Affinage

NR1D1

Nuclear receptor subfamily 1 group D member 1 · UniProt P20393

Length
614 aa
Mass
66.8 kDa
Annotated
2026-04-29
100 papers in source corpus 39 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR1D1 (REV-ERBα) is a ligand-independent nuclear receptor that functions as a constitutive transcriptional repressor, integrating circadian clock regulation with metabolism, inflammation, autophagy, DNA repair, and innate immunity. It binds ROR-responsive elements (ROREs) and direct repeat elements as a monomer, lacks a classical activation function 2 (AF-2) helix, and recruits the corepressor N-CoR via a hydrophobic surface formed by helices H3–H4/H11 and two corepressor interaction regions (CIR-1/CIR-2) in its ligand-binding domain, directly repressing BMAL1, IL-6, IL-1β, NLRP3, ATG5, BNIP3, StAR, CYP19A1, ACO2, HMGA2, and other target gene promoters (PMID:8474464, PMID:9482666, PMID:10809233, PMID:34956438, PMID:33957581, PMID:34936504, PMID:34795498, PMID:35880522, PMID:39551321). Beyond transcriptional repression, NR1D1 physically interacts with PARP1, inhibits its catalytic poly-ADP-ribosylation activity, and modulates DNA double-strand break repair by blocking recruitment of SIRT6, pNBS1, and BRCA1 to damage sites; PARP1-mediated PARylation reciprocally drives NR1D1 recruitment to DNA lesions (PMID:28249904, PMID:28599788). NR1D1 also promotes cytosolic DNA accumulation and cGAS-STING-dependent type I interferon signaling to enhance antitumor immunity, while its own protein turnover is regulated by LC3-LIR-mediated mitophagy-dependent degradation and m6A-directed mRNA destabilization (PMID:37395684, PMID:38732079, PMID:36813093).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Establishing that NR1D1 is an orphan nuclear receptor: the receptor was shown not to bind thyroid hormone (T3) despite being encoded antisense to the c-erbAα locus, resolving its classification as a true orphan.

    Evidence Radioligand binding assay with purified receptor, cDNA cloning and Northern blot

    PMID:1971514

    Open questions at the time
    • No endogenous ligand identified at this stage
    • Physiological function unknown
  2. 1993 High

    Defining DNA-binding specificity: NR1D1 was found to bind as a monomer to an asymmetric 11-bp element (later called RORE) and to DR4 elements, establishing the receptor's monomeric DNA-binding mode distinct from TR/RXR heterodimers.

    Evidence SELEX with purified protein, EMSA, mutagenesis, and reporter assays in transfected cells

    PMID:8015547 PMID:8474464

    Open questions at the time
    • Whether NR1D1 can also bind as dimers on certain elements
    • In vivo relevance of monomeric binding unclear
  3. 1996 High

    Identifying the corepressor mechanism: NR1D1's ligand-binding domain (LBD) was shown to contain an intrinsic transcriptional silencing function mediated by interaction with N-CoR/RIP13 through two corepressor interaction regions (CIR-1 and CIR-2), with critical phenylalanine residues required for repression.

    Evidence Mammalian two-hybrid, GAL4 chimeras, fine deletion/point mutagenesis, dominant-negative rescue

    PMID:8836173 PMID:8948627 PMID:9482666

    Open questions at the time
    • Whether SMRT or other corepressors also participate
    • No crystal structure of NR1D1-corepressor complex
  4. 2000 High

    Mapping the corepressor-binding surface: homology modeling and mutagenesis revealed that the absence of helix 12 (AF-2) exposes a hydrophobic surface (H3–H4/H11) that directly contacts N-CoR, explaining why NR1D1 is a constitutive repressor.

    Evidence Homology modeling, site-directed mutagenesis, in vitro pulldown, co-transfection repression assay

    PMID:10809233

    Open questions at the time
    • No experimental 3D structure at this point
    • Coactivator recruitment possibility not fully excluded
  5. 2004 Medium

    In vivo physiological role established: Nr1d1 knockout mice showed altered skeletal muscle fiber type composition, providing the first genetic evidence that NR1D1 regulates tissue-specific gene programs beyond circadian genes.

    Evidence Nr1d1 knockout mouse, MyHC isoform quantification in soleus muscle

    PMID:15374821

    Open questions at the time
    • Downstream target genes in muscle not identified
    • Redundancy with NR1D2/REV-ERBβ not addressed
  6. 2013 High

    Discovery of a non-nuclear-receptor protein partner modulating NR1D1 chromatin recruitment: ApoA-IV was shown to directly bind NR1D1 and stimulate its recruitment to gluconeogenic gene promoters, linking NR1D1 to metabolic regulation beyond circadian clock targets.

    Evidence Bacterial two-hybrid, Co-IP, proximity ligation assay, ChIP, luciferase reporter, siRNA knockdown

    PMID:24311788

    Open questions at the time
    • Physiological relevance of ApoA-IV–NR1D1 interaction in vivo
    • Whether other apolipoproteins modulate NR1D1
  7. 2016 High

    Direct transcriptional regulation of autophagy genes by NR1D1 was established, positioning it as a circadian gatekeeper of autophagy.

    Evidence TALEN-generated nr1d1 mutant zebrafish, ChIP, luciferase reporter; reciprocal BMAL1 regulation confirmed in human chondrocytes by siRNA/RNA-seq

    PMID:27171500 PMID:27884645

    Open questions at the time
    • Specific autophagy gene promoter elements not fully mapped in mammals at this time
    • Whether NR1D1 regulation of autophagy is tissue-specific
  8. 2017 High

    A non-transcriptional function was uncovered: NR1D1 physically interacts with PARP1 via its LBD, inhibits PARP1 catalytic activity, and is itself PARylated and recruited to DNA damage sites, establishing NR1D1 as a modulator of DNA repair through NHEJ and HR suppression.

    Evidence Co-IP, PARP1 activity assay, γH2AX foci clearance, NHEJ/HR repair assays, LBD deletion mutants, PARP1 inhibitor, in vivo doxorubicin sensitivity

    PMID:28249904 PMID:28599788

    Open questions at the time
    • Crystal structure of NR1D1–PARP1 complex lacking
    • Whether PARylation-mediated recruitment is circadian-dependent
  9. 2017 High

    NR1D1 was shown to be required for cortical neuron migration and morphogenesis; the ASD-associated R500H mutation failed to rescue knockdown phenotypes, linking NR1D1 to neurodevelopmental processes.

    Evidence In utero electroporation knockdown in mouse cortex, time-lapse imaging, WT vs. R500H mutant rescue

    PMID:28262759

    Open questions at the time
    • Direct transcriptional targets mediating migration are unknown
    • Broader ASD cohort validation of R500H needed
  10. 2018 High

    Cooperative chromatin regulation with GR was demonstrated: NR1D1 physically interacts with GR, facilitates its chromatin recruitment by maintaining histone acetylation, and modulates circadian glucocorticoid sensitivity in liver, linking NR1D1 to metabolic disease through GR co-regulation.

    Evidence Reciprocal Co-IP, ChIP-seq co-binding analysis, conditional Reverba KO mice, metabolic phenotyping

    PMID:30179226

    Open questions at the time
    • Whether NR1D1–GR interaction is direct or bridged by chromatin
    • Mechanism by which NR1D1 maintains histone acetylation unclear
  11. 2021 High

    NR1D1's direct repression of specific target promoters via RORE elements was mapped with high resolution across multiple tissues: StAR (Leydig cells), ATG5 (granulosa cells), CYP19A1 (granulosa cells), IL-1β/NLRP3 (macrophages), and ULK1 (spermatogonia), solidifying RORE-mediated repression as the core mechanism across steroidogenesis, autophagy, and inflammation.

    Evidence EMSA, dual-luciferase reporters with RORE deletion/mutation, ChIP, siRNA/agonist modulation, genetic epistasis with Stra8

    PMID:31059511 PMID:33957581 PMID:34933195 PMID:34936504 PMID:34956438

    Open questions at the time
    • Genome-wide RORE occupancy map in most tissues still lacking
    • Cofactor requirements at individual promoters not distinguished
  12. 2022 High

    Cell-type-specific conditional KO studies revealed that NR1D1 in vascular smooth muscle cells trans-represses ACO2 to regulate mitochondrial TCA cycle function and aneurysm formation, while in skeletal muscle it represses myoregulin to control SR calcium uptake, demonstrating tissue-specific metabolic target selection.

    Evidence VSMC/EC/myeloid-specific conditional KO, ChIP/reporter for ACO2 and myoregulin, metabolic and Ca²⁺ uptake assays, in vivo rescue

    PMID:35880522 PMID:35917173

    Open questions at the time
    • How NR1D1 selects tissue-specific targets is mechanistically unexplained
    • Redundancy with NR1D2 in these tissues not fully addressed
  13. 2023 High

    NR1D1 was connected to innate immune sensing: it promotes cytosolic DNA accumulation after DNA damage, activates cGAS-STING signaling and type I IFN production, and enhances antitumor CD8⁺ T cell and NK cell responses; separately, NR1D1 loss in hepatic stellate cells increases mitochondrial DNA release and cGAS activation via impaired DRP1-mediated fission.

    Evidence Nr1d1⁻/⁻;MMTV-PyMT mice, transcriptomics, cytosolic DNA quantification, cGAS-STING pathway analysis; CCl4 fibrosis model with AAV rescue, DRP1 phosphorylation assay

    PMID:36813093 PMID:37395684

    Open questions at the time
    • Whether cGAS-STING activation is transcription-dependent or DNA-repair-dependent
    • Context-dependent opposing effects of NR1D1 on cGAS in tumor vs. fibrosis need reconciliation
  14. 2023 High

    Genome-wide target identification by ChIP-seq in microglia identified HMGA2 as a direct NR1D1 repression target, connecting NR1D1 to NF-κB suppression and anti-inflammatory function in the CNS.

    Evidence ChIP-seq, RNA-seq, EMSA, luciferase reporter, HMGA2 overexpression rescue in BV2 microglia

    PMID:34795498

    Open questions at the time
    • Whether HMGA2 repression generalizes to peripheral macrophages
    • Full ChIP-seq target list not functionally validated
  15. 2024 Medium

    Protein-level regulation of NR1D1 was clarified: LC3 directly binds NR1D1 via LIR motifs, targeting it for mitophagy-dependent degradation; this links mitophagy status to circadian clock output via BMAL1 de-repression, and m6A-dependent mRNA degradation provides an additional post-transcriptional control layer.

    Evidence Co-IP (LC3–NR1D1), LIR motif identification, mitophagy inhibition, m6A analysis, BMAL1 expression readout

    PMID:36813093 PMID:38732079

    Open questions at the time
    • Which E3 ligase or selective autophagy receptor mediates NR1D1 degradation
    • Quantitative contribution of m6A vs. mitophagy to NR1D1 turnover unknown
    • LC3-LIR interaction awaits structural validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: whether NR1D1 has a true endogenous ligand or functions entirely as a constitutive repressor; the structural basis of the NR1D1–PARP1 interaction; how tissue-specific target gene selection is achieved; and the full reconciliation of NR1D1's opposing roles in cGAS-STING activation across different cellular contexts (tumor immunity vs. fibrosis).
  • No crystal structure of full-length NR1D1 with corepressor or PARP1
  • Endogenous ligand question unresolved despite heme identification by other groups not captured in this timeline
  • Tissue-specific cofactor logic unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 14 GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-74160 Gene expression (Transcription) 13 R-HSA-9612973 Autophagy 5 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-73894 DNA Repair 3 R-HSA-9909396 Circadian clock 3
Partners
APOA4BRCA1MAP1LC3BNCOR1NR3C1PARP1

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 NR1D1 (Rev-ErbAα) binds to a unique asymmetric 11-bp sequence consisting of a specific 5-bp A/T-rich sequence adjacent to a TR half-site, contacts this entire sequence as a monomer (not enhanced by RXR, TR, or other nuclear proteins), and activates transcription through this binding site in the absence of exogenous ligand. In vitro SELEX with bacterially-purified protein, gel shift assay, transfection reporter assay, mutagenesis of binding site Molecular and cellular biology High 8474464
1994 NR1D1 (Rev-ErbAα) does not bind thyroid hormone (T3), and the human protein is encoded by transcription from the noncoding strand of the c-erbAα genomic locus, sharing 269 bp of sequence identity with c-erbAα-2 cDNA used in opposite orientations. cDNA cloning, Northern blot, radioligand binding assay DNA and cell biology High 1971514
1994 NR1D1 (Rev-ErbAα) binds direct repeat (DR4) thyroid hormone response elements but not palindromic or inverted palindromic TREs, and activates transcription via DR4 elements in transfected cells; deletion mapping of the ligand-binding domain identified regions modulating DNA binding. EMSA with GST-fusion proteins, transfection reporter assay with DR4/TREpal/F2H elements, deletion analysis Molecular endocrinology High 8015547
1995 Constitutive overexpression of NR1D1 (Rev-ErbAα) in C2C12 myoblasts completely abolished differentiation, suppressed myoD mRNA, and abrogated myogenin induction; the ligand-binding domain (LBD) contains an active transcriptional silencer; the receptor disrupts TR homodimer and TR/RXR heterodimer formation on TREs in the myoD gene family promoters. Stable overexpression in C2C12 cells, Northern blot, GAL4 chimera transfection assay, deletion/domain analysis Molecular endocrinology High 8614403
1996 NR1D1 (Rev-ErbAα) and RVR interact with nuclear receptor corepressor N-CoR/RIP13 via two receptor interaction domains (ID-I and ID-II); the physical association requires an intact E region (LBD) of NR1D1; overexpression of dominant-negative N-CoR interaction domains alleviates NR1D1-mediated repression. Mammalian two-hybrid system, transfection repression assay, domain deletion analysis Nucleic acids research High 8948627
1996 Transcriptional repression by NR1D1 (Rev-ErbAα) is mediated by a minimal 34-amino acid domain (aa 455–488) in the E region containing the LBD signature motif and helix 5; mutagenesis of either element impairs repression; an alternative study using the same interaction domain of N-CoR (aa 2218–2451) found no interaction, suggesting that this particular N-CoR region (interacting with TR/RAR) does not mediate NR1D1 repression. GAL4 hybrid system, fine deletions, site-specific mutagenesis, mammalian two-hybrid with N-CoR interaction domain Nucleic acids research High 8836173
1998 NR1D1 (Rev-ErbAα) contains two corepressor interaction regions (CIR-1 and CIR-2) in its E region; CIR-1 maps to the N-terminal portion of helix 3 with critical phenylalanine residues (F441 in Rev-ErbAα); mutations in CIR-1 or deletion of CIR-2 impair interaction with N-CoR, RIP13a, and RIP13δ1 and reduce repression of the native Rev-ErbAα promoter. Mammalian two-hybrid, co-transfection repression assays, mutagenesis of CIR-1, corepressor domain overexpression (dominant-negative rescue) Molecular endocrinology High 9482666
2000 Homology modeling of NR1D1/RVR LBDs revealed that the putative ligand cavity is occupied by side chains (suggesting no endogenous ligand) and that the absence of helix 12 exposes a large hydrophobic surface (H3, loop 3–4, H4, H11); mutagenesis of residues on this surface severely impairs in vitro and in vivo interaction with N-CoR/RIP13δ1 and reduces transcriptional repression, demonstrating that corepressors bind the H3–H4/H11 surface of NR1D1. Homology modeling, site-directed mutagenesis, in vitro pulldown, co-transfection repression assay Molecular endocrinology High 10809233
2004 Nr1d1-null mice exhibit aberrant myosin heavy chain (MyHC) isoform expression in slow-twitch soleus muscle, with significantly higher relative amounts of β/slow (type I) MyHC in both heterozygous and homozygous knockout mice vs. wild-type, demonstrating a role for NR1D1 in regulating skeletal muscle fiber type composition. Nr1d1 knockout mouse model, muscle fiber type analysis, MyHC isoform quantification; ruled out TRα2 involvement by comparing TRα2-deficient mice American journal of physiology. Regulatory, integrative and comparative physiology Medium 15374821
2011 NR1D1 is co-expressed with NR2E3 in the outer neuroblastic layer of the developing mouse retina and in rods/cones of adult retina; knockdown of Nr1d1 in developing retina causes pan-retinal spotting and reduced ERG function; NR1D1 co-regulates a transcriptional network including Nr2c1, Recoverin, Rgr, and Pde8a together with NR2E3. In vivo Nr1d1 knockdown, electroretinogram, immunohistochemistry, gene expression analysis; cycling of Nr1d1 and Nr2e3 over 24 h PloS one Medium 21408158
2013 ApoA-IV binds NR1D1 directly (identified by bacterial two-hybrid screening; confirmed by coimmunoprecipitation and proximity ligation assay); ApoA-IV stimulates NR1D1 recruitment to the Glc-6-Pase promoter (by ChIP), reducing gluconeogenic gene expression; in NR1D1-knockdown cells, ApoA-IV fails to inhibit PEPCK and Glc-6-Pase. Bacterial two-hybrid library screen, coimmunoprecipitation, in situ proximity ligation assay, ChIP, luciferase reporter, siRNA knockdown The Journal of biological chemistry High 24311788
2016 In zebrafish, Nr1d1/Rev-erbα directly regulates autophagy gene transcription (demonstrated by luciferase reporter and ChIP assays); nr1d1 mutant fish show significantly upregulated autophagy genes and cebpb, indicating Nr1d1 is a direct transcriptional repressor of autophagy genes in the circadian-autophagy axis. TALEN-generated nr1d1 mutant zebrafish, luciferase reporter assay, ChIP, transcriptome analysis Autophagy High 27171500
2016 siRNA knockdown of NR1D1 in human chondrocytes predominantly affects TGF-β signaling pathway gene expression (RNA-seq), and NR1D1 knockdown increases BMAL1 expression while BMAL1 knockdown decreases NR1D1, demonstrating reciprocal regulation within the circadian clock network with functional consequences on chondrocyte TGF-β signaling. siRNA knockdown, RNA sequencing, quantitative PCR, synchronized human chondrocyte cultures Osteoarthritis and cartilage Medium 27884645
2017 NR1D1 inhibits both non-homologous end joining and homologous recombination DNA double-strand break repair; PARP1 PARylates NR1D1 and drives its recruitment to damaged DNA lesions; the LBD of NR1D1 interacts with PARP1; NR1D1 inhibits recruitment of SIRT6, pNBS1, and BRCA1 to DNA lesion sites; PARP1 inhibitor suppresses NR1D1 recruitment to damaged DNA. γH2AX foci clearance assay, NHEJ/HR repair assays, Co-IP (NR1D1-PARP1), LBD deletion mutants, PARP1 inhibitor treatment, in vitro/in vivo doxorubicin sensitivity Cancer research High 28249904
2017 NR1D1 interacts with PARP1 and inhibits its catalytic (poly-ADP-ribosylation) activity, thereby enhancing accumulation of ROS-induced DNA damage and sensitizing breast cancer cells to oxidative stress. Co-IP (NR1D1-PARP1), PARP1 activity assay, ROS-induced DNA damage accumulation assay Molecular and cellular endocrinology High 28599788
2018 REVERBα (NR1D1) physically interacts with the glucocorticoid receptor (GR) and co-binds chromatin with liver-specific HNFs; REVERBα promotes efficient GR recruitment to chromatin during the day by maintaining histone acetylation; deletion of Reverba inverts circadian liver GC sensitivity and protects mice from GC-induced hepatosteatosis. Reciprocal Co-IP (GR-REVERBα), ChIP-seq (co-binding analysis), conditional Reverba knockout mice, metabolic phenotyping The Journal of clinical investigation High 30179226
2019 STRA8 binds to the Nr1d1 promoter and directly represses its transcription in spermatogonia; NR1D1 in turn binds to the Ulk1 promoter to activate autophagy; genetic deletion or pharmacologic inhibition of NR1D1 rescues meiotic initiation defects in Stra8-deficient male germ cells, placing NR1D1 downstream of STRA8 in a STRA8→NR1D1→ULK1→autophagy axis. ChIP (STRA8 on Nr1d1 promoter; NR1D1 on Ulk1 promoter), genetic deletion of Nr1d1, pharmacologic NR1D1 inhibition (SR8278), autophagy assays PLoS genetics High 31059511
2021 NR1D1 directly represses StAR expression in Leydig cells by binding to a canonical RORE element in the StAR promoter (demonstrated by dual-luciferase reporter and EMSA), reducing testosterone synthesis; glyphosate-induced upregulation of NR1D1 mediates inhibition of StAR and testosterone production. Dual-luciferase reporter assay, EMSA, siRNA/agonist (SR9009) modulation, in vitro and in vivo testosterone measurement The Science of the total environment High 33957581
2021 NR1D1 directly represses ATG5 transcription by binding to two putative RORE elements within the Atg5 promoter (shown by dual-luciferase reporter and EMSA), thereby regulating granulosa cell autophagy; Nr1d1 knockdown increases ATG5 expression and autophagy. Dual-luciferase reporter, EMSA, siRNA knockdown, SR9009 agonist treatment, Bmal1-/- mouse model American journal of physiology. Cell physiology High 34936504
2021 NR1D1 directly represses CYP19A1 transcription in granulosa cells by binding to a RORE on the CYP19A1 promoter, reducing estradiol synthesis; NR1D1 activation (SR9009) decreases estradiol; NR1D1 interference increases CYP19A1 expression and estradiol production. Luciferase reporter, ChIP (implied from promoter binding), SR9009 agonist, siRNA knockdown, steroid hormone measurement Theriogenology Medium 34933195
2022 NR1D1 deficiency in mice impairs SERCA-dependent sarcoplasmic reticulum Ca2+ uptake in skeletal muscle; NR1D1 represses the SERCA inhibitor myoregulin by direct binding to its promoter; restoration of myoregulin counteracts NR1D1 overexpression on SR calcium content; pharmacological NR1D1 activation ameliorates SR calcium homeostasis and improves muscle structure/function in dystrophic mdx/Utr+/- mice. Nr1d1 KO mouse, ChIP (NR1D1 on myoregulin promoter), Ca2+ uptake assay, myoregulin rescue experiment, in vivo SR9009 treatment in mdx/Utr+/- mice JCI insight High 35917173
2022 NR1D1 identifies ACO2 (aconitase-2, a TCA cycle enzyme) as a direct transcriptional target that it trans-represses in vascular smooth muscle cells; NR1D1 deficiency restores ACO2 dysregulation and mitochondrial dysfunction; VSMC-specific (but not endothelial or myeloid) Nr1d1 KO inhibits AAA formation in two mouse models. VSMC/EC/myeloid-specific conditional Nr1d1 KO mice, two AAA models (AngII, CaPO4), ChIP/reporter for ACO2 promoter, mitochondrial metabolic assays, αKG supplementation rescue Circulation High 35880522
2023 NR1D1 promotes DNA damage-induced accumulation of cytosolic DNA fragments and activates cGAS-STING signaling, increasing type I IFN production and downstream chemokines CCL5 and CXCL10, thereby enhancing CD8+ T cell and NK cell antitumor responses; Nr1d1 deletion in tumor cells (MMTV-PyMT) increases tumor growth and suppresses type I IFN signaling. Nr1d1-/-;MMTV-PyMT transgenic mice, orthotopic allograft, transcriptome analysis, cytosolic DNA quantification, cGAS-STING pathway analysis, SR9009 pharmacological treatment Cancer research High 37395684
2023 NR1D1 degradation via m6A (N6-methyladenosine) methylation in hepatic stellate cells inhibits DRP1-S616 phosphorylation, impairing mitochondrial fission and increasing mitochondrial DNA release, which activates the cGAS pathway and drives liver fibrosis; NR1D1 overexpression restores DRP1S616 phosphorylation and suppresses cGAS pathway. Nr1d1-deficient mice (CCl4 model), NR1D1 overexpression (AAV), m6A methylation analysis, DRP1-S616 phosphorylation assay, cGAS pathway readout Pharmacological research Medium 36813093
2021 NR1D1 binds promoters of IL-1β and NLRP3 to directly repress their transcription in macrophages, thereby inhibiting NLRP3 inflammasome assembly; NR1D1 deficiency in ApoE-/- mice augments plaque vulnerability and macrophage pyroptosis in a NLRP3-dependent manner. NR1D1-/-ApoE-/- double-KO mice, BMDM experiments, ChIP (NR1D1 on IL-1β/NLRP3 promoters, implied from mechanistic statement), SR9009 agonist treatment, pyroptosis assays Oxidative medicine and cellular longevity Medium 34956438
2021 In the nucleus accumbens, Nr1d1 knockdown via AAV-shRNA enhances sociability and reduces anxiety in female mice; knockdown upregulates Per1 and Per2, and alters opioid-related genes (Oprd1, Penk), demonstrating a sex-specific role for NR1D1 in behavioral regulation through the circadian and opioid gene networks. AAV-shRNA knockdown in NAc, behavioral testing, microarray, qPCR The European journal of neuroscience Medium 30028550 30326159
2017 Acute in utero electroporation-mediated knockdown of Nr1d1 in mouse cerebral cortex caused abnormal positioning of cortical neurons, impaired neuronal migration (time-lapse imaging), suppressed axon extension and dendritic arbor formation; wild-type Nr1d1 but not the p.R500H ASD-associated mutant rescued the abnormal phenotype, establishing Nr1d1 as required for cortical neuron migration and morphogenesis. In utero electroporation knockdown, time-lapse imaging, rescue with WT vs. mutant Nr1d1, cortical neuron positioning analysis Scientific reports High 28262759
2023 NR1D1 directly represses Hmga2 transcription by binding its promoter (shown by ChIP-seq and EMSA), thereby suppressing NF-κB signaling and microglial activation; overexpressed HMGA2 partially abolishes the anti-inflammatory effects of NR1D1 in microglia. ChIP-seq (NR1D1 in BV2 microglia), RNA-seq, EMSA, luciferase reporter, Hmga2 overexpression rescue, BETA tool integration Journal of inflammation research High 34795498
2023 NR1D1 directly represses BNIP3 expression by binding its promoter (ChIP), acting as a positive regulator of mitophagy in intestinal epithelial cells; NR1D1 ablation leads to disrupted mitophagy and increased inflammation/apoptosis; SR9009 (agonist) ameliorates colitis by rectifying defective mitophagy. Intestinal-specific Nr1d1 KO mice, DSS colitis model, RNA-seq, ChIP, dual-luciferase reporter, transmission electron microscopy, confocal microscopy International journal of molecular sciences High 37762536
2023 Ran GTPase, through miR4472 maturation, destabilizes NR1D1 mRNA; NR1D1 interacts with both PARP1 and BRCA1 leading to inhibition of DNA repair; Ran inhibition induces NR1D1 upregulation and DNA damage accumulation in aneuploid ovarian cancer cells. miRNA maturation assay, mRNA stability assay, Co-IP (NR1D1 with PARP1 and BRCA1), DNA damage assays, Ran inhibition Oncogene Medium 34743206
2023 Glucocorticoid receptor (GR/NR3C1) binds the Nr1d1 promoter E-box to suppress Nr1d1 expression in colon epithelium during stress; GR alters chromatin 3D structure at the Ikzf3-Nr1d1 super-enhancer; intestinal-specific Nr3c1 deletion abolishes stress-induced Nr1d1 suppression and associated IBS phenotypes. ChIP (GR at Nr1d1 promoter E-box), chromatin conformation (3D structure analysis), intestinal-specific Nr3c1 KO mice, water avoidance stress model iScience Medium 37404374
2023 NR1D1 binds to IL-1β and NLRP3 promoters (shown by ChIP) in nucleus pulposus cells to repress their expression; NR1D1 activation (SR9009) inhibits NLRP3 inflammasome assembly and IL-1β production, and increases ECM synthesis in disc cells. ChIP (NR1D1 on IL-1β/NLRP3 promoters), luciferase reporter, SR9009 treatment, in vitro NPMSC model, in vivo disc degeneration model iScience Medium 38689641
2024 NR1D1 directly represses IL-6 transcription in bovine endometrial epithelial cells by binding to a retinoic acid receptor-related orphan receptor-responsive element (RORE; -473 to -479) in the IL-6 promoter, as demonstrated by dual-luciferase reporter and deletion analysis; NR1D1 has predominantly nuclear localization in these cells. Dual-luciferase reporter with RORE deletion, siRNA/overexpression, SR9009 treatment, immunofluorescence (nuclear localization), primary cell culture International journal of biological macromolecules High 39551321
2024 LC3 (autophagosome marker) directly binds to NR1D1 via LC3-interacting region (LIR) motifs, leading to NR1D1 degradation in a mitophagy-dependent manner; mitophagy defects lead to NR1D1 accumulation and subsequent BMAL1 suppression, disrupting circadian rhythms. Co-IP (LC3-NR1D1), LIR motif identification, mitophagy inhibition experiments, urolithin A (mitophagy activator) treatment, rat simulated microgravity model International journal of molecular sciences Medium 38732079
2024 NR1D1 trans-represses Dusp1 (dual specificity phosphatase 1) transcription in pulmonary artery smooth muscle cells; NR1D1 deficiency restores Dusp1 expression, deactivating ERK1/2 and reducing DRP1-mediated mitochondrial fission; AAV1-mediated Nr1d1 knockdown inhibits PH progression in chronic intermittent hypoxia models. ChIP/reporter for Dusp1 promoter, AAV1 KD in vivo, ERK1/2 inhibitor and PMA pharmacology, Dusp1 KO mice, mitochondrial fission assays Cell death discovery Medium 39472573
2023 NR1D1 is transactivated in cisplatin-resistant neuroblastoma cells and drives expression of lncRNA NUTM2A-AS1, which in turn inhibits B7-H3 protein degradation, promoting immune evasion and chemoresistance. Gain/loss-of-function of NR1D1 and NUTM2A-AS1, Co-IP/RIP (NUTM2A-AS1 with B7-H3), cisplatin sensitivity assays, luciferase reporter (NR1D1 → NUTM2A-AS1 promoter) Journal of cellular and molecular medicine Medium 38785199
2025 NR1D1 depletion enhances autophagic flux and mitophagy in human cell lines and AD model organisms; Nr1d1 knockdown in 5xFAD mice restores autophagy marker expression; depletion of the C. elegans ortholog nhr-85 improves neuronal mitophagy and extends lifespan in amyloid-β models; NR1D1 knockdown activates SIRT1 and Cathepsin B (CTSB), both linked to autophagy. NR1D1 KD in human cell lines, 5xFAD mouse KD, C. elegans nhr-85 depletion, autophagic flux assay, mitophagy assay, SIRT1/CTSB activity Aging and disease Medium 39812544
2025 NR1D1 suppresses HSD17B12 transcription by binding to its promoter (CUT&Tag-qPCR and dual-luciferase reporter), reducing antioxidant capacity and promoting ROS-induced apoptosis in sheep granulosa cells via the AMPK pathway; NR1D1 knockdown of HSD17B12 partially alleviates the effects of NR1D1 overexpression on GC function. ATAC-seq, CUT&Tag-qPCR, dual-luciferase reporter, NR1D1 OE/KD, AMPK pathway assays, ROS and apoptosis measurements International journal of biological macromolecules Medium 39986531

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 The orphan receptor Rev-ErbA alpha activates transcription via a novel response element. Molecular and cellular biology 208 8474464
1993 Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation. The Journal of biological chemistry 172 8344913
1984 Growth of a fish ear: 1. Quantitative analysis of hair cell and ganglion cell proliferation. Hearing research 154 6490539
2020 NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis. Cell death & disease 108 32071294
1998 Regulation of leaf initiation by the terminal ear 1 gene of maize. Nature 95 9603518
1993 THRA1 and D17S183 flank an interval of < 4 cM for the breast-ovarian cancer gene (BRCA1) on chromosome 17q21. American journal of human genetics 91 8460637
2016 The circadian clock regulates autophagy directly through the nuclear hormone receptor Nr1d1/Rev-erbα and indirectly via Cebpb/(C/ebpβ) in zebrafish. Autophagy 87 27171500
1995 Constitutive expression of the orphan receptor, Rev-erbA alpha, inhibits muscle differentiation and abrogates the expression of the myoD gene family. Molecular endocrinology (Baltimore, Md.) 85 8614403
2022 Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2. Circulation 79 35880522
1996 Two receptor interaction domains in the corepressor, N-CoR/RIP13, are required for an efficient interaction with Rev-erbA alpha and RVR: physical association is dependent on the E region of the orphan receptors. Nucleic acids research 79 8948627
2016 Dysregulated circadian rhythm pathway in human osteoarthritis: NR1D1 and BMAL1 suppression alters TGF-β signaling in chondrocytes. Osteoarthritis and cartilage 73 27884645
2010 An RNA interference screen identifies metabolic regulators NR1D1 and PBP as novel survival factors for breast cancer cells with the ERBB2 signature. Cancer research 65 20160030
2018 REVERBa couples the circadian clock to hepatic glucocorticoid action. The Journal of clinical investigation 62 30179226
2011 Nuclear receptor Rev-erb alpha (Nr1d1) functions in concert with Nr2e3 to regulate transcriptional networks in the retina. PloS one 60 21408158
2000 Structure-function analysis of the Rev-erbA and RVR ligand-binding domains reveals a large hydrophobic surface that mediates corepressor binding and a ligand cavity occupied by side chains. Molecular endocrinology (Baltimore, Md.) 55 10809233
2013 Apolipoprotein A-IV reduces hepatic gluconeogenesis through nuclear receptor NR1D1. The Journal of biological chemistry 53 24311788
2008 Association analysis of nuclear receptor Rev-erb alpha gene (NR1D1) with mood disorders in the Japanese population. Neuroscience research 52 18804497
2020 Bisphenol A attenuates testosterone production in Leydig cells via the inhibition of NR1D1 signaling. Chemosphere 51 33297044
2021 Adipocyte NR1D1 dictates adipose tissue expansion during obesity. eLife 48 34350828
2017 NR1D1 Recruitment to Sites of DNA Damage Inhibits Repair and Is Associated with Chemosensitivity of Breast Cancer. Cancer research 45 28249904
2015 Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder. PloS one 44 25789810
2015 NR1D1 ameliorates Mycobacterium tuberculosis clearance through regulation of autophagy. Autophagy 43 26390081
2009 Nr1d1, an important circadian pathway regulatory gene, is suppressed by cigarette smoke in murine lungs. Integrative cancer therapies 42 19926613
1990 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. DNA and cell biology 41 1971514
2019 Meiotic gatekeeper STRA8 suppresses autophagy by repressing Nr1d1 expression during spermatogenesis in mice. PLoS genetics 40 31059511
1998 Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha. Molecular endocrinology (Baltimore, Md.) 39 9482666
2023 NR1D1 Stimulates Antitumor Immune Responses in Breast Cancer by Activating cGAS-STING Signaling. Cancer research 38 37395684
2014 Modifier genes as therapeutics: the nuclear hormone receptor Rev Erb alpha (Nr1d1) rescues Nr2e3 associated retinal disease. PloS one 38 24498227
2004 Aberrant expression of myosin isoforms in skeletal muscles from mice lacking the rev-erbAalpha orphan receptor gene. American journal of physiology. Regulatory, integrative and comparative physiology 37 15374821
2021 Glyphosate exposure attenuates testosterone synthesis via NR1D1 inhibition of StAR expression in mouse Leydig cells. The Science of the total environment 34 33957581
2019 Bisphenol A Alters Bmal1, Per2, and Rev-Erba mRNA and Requires Bmal1 to Increase Neuropeptide Y Expression in Hypothalamic Neurons. Endocrinology 33 30500912
2021 Circadian clock regulates granulosa cell autophagy through NR1D1-mediated inhibition of ATG5. American journal of physiology. Cell physiology 31 34936504
2023 m6A methylation-induced NR1D1 ablation disrupts the HSC circadian clock and promotes hepatic fibrosis. Pharmacological research 30 36813093
2023 Targeting NR1D1 in organ injury: challenges and prospects. Military Medical Research 29 38072952
2017 Effect of ApoA4 on SERPINA3 mediated by nuclear receptors NR4A1 and NR1D1 in hepatocytes. Biochemical and biophysical research communications 28 28412351
2018 The circadian gene Nr1d1 in the mouse nucleus accumbens modulates sociability and anxiety-related behaviour. The European journal of neuroscience 27 30028550
2017 Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders. Scientific reports 27 28262759
2009 Interacting genes in lithium prophylaxis: preliminary results of an exploratory analysis on the role of DGKH and NR1D1 gene polymorphisms in 199 Sardinian bipolar patients. Neuroscience letters 27 19818381
1998 Prenatal diagnosis of Glanzmann thrombasthenia using the polymorphic markers BRCA1 and THRA1 on chromosome 17. British journal of haematology 26 9695977
2020 Sleep Disturbance Induces Increased Cholesterol Level by NR1D1 Mediated CYP7A1 Inhibition. Frontiers in genetics 24 33424933
2021 NR1D1 suppressed the growth of ovarian cancer by abrogating the JAK/STAT3 signaling pathway. BMC cancer 23 34330232
2021 NR1D1 Deletion Induces Rupture-Prone Vulnerable Plaques by Regulating Macrophage Pyroptosis via the NF-κB/NLRP3 Inflammasome Pathway. Oxidative medicine and cellular longevity 23 34956438
2020 The Core-Clock Gene NR1D1 Impacts Cell Motility In Vitro and Invasiveness in A Zebrafish Xenograft Colon Cancer Model. Cancers 23 32244760
2015 Interaction of ApoA-IV with NR4A1 and NR1D1 Represses G6Pase and PEPCK Transcription: Nuclear Receptor-Mediated Downregulation of Hepatic Gluconeogenesis in Mice and a Human Hepatocyte Cell Line. PloS one 22 26556724
1994 Rat Rev-erbA alpha, an orphan receptor related to thyroid hormone receptor, binds to specific thyroid hormone response elements. Molecular endocrinology (Baltimore, Md.) 22 8015547
2022 Regulation of Circadian Genes Nr1d1 and Nr1d2 in Sex-Different Manners during Liver Aging. International journal of molecular sciences 21 36077427
2021 NR1D1 targeting CYP19A1 inhibits estrogen synthesis in ovarian granulosa cells. Theriogenology 21 34933195
1994 Identification of a novel member of the nuclear receptor superfamily which is closely related to Rev-ErbA. Biochemical and biophysical research communications 20 7945391
1996 Transcriptional repression by Rev-erbA alpha is dependent on the signature motif and helix 5 in the ligand binding domain: silencing does not involve an interaction with N-CoR. Nucleic acids research 18 8836173
1994 Mutation analysis of the THRA1 gene in breast cancer: deletion/fusion of the gene to a novel sequence on 17q in the BT474 cell line. Cancer research 16 7511052
2022 Inhibition of mPGES-2 ameliorates NASH by activating NR1D1 via heme. Hepatology (Baltimore, Md.) 15 35839302
2006 Functional characterization of an orphan nuclear receptor, Rev-ErbAalpha, in chondrocytes and its potential role in osteoarthritis. Arthritis and rheumatism 15 17075855
1996 Expression of c-erbA alpha, c-erbA beta and Rev-erbA alpha mRNA during the conversion of brown adipose tissue into white adipose tissue. Molecular and cellular endocrinology 15 8822265
2024 Depletion of ApoA5 aggravates spontaneous and diet-induced nonalcoholic fatty liver disease by reducing hepatic NR1D1 in hamsters. Theranostics 14 38505614
2023 NR1D1 deficiency in the tumor microenvironment promotes lung tumor development by activating the NLRP3 inflammasome. Cell death discovery 14 37524704
2017 NR1D1 enhances oxidative DNA damage by inhibiting PARP1 activity. Molecular and cellular endocrinology 14 28599788
2021 Clock Gene Nr1d1 Alleviates Retinal Inflammation Through Repression of Hmga2 in Microglia. Journal of inflammation research 13 34795498
2022 NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression. JCI insight 12 35917173
2019 Suberoylanilide Hydroxamic Acid Attenuates Autoimmune Arthritis by Suppressing Th17 Cells through NR1D1 Inhibition. Mediators of inflammation 12 31780863
2009 Orphan nuclear receptor Rev-erb alpha gene (NR1D1) and fluvoxamine response in major depressive disorder in the Japanese population. Neuropsychobiology 12 19571598
2025 Light Exposure, Physical Activity, and Indigeneity Modulate Seasonal Variation in NR1D1 (REV-ERBα) Expression. Biology 11 40136488
2023 Uncovering the Novel Role of NR1D1 in Regulating BNIP3-Mediated Mitophagy in Ulcerative Colitis. International journal of molecular sciences 11 37762536
2022 The combination of nuclear receptor NR1D1 and ULK1 promotes mitophagy in adipocytes to ameliorate obesity. Adipocyte 11 35410572
2022 Nr1d1 Mediated Cell Senescence in Mouse Heart-Derived Sca-1+CD31- Cells. International journal of molecular sciences 11 36293311
2021 NR1D1 regulation by Ran GTPase via miR4472 identifies an essential vulnerability linked to aneuploidy in ovarian cancer. Oncogene 11 34743206
2020 Soft tissue tumor with novel NR1D1-MAML1 fusion in a pediatric case. Virchows Archiv : an international journal of pathology 11 32474730
2005 Thyroid cancer susceptibility and THRA1 and BAT-40 repeats polymorphisms. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 11 15767343
2025 Overexpression of NR1D1 Portends Disease Recurrence in Thyroid Cancer. The Journal of clinical endocrinology and metabolism 10 39359072
2024 SR9009 attenuates inflammation-related NPMSC pyroptosis and IVDD through NR1D1/NLRP3/IL-1β pathway. iScience 10 38689641
2021 The Distribution, Expression Patterns and Functional Analysis of NR1D1 and NR4A2 in the Reproductive Axis Tissues of the Male Tianzhu White Yak. Animals : an open access journal from MDPI 10 34827849
2020 Maternal Separation Early in Life Alters the Expression of Genes Npas4 and Nr1d1 in Adult Female Mice: Correlation with Social Behavior. Behavioural neurology 10 32190129
2021 One Bout of Aerobic Exercise Can Enhance the Expression of Nr1d1 in Oxidative Skeletal Muscle Samples. Frontiers in physiology 9 33597895
2016 Deletion of exons 3 and 4 in the mouse Nr1d1 gene worsens high-fat diet-induced hepatic steatosis. Life sciences 9 27720799
2023 NR1D1::MAML1 epithelioid and spindle cell sarcoma mimicking pseudomyogenic hemangioendothelioma in core biopsy: A case report and review of the literature. Genes, chromosomes & cancer 8 37326138
2023 Glucocorticoid receptor-mediated Nr1d1 chromatin circadian misalignment in stress-induced irritable bowel syndrome. iScience 8 37404374
2022 Expanding the spectrum of mesenchymal neoplasms with NR1D1-rearrangement. Genes, chromosomes & cancer 8 35168293
2022 NR1D1 downregulation in astrocytes induces a phenotype that is detrimental to cocultured motor neurons. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 35319791
2024 NR1D1-transactivated lncRNA NUTM2A-AS1 promotes chemoresistance and immune evasion in neuroblastoma via inhibiting B7-H3 degradation. Journal of cellular and molecular medicine 7 38785199
2024 NR1D1 activation alleviates inflammatory response through inhibition of IL-6 expression in bovine endometrial epithelial cells. International journal of biological macromolecules 7 39551321
2020 Nr1d1 affects autophagy in the skeletal muscles of juvenile Nile tilapia by regulating the rhythmic expression of autophagy-related genes. Fish physiology and biochemistry 7 32072342
2016 Hippocampal Transcriptome Profile of Persistent Memory Rescue in a Mouse Model of THRA1 Mutation-Mediated Resistance to Thyroid Hormone. Scientific reports 7 26743578
2025 Dihydroartemisinin requires NR1D1 mediated Rab7 ubiquitination to regulate hepatic stellate cells lipophagy in liver fibrosis. International journal of biological macromolecules 6 39956231
2023 Clock gene NR1D1 might be a novel target for the treatment of bladder cancer. Urologic oncology 6 37208228
2021 Elimination of endogenous high molecular weight FGF2 prevents pressure-overload-induced systolic dysfunction, linked to increased FGFR1 activity and NR1D1 expression. Cell and tissue research 6 34057573
2024 Nr1d1 inhibition mitigates intermittent hypoxia-induced pulmonary hypertension via Dusp1-mediated Erk1/2 deactivation and mitochondrial fission attenuation. Cell death discovery 5 39472573
2023 NR1D1-rearranged soft tissue tumour: A clinicopathological and molecular analysis of four additional cases. Histopathology 5 38084644
2015 Associations between polymorphisms in the NR1D1 gene encoding for nuclear receptor REV-ERBα and circadian typologies. Chronobiology international 5 25798852
2011 Association Analysis of Nuclear Receptor Rev-erb Alpha Gene (NR1D1) and Japanese Methamphetamine Dependence. Current neuropharmacology 5 21886577
2024 THRA1/PGC-1α/SIRT3 pathway regulates oxidative stress and is implicated in hypertension of maternal hypothyroid rat offspring. Hypertension research : official journal of the Japanese Society of Hypertension 4 39639130
2023 Hypoxia activation attenuates progesterone synthesis in goat trophoblast cells via NR1D1 inhibition of StAR expression†. Biology of reproduction 4 37552055
2018 The circadian gene Nr1d1 in the mouse nucleus accumbens modulates sociability and anxiety-related behavior. The European journal of neuroscience 4 30326159
1996 Localization of the Rev-ErbA orphan receptors in the brain. Brain research 4 9017260
2025 A novel nuclear receptor NR1D1 suppresses HSD17B12 transcription to regulate granulosa cell apoptosis and autophagy via the AMPK pathway in sheep. International journal of biological macromolecules 3 39986531
2025 Role of NR1D1 in Bisphenol A-Induced Anxiety-like Behavior and Inflammation in Zebrafish Larvae. Toxics 3 40559921
2024 Low expression of NR1D1 and NR2E3 is associated with advanced features of retinoblastoma. International ophthalmology 3 38480634
2024 Mitophagy Regulates the Circadian Rhythms by Degrading NR1D1 in Simulated Microgravity and Isolation Environments. International journal of molecular sciences 3 38732079
2023 An in silico investigation: Can melatonin serve as an adjuvant in NR1D1-linked chronotherapy for amyotrophic lateral sclerosis? Chronobiology international 3 37781884
2023 REVERBA couples the circadian clock to Leydig cell steroidogenesis. BioFactors (Oxford, England) 3 38147453
2019 Sema3A - mediated modulation of NR1D1 expression may be involved in the regulation of axonal guidance signaling by the microbiota. Life sciences 3 30872177
2025 NR1D1 Inhibition Enhances Autophagy and Mitophagy in Alzheimer's Disease Models. Aging and disease 2 39812544