (Klb) in white adipose tissue, establishing βKlotho as a tissue-specific Rev-erbα target that modulates FGF21 signaling specifically in adipose (but not liver); Rev-erbα ablation markedly enhances FGF21 effects in WAT.\",\n      \"method\": \"Rev-erbα KO mice, ChIP-seq, gene expression, FGF21 treatment of adipose tissue, cistromic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO plus cistromic identification of direct target with functional consequence, single lab\",\n      \"pmids\": [\"27002153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nr1d1/Rev-erbα in zebrafish directly regulates autophagy genes through binding to their promoters (ChIP assay) and also modulates c/ebpβ transcription; nr1d1 mutant zebrafish show significantly upregulated autophagy-lysosome genes, establishing a direct circadian clock–autophagy regulatory axis.\",\n      \"method\": \"Luciferase reporter, ChIP assay, TALEN-generated nr1d1 mutant zebrafish, transcriptome analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus genetic mutant with transcriptomic readout, single lab\",\n      \"pmids\": [\"27171500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"REV-ERBα influences the stability and nuclear localization of the glucocorticoid receptor (GR) by competing for binding to HSP90α/HSP90β chaperone (REV-ERBα binds the C-terminal portion, GR binds the N-terminal portion), thereby affecting expression of GR target genes including IκBα and Adh1.\",\n      \"method\": \"Co-immunoprecipitation (REV-ERBα and GR with HSP90α/β), GR nuclear localization assay, GR target gene expression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal Co-IP showing binding domains plus functional gene expression consequence; single lab, mechanism partially unresolved\",\n      \"pmids\": [\"27686098\"],\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-mediated PARylation of NR1D1 drives its recruitment to DNA damage lesions, and NR1D1 then inhibits recruitment of SIRT6, pNBS1, and BRCA1 to damage sites. Deletion of the NR1D1 ligand-binding domain (which interacts with PARP1) suppresses this recruitment.\",\n      \"method\": \"γH2AX foci assay, NHEJ/HR reporter assays, PARP1 inhibitor, domain deletion mutants, co-immunoprecipitation, ChIP at damage sites\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal assays (repair assay, domain mutant, co-IP, ChIP at lesions) in a single study establishing mechanism\",\n      \"pmids\": [\"28249904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NR1D1 interacts with PARP1 and inhibits its catalytic (PARylation) activity, thereby enhancing accumulation of ROS-induced DNA damage and increasing breast cancer cell sensitivity to oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation, PARP1 activity assay, DNA damage accumulation assay\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro enzymatic activity assay plus Co-IP; single lab, single study\",\n      \"pmids\": [\"28599788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"REV-ERBα directly represses LRH-1 transcription (shown by luciferase reporter, EMSA, and ChIP), and conditional hepatic deletion of Lrh-1 abrogates Rev-erbα regulation of Cyp7a1 and cholesterol metabolism, establishing REV-ERBα→LRH-1→CYP7A1 as the pathway by which Rev-erbα controls bile acid synthesis.\",\n      \"method\": \"Luciferase reporter, EMSA, ChIP, conditional liver Lrh-1 knockout, cholesterol/bile acid measurements\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — three orthogonal biochemical assays for direct binding plus genetic epistasis (conditional KO) confirming the pathway\",\n      \"pmids\": [\"29237721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Rev-erbα overexpression attenuates atrophy-related gene (atrogene) expression and increases fiber size in skeletal muscle; Rev-erbα deficiency causes increased atrogene expression and reduced muscle mass/fiber size; pharmacological Rev-erbα activation blocks dexamethasone-induced muscle atrophy.\",\n      \"method\": \"Gain- and loss-of-function in vivo and in vitro, muscle histology, gene expression, dexamethasone atrophy model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both KO and OE with consistent phenotypes, plus pharmacological validation; single lab\",\n      \"pmids\": [\"29085009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"REV-ERBα binds near driver transcription factor binding sites across the cardiac genome; pharmacological REV-ERBα activation selectively suppresses aberrant pathological gene expression and prevents cardiomyocyte hypertrophy in vitro and in vivo in mouse heart failure models.\",\n      \"method\": \"ChIP-seq, cardiomyocyte hypertrophy assay, in vivo cardiac hypertrophy and heart failure models, gene expression profiling\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cistromic analysis plus in vivo pharmacological/genetic study; single lab\",\n      \"pmids\": [\"28878135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"REV-ERBα opposes functional chromatin loop formation between enhancers and circadian gene promoters by recruiting the NCoR-HDAC3 co-repressor complex, causing histone deacetylation and eviction of elongation factor BRD4 and looping factor MED1, thereby controlling circadian gene transcription through rhythmic chromatin remodeling.\",\n      \"method\": \"Hi-C/chromatin interaction analysis, ChIP-seq, HDAC3/NCoR co-immunoprecipitation, BRD4/MED1 eviction assays\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal genomic and biochemical methods (chromatin looping, ChIP-seq, co-repressor recruitment, histone deacetylation) in a single rigorous study\",\n      \"pmids\": [\"29439026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"REV-ERBα directly represses Nlrp3 transcription by binding to the NLRP3 promoter, and also indirectly represses NLRP3 via repression of p65 (NF-κB); Rev-erbα ablation activates the NLRP3 inflammasome and exacerbates experimental colitis; protective effects of SR9009 are lost in Nlrp3-/- and Rev-erbα-/- mice.\",\n      \"method\": \"ChIP assay, luciferase reporter, Rev-erbα KO and Nlrp3 KO mice, DSS colitis model, cell-based inflammasome assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct promoter binding (ChIP + reporter) combined with genetic epistasis (double KO rescue) and multiple in vivo models\",\n      \"pmids\": [\"30315268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"REVERBα physically interacts with the glucocorticoid receptor (GR) and co-binds with liver-specific HNF4A/HNF6 on chromatin; REVERBα promotes efficient GR recruitment to chromatin during the day by maintaining histone acetylation, directing temporal segregation of GC-regulated carbohydrate and lipid metabolism; deletion of Reverba inverts circadian hepatic GC sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq (GR + REVERBα co-binding), conditional Reverba KO, histone acetylation assays, glucocorticoid metabolic phenotyping\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — physical interaction (Co-IP) plus genome-wide co-binding (ChIP-seq) plus conditional KO with metabolic phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"30179226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Inflammatory challenges cause rapid degradation of REV-ERBα protein driven by SUMOylation and ubiquitination; a selective inverse agonist protects REV-ERBα from this degradation, revealing how proinflammatory cytokines trigger REV-ERBα instability to elaborate an inflammatory response.\",\n      \"method\": \"Protein stability assays, SUMOylation/ubiquitination assays, selective antagonist pharmacology, inflammatory cytokine treatment\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — PTM assays (SUMOylation, ubiquitination) plus pharmacological rescue; single lab\",\n      \"pmids\": [\"29533925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"REV-ERBα competes with RORγt for shared RORE DNA consensus sequences in Th17 cells, repressing RORγt-dependent genes including Il17a and Il17f; REV-ERBα deletion enhances TH17-mediated inflammation and exacerbates EAE and colitis.\",\n      \"method\": \"RORE binding competition assay, REV-ERBα KO mice, EAE and colitis models, cytokine expression, REV-ERB synthetic ligand treatment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — DNA binding competition established, genetic KO phenotype replicated in two disease models, pharmacological validation; independently confirmed by Chang et al. 2019\",\n      \"pmids\": [\"30590045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rev-erbα chromatin immunoprecipitation in primary microglia shows direct interaction with promoter regions of several NF-κB-related genes; Rev-erbα deletion causes spontaneous microglial activation, increased NF-κB signaling, and enhanced neuroinflammatory responses in vivo.\",\n      \"method\": \"ChIP in primary microglia, Rev-erbα KO mice, NF-κB activation assay, inflammatory transcript profiling, LPS neuroinflammation model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct promoter binding plus KO phenotype with multiple readouts; single lab\",\n      \"pmids\": [\"30792350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"REV-ERBα inhibits BMAL1 and over-expression or agonist activation of REV-ERBα perturbs lipid signaling pathways used by HCV; genetic knockout of Bmal1 and REV-ERBα activation (by agonist) both inhibit HCV and related flavivirus (dengue, Zika) replication via lipid signaling pathway perturbation.\",\n      \"method\": \"Genetic knockout (Bmal1 KO), REV-ERB agonist treatment, HCV/dengue/Zika replication assays, lipid signaling pathway analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological approaches with functional replication assays, single lab\",\n      \"pmids\": [\"30670689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"REV-ERBα binds RORE elements in Th17 cells and inhibits expression of RORγt-dependent genes Il17a and Il17f; pharmacological REV-ERB agonism delays EAE onset and reduces severity.\",\n      \"method\": \"RORE ChIP/binding assay, Rev-erbα KO, EAE model, cytokine expression, synthetic ligand treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA binding plus KO phenotype plus pharmacology; replicates Amir et al. 2018 with slightly different methods\",\n      \"pmids\": [\"31455731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STRA8 binds the Nr1d1 promoter and directly represses Nr1d1 transcription during spermatogenesis; Nr1d1 upregulation in Stra8-deficient testes drives autophagy through NR1D1 binding to the Ulk1 promoter; genetic deletion or pharmacologic inhibition of Nr1d1 partially rescues meiotic initiation defects in Stra8-deficient mice.\",\n      \"method\": \"ChIP (STRA8 on Nr1d1 promoter; NR1D1 on Ulk1 promoter), Nr1d1 KO, SR8278 pharmacological inhibition, Stra8 KO rescue experiments\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct promoter binding by ChIP plus genetic epistasis (double KO rescue) plus pharmacological confirmation; multiple orthogonal methods\",\n      \"pmids\": [\"31059511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rev-erbα directly represses Pck1 (PEPCK1) transcription through direct binding to a RevRE site at −325 to −320 bp in the Pck1 promoter, as shown by luciferase reporter, EMSA, and ChIP; SR9009 reduces fasting plasma glucose and Pck1 expression in normal and diabetic mice.\",\n      \"method\": \"Luciferase reporter, EMSA, ChIP, Rev-erbα agonist (SR9009) in vivo treatment, glucose tolerance test\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — three orthogonal biochemical methods for direct binding plus in vivo pharmacological confirmation; single lab\",\n      \"pmids\": [\"30639375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rev-erbα directly represses Ugt2b36 transcription by binding to −30 to −18 bp of its promoter (luciferase, EMSA, ChIP); Rev-erbα KO mice lose Ugt2b rhythmicity in liver, and glucuronidation of morphine is dosing-time dependent consistent with Rev-erbα rhythmic control of Ugt2b enzymes.\",\n      \"method\": \"Luciferase reporter, EMSA, ChIP, Rev-erbα KO mice, morphine glucuronidation kinetics, circadian expression profiling\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — three orthogonal direct binding assays plus genetic KO with functional pharmacokinetic phenotype; single lab\",\n      \"pmids\": [\"30639455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rev-erbα exerts cell-autonomous inhibitory effects on myogenic precursor cell proliferation and differentiation, and directly controls the Wnt signaling cascade and proliferative pathway transcriptionally; Rev-erbα loss-of-function augments satellite cell expansion and regeneration after muscle injury.\",\n      \"method\": \"Rev-erbα KO, primary myoblast assays, pharmacological activation/inhibition, muscle injury regeneration model, gene expression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and pharmacological (agonist + antagonist) with consistent myogenic phenotypes; single lab\",\n      \"pmids\": [\"30872796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"REV-ERBα deletion causes increased complement gene expression (C4b, C3) in hippocampal neurons and astrocytes, increased microglial synaptic phagocytosis and synapse loss in CA3, and abolishes diurnal variation in synaptic phagocytosis, establishing BMAL1-REV-ERBα as a regulator of complement and synaptic homeostasis.\",\n      \"method\": \"Rev-erbα KO mice, BMAL1 KO mice, complement gene expression (ChIP/RNA), synapse phagocytosis assay, diurnal profiling\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent KO models with consistent phenotypes; single lab\",\n      \"pmids\": [\"33258449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"REV-ERBα directly regulates NRF2 transcription and its downstream antioxidant targets SOD1 and catalase in the retinal pigment epithelium (RPE); REV-ERBα deficiency causes accumulated oxidative stress and AMD-like degeneration, while pharmacological activation protects RPE from oxidative damage.\",\n      \"method\": \"RPE-specific Rev-erbα KO, global KO, ChIP (REV-ERBα on NRF2 promoter), antioxidant enzyme expression, oxidative damage assays, pharmacological agonist\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO plus ChIP for direct target plus pharmacological validation; single lab\",\n      \"pmids\": [\"35176707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hepatocyte-specific REVERBα ChIP-seq reveals binding exclusively at RORE/RevDR2 motifs with no evidence for tethering/DNA-binding domain-independent action; hepatocyte-specific Reverbα deletion causes only modest transcriptional dysregulation limited to circadian processes under basal conditions, challenging the view that REVERBα is a dominant driver of basal hepatic lipogenesis.\",\n      \"method\": \"Antibody-independent ChIP-seq, hepatocyte-specific Reverbα KO, RNA-seq, metabolic phenotyping under basal and metabolic challenge conditions\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — novel antibody-independent ChIP-seq plus conditional KO with transcriptomic readout; directly contradicts prior tethering model\",\n      \"pmids\": [\"32989157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NR1D1 directly represses Atg5 transcription by binding to two RORE sites in the Atg5 promoter (dual-luciferase reporter and EMSA); NR1D1 activation reduces autophagy in granulosa cells and Nr1d1 knockdown increases ATG5 expression, regulating follicular autophagy.\",\n      \"method\": \"Dual-luciferase reporter, EMSA, siRNA knockdown, SR9009 agonist treatment, Bmal1 KO mice (indirect)\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct promoter-binding assays (reporter + EMSA) plus functional KD; single lab\",\n      \"pmids\": [\"34936504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NR1D1 directly represses CYP19A1 transcription by binding to RORE on the CYP19A1 promoter in ovarian granulosa cells; NR1D1 activation reduces estradiol production and NR1D1 interference eliminates this repression.\",\n      \"method\": \"Luciferase reporter (RORE binding), NR1D1 activation/interference, estradiol RIA\",\n      \"journal\": \"Theriogenology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — reporter assay plus functional hormonal output; single lab, limited orthogonal validation\",\n      \"pmids\": [\"34933195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NR1D1 upregulates SOCS3 expression to suppress JAK/STAT3 signaling in ovarian cancer cells; SOCS3 silencing abolishes NR1D1's antiproliferative effect, establishing the NR1D1→SOCS3→JAK/STAT3 pathway in cancer cell growth control.\",\n      \"method\": \"NR1D1 overexpression/knockdown, CCK8/flow cytometry proliferation assays, Western blot (JAK/STAT3), siRNA (SOCS3 rescue), xenograft model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (SOCS3 siRNA rescue) plus xenograft in vivo; single lab\",\n      \"pmids\": [\"34330232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Adipocyte-selective NR1D1 deletion does not alter basal WAT lipogenesis but, under high-fat diet, adipocyte NR1D1 KO mice develop profound obesity without accompanying WAT inflammation and fibrosis; NR1D1 cistrome in WAT shows broad metabolic gene control revealed only under obese conditions, indicating NR1D1 is a state-dependent metabolic regulator in adipocytes.\",\n      \"method\": \"Adipocyte-specific Nr1d1 KO, HFD feeding, WAT cistromic analysis (ChIP-seq), RNA-seq, metabolic/inflammatory phenotyping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with cistromic analysis and transcriptomic profiling under two metabolic states; multiple orthogonal methods\",\n      \"pmids\": [\"34350828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR1D1 directly trans-represses ACO2 (aconitase-2) in vascular smooth muscle cells; VSMC-specific Nr1d1 KO inhibits AAA formation and restores mitochondrial function by derepressing ACO2; α-ketoglutarate (downstream of ACO2) supplementation prevents/treats AAA in a NR1D1-dependent manner in VSMCs.\",\n      \"method\": \"VSMC-specific Nr1d1 KO mice, AAA models (AngII and CaPO4), ChIP (NR1D1 on ACO2 promoter), mitochondrial metabolism assays, αKG supplementation rescue\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — cell-type-specific KO plus ChIP for direct target plus metabolic rescue experiment; multiple orthogonal methods in rigorous in vivo study\",\n      \"pmids\": [\"35880522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rev-erbα in platelets potentiates activation via the oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway; mass spectrometry and co-immunoprecipitation identified oligophrenin-1 as a Rev-erbα interacting partner; platelet-specific Rev-erbα KO mice show impaired agonist-induced aggregation, integrin αIIbβ3 activation, and α-granule release.\",\n      \"method\": \"Platelet-specific Rev-erbα KO, mass spectrometry, co-immunoprecipitation, platelet aggregation/activation assays, thrombosis models\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — MS-identified interactor confirmed by Co-IP, platelet-specific KO with multiple functional assays, in vivo thrombosis models\",\n      \"pmids\": [\"35267019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR1D1 controls skeletal muscle sarcoplasmic reticulum calcium homeostasis by directly repressing myoregulin (a SERCA inhibitor) through binding to the myoregulin promoter; NR1D1 deficiency impairs SERCA-dependent SR calcium uptake; restoration of myoregulin counteracts NR1D1 overexpression effects; pharmacological NR1D1 activation improves SR calcium homeostasis and muscle function in dystrophic mdx/Utr+/- mice.\",\n      \"method\": \"NR1D1 KO mice, ChIP (NR1D1 on myoregulin promoter), SR calcium uptake assays, myoregulin rescue/KO, pharmacological activation, dystrophic mouse model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct target identification (ChIP) plus genetic epistasis (myoregulin rescue) plus in vivo disease model; multiple orthogonal methods\",\n      \"pmids\": [\"35917173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR1D1 protein is degraded in hepatic stellate cells via m6A methylation-induced mRNA ablation during liver fibrosis; NR1D1 deficiency inhibits DRP1S616 phosphorylation, reducing mitochondrial fission and increasing mtDNA release that activates the cGAS pathway, driving local inflammation and fibrosis; NR1D1 overexpression restores DRP1S616 phosphorylation and inhibits cGAS.\",\n      \"method\": \"NR1D1 KO mice, m6A methylation assay, DRP1 phosphorylation Western blot, mitochondrial fission imaging, cGAS pathway assay, NR1D1 overexpression\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and OE with mechanistic pathway (DRP1-cGAS) and PTM assay; single lab\",\n      \"pmids\": [\"36813093\"],\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 antitumor CD8+ T cell responses; Nr1d1 deletion in MMTV-PyMT tumor cells suppresses type I IFNs and reduces immune infiltration, promoting tumor growth and lung metastasis.\",\n      \"method\": \"Nr1d1 KO in MMTV-PyMT model, orthotopic allograft, cGAS-STING pathway assays, cytosolic DNA quantification, flow cytometry (CD8+ T, NK cells), SR9009 pharmacological treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological approaches with mechanistic cGAS-STING pathway validation; single lab\",\n      \"pmids\": [\"37395684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia, impairing microglial tau phagocytosis; LD formation blockade partially rescues phagocytosis; microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in tauopathy models in a sex-dependent manner.\",\n      \"method\": \"Microglial-specific Rev-erbα KO, lipid droplet imaging, tau phagocytosis assay, LD inhibitor rescue, two tauopathy mouse models, sex-stratified analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with mechanistic epistasis (LD rescue), replicated in two disease models, sex-dependent effect characterized; multiple orthogonal methods\",\n      \"pmids\": [\"37626048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR1D1 directly binds IL-1β and NLRP3 promoters (shown by ChIP); NR1D1 activation inhibits NLRP3 inflammasome assembly and IL-1β production in nucleus pulposus cells, and delays intervertebral disc degeneration in vivo.\",\n      \"method\": \"ChIP (NR1D1 on IL-1β and NLRP3 promoters), siRNA knockdown, SR9009 agonist treatment, in vivo disc degeneration model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP for direct binding plus in vivo pharmacological model; single lab\",\n      \"pmids\": [\"38689641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Polyamines stimulate REV-ERBα protein synthesis at the translational level through enhancement of ribosomal shunting mediated by the 5'-UTR of Rev-erbα mRNA; polyamine reduction lengthens circadian period and reduces REV-ERBα protein, identifying Rev-erbα as a member of the 'polyamine modulon'.\",\n      \"method\": \"Polyamine-reduced cell lines, 5'-UTR reporter constructs (EGFP fusion), circadian period assay, translation assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — ribosomal shunting mechanism via 5'-UTR reporter; single lab, single study\",\n      \"pmids\": [\"33525630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"REV-ERBα overexpression activates mTORC1 signaling by transcriptionally inhibiting the mTORC1 inhibitor Tsc1, leading to increased BMAL1 phosphorylation; REV-ERBα silencing downregulates mTORC1 signaling, linking REV-ERBα to mTOR-mediated circadian clock regulation.\",\n      \"method\": \"REV-ERBα overexpression/silencing, mTORC1 activity assay (S6K phosphorylation), Tsc1 expression (qPCR), BMAL1 phosphorylation, leucine/rapamycin pharmacology\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — OE/KD with pathway readouts and pharmacological validation; single lab, mechanistic link to Tsc1 is indirect\",\n      \"pmids\": [\"33285244\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR1D1 (REV-ERBα) is a heme-liganded nuclear receptor that functions as a potent transcriptional repressor by recruiting the NCoR-HDAC3 corepressor complex; it operates as an integral component of the core circadian clock by directly competing with ROR factors at RORE/RevDR2 motifs to repress BMAL1 and other positive-limb genes, while in metabolic tissues it is tethered by lineage-specific transcription factors (e.g., HNF4A, HNF6) to impose tissue-specific rhythmic repression of lipid, glucose, bile acid, and drug metabolism genes; its protein abundance is controlled by CDK1 phosphorylation-triggered FBXW7 ubiquitination and by Siah2-mediated degradation, as well as by inflammatory SUMOylation/ubiquitination; in addition to these transcriptional roles, NR1D1 interacts with PARP1 (inhibiting PARylation and DNA repair), modulates chromatin looping via NCoR-HDAC3-mediated BRD4/MED1 eviction, regulates microglial lipid metabolism and neuroinflammation, controls platelet activation via oligophrenin-1/RhoA/ERM signaling, maintains skeletal muscle calcium homeostasis by repressing myoregulin, and suppresses inflammasome (NLRP3/NF-κB) activation across multiple cell types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR1D1 (REV-ERBα) is a heme-liganded nuclear receptor that operates as a potent transcriptional repressor at the interface of the circadian clock and tissue metabolism [#4, #8, #13]. Heme binds directly to its ligand-binding domain and gates recruitment of the NCoR-HDAC3 corepressor complex to target promoters [#4, #5]. Two mechanistically distinct modes of action govern its genomic output: at the clock, REV-ERBα directly competes with ROR factors at RORE/RevDR2 motifs to repress BMAL1 and other positive-limb genes, while at metabolic genes it is tethered by lineage-determining transcription factors such as HNF6 to impose tissue-specific repression of lipid, glucose, bile acid, and drug-metabolism programs [#13, #16, #22, #34, #35]. NR1D1 and the paralogous REV-ERBβ share the great majority of genomic binding sites and act redundantly; their combined loss abolishes cell-autonomous rhythms and produces hepatic steatosis with derepression of clock and metabolic genes [#8, #9]. Mechanistically, REV-ERBα-NCoR-HDAC3 deacetylates enhancer histones and evicts BRD4 and MED1 to oppose enhancer-promoter chromatin looping, providing the molecular basis for rhythmic transcriptional repression [#25]. REV-ERBα protein abundance is tightly controlled by degradation: CDK1 phosphorylation primes FBXW7-mediated ubiquitination, Siah2 drives circadian turnover, and inflammatory SUMOylation/ubiquitination triggers rapid loss during immune challenge [#14, #15, #28]. Beyond core clock and metabolic transcription, NR1D1 directly represses inflammasome components (NLRP3, IL-1β) and NF-κB signaling to restrain inflammation across colitis, microglial, and disc-degeneration models [#26, #30, #50], suppresses RORγt-dependent Th17 cytokines [#29], binds PARP1 to inhibit PARylation and DNA double-strand break repair [#20, #21], regulates microglial lipid-droplet metabolism and tau phagocytosis [#49], and maintains skeletal-muscle SR calcium homeostasis by repressing myoregulin [#46]. Its activity is further integrated with cellular state through polyamine-driven translational control and mTORC1 signaling [#51, #52].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that human NR1D1/Rev-ErbAα, arising from opposite-strand transcription of the c-erbAα locus, is an orphan-like receptor that does not bind thyroid hormone, framing it as a distinct receptor whose ligand and function were unknown.\",\n      \"evidence\": \"cDNA cloning, Northern analysis, and thyroid hormone ligand-binding assay\",\n      \"pmids\": [\"1971514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No endogenous ligand identified\", \"No transcriptional target or mechanism defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated NR1D1 acts as a sequence-specific repressor that antagonizes PPARα/RXRα at a defined response element, giving early evidence of direct DNA-binding repressor activity over metabolic genes.\",\n      \"evidence\": \"In vitro binding and transient transfection reporter assays on the HD-PPRE\",\n      \"pmids\": [\"10428876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro only, single study\", \"Corepressor machinery not yet defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified heme as the endogenous ligand binding the LBD and controlling NCoR corepressor recruitment, resolving the long-standing question of how REV-ERBα repressor activity is regulated.\",\n      \"evidence\": \"Direct LBD ligand-binding biochemistry plus corepressor recruitment assay for REV-ERBα/β\",\n      \"pmids\": [\"18218725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological heme dynamics not addressed\", \"Full corepressor complex composition not defined here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Synthesized the model that heme-liganded REV-ERBα recruits NCoR-HDAC3 to repress BMAL1, positioning it as the negative limb of the core clock.\",\n      \"evidence\": \"Review integrating ligand-binding, corepressor recruitment, and gene expression data\",\n      \"pmids\": [\"20414452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide binding not yet mapped\", \"Redundancy with REV-ERBβ unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed REV-ERBα and REV-ERBβ are largely redundant integral clock components: they share most genomic sites, overlap BMAL1 cistromes near metabolic genes, and their combined loss causes arrhythmia and hepatic steatosis, establishing clock-metabolism coupling.\",\n      \"evidence\": \"ChIP-seq cistromes, double-knockout mice/MEFs, behavioural and lipid metabolic profiling\",\n      \"pmids\": [\"22460952\", \"22474260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mode of metabolic gene targeting (direct vs tethered) unresolved\", \"Tissue specificity of metabolic effects not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how one receptor achieves both universal clock control and tissue-specific metabolic control by defining two modes: ROR competition at cognate sites versus HDAC3 recruitment at lineage-TF-tethered sites.\",\n      \"evidence\": \"ChIP-seq, domain mutagenesis, HDAC3 recruitment and liver TF tethering analysis\",\n      \"pmids\": [\"26044300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of all tethering factors incomplete\", \"Extent of tethering across tissues unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the degradation circuits controlling REV-ERBα abundance — Siah2-mediated circadian turnover and a CDK1-phosphorylation/FBXW7-ubiquitination axis — explaining how repressor amplitude and period are set post-translationally.\",\n      \"evidence\": \"E3-ligase screen, siRNA/overexpression, phosphorylation and ubiquitination assays, hepatic FBXW7 KO mice\",\n      \"pmids\": [\"26392558\", \"27238018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between Siah2 and FBXW7 pathways unclear\", \"Upstream signals triggering CDK1 phosphorylation in vivo not fully defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed lineage-TF tethering in liver by showing HNF6 recruits Rev-erbα to shared lipid-gene promoters, with HNF6 loss abolishing Rev-erbα binding and derepressing lipogenesis.\",\n      \"evidence\": \"Liver-specific HNF6 KO with ChIP-seq and expression profiling\",\n      \"pmids\": [\"27445394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tethering is required outside liver lipid genes unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the chromatin-level mechanism of repression: REV-ERBα-NCoR-HDAC3 deacetylates enhancers and evicts BRD4/MED1 to oppose enhancer-promoter looping, explaining rhythmic transcriptional output.\",\n      \"evidence\": \"Chromatin interaction analysis, ChIP-seq, corepressor Co-IP, BRD4/MED1 eviction assays\",\n      \"pmids\": [\"29439026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of looping control beyond tested loci not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended REV-ERBα function into immunity, showing direct repression of Nlrp3 and indirect repression via NF-κB p65, with genetic epistasis linking it to inflammasome and Th17 control.\",\n      \"evidence\": \"ChIP, reporter assays, Rev-erbα/Nlrp3 KO mice, colitis/EAE models, RORE competition assays\",\n      \"pmids\": [\"30315268\", \"30590045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of direct vs NF-κB-mediated repression not quantified\", \"Cell-type specificity of anti-inflammatory effect not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked REV-ERBα degradation to inflammation, showing proinflammatory challenge triggers SUMOylation/ubiquitination-driven loss, and to glucocorticoid signaling via physical GR interaction and chromatin co-binding that times hepatic GC sensitivity.\",\n      \"evidence\": \"PTM and protein-stability assays, Co-IP, GR/REVERBα ChIP-seq, conditional KO metabolic phenotyping\",\n      \"pmids\": [\"29533925\", \"30179226\", \"27686098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SUMO/ubiquitin sites not all mapped\", \"Mechanism of GR-HSP90 competition partially unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established a non-transcriptional genome-protective role: NR1D1 binds PARP1, inhibits PARylation, is recruited to damage sites, and blocks repair-factor (SIRT6/pNBS1/BRCA1) recruitment, inhibiting both NHEJ and HR.\",\n      \"evidence\": \"DSB reporter assays, domain-deletion mutants, Co-IP, ChIP at lesions, PARP1 activity assays\",\n      \"pmids\": [\"28249904\", \"28599788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological/circadian regulation of DNA-repair role unclear\", \"Interplay with transcriptional functions not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Challenged the dominant hepatic tethering/lipogenesis model, showing antibody-independent hepatocyte ChIP-seq detects binding only at RORE/RevDR2 motifs and that hepatocyte-specific deletion causes only modest, circadian-restricted dysregulation under basal conditions.\",\n      \"evidence\": \"Antibody-independent ChIP-seq, hepatocyte-specific KO, RNA-seq under basal and challenge states\",\n      \"pmids\": [\"32989157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with prior tethering data unresolved\", \"Condition-dependence of metabolic role needs broader testing\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated state-dependent and tissue-specific metabolic roles, with adipocyte NR1D1 controlling diet-induced obesity and a WAT cistrome revealed only under metabolic challenge, alongside direct repression of mitochondrial/metabolic targets (ACO2) in vascular smooth muscle.\",\n      \"evidence\": \"Adipocyte- and VSMC-specific KO, ChIP-seq/ChIP, HFD and AAA disease models, metabolite rescue\",\n      \"pmids\": [\"34350828\", \"35880522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that unmask the obese-state cistrome unknown\", \"Generality across other metabolic tissues unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered cytoplasmic and tissue-specific effector roles: a platelet oligophrenin-1/RhoA/ERM activation pathway and direct repression of myoregulin to maintain skeletal-muscle SR calcium homeostasis.\",\n      \"evidence\": \"Platelet- and muscle-specific KO, mass spectrometry, Co-IP, ChIP, SR calcium and aggregation assays, dystrophic mouse model\",\n      \"pmids\": [\"35267019\", \"35917173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking REV-ERBα to oligophrenin-1 at molecular level partial\", \"Whether platelet role is transcription-independent unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected REV-ERBα to lipid-droplet and innate-immune signaling in disease contexts, including sex-dependent microglial lipid-droplet accumulation impairing tau phagocytosis and modulation of cGAS-STING/type I IFN responses in tumors.\",\n      \"evidence\": \"Cell-type-specific KO, lipid-droplet imaging, tauopathy models, cGAS-STING assays, MMTV-PyMT tumor model, pharmacological SR9009\",\n      \"pmids\": [\"37626048\", \"37395684\", \"36813093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of sex-dependence unknown\", \"Context-dependent pro- vs anti-tumor effects not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How REV-ERBα's distinct transcriptional, chromatin-looping, DNA-repair, and cytoplasmic effector activities are coordinated, and how its degradation circuits are integrated to set output in each cell type and metabolic state, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking nuclear and cytoplasmic functions\", \"Structural basis of tethering versus direct binding not defined\", \"Reconciliation of conflicting hepatic metabolic models incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 13, 8, 25, 26, 34, 22]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [13, 34, 35, 40, 39]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [20, 21, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 25, 26]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [25, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [5, 8, 9, 13, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13, 25, 26, 34]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 9, 16, 22, 43]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26, 29, 30, 50]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [20, 21]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"complexes\": [\"NCoR-HDAC3 corepressor complex\"],\n    \"partners\": [\"NCOR1\", \"HDAC3\", \"PARP1\", \"NR1H2\", \"HNF6\", \"NR3C1\", \"OPHN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}