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Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 614 | 17q21.1 | NR1D1 | nuclear receptor subfamily 1 group D member 1 | 12-14 |
| Mouse | 615 | 11 D | Nr1d1 | nuclear receptor subfamily 1, group D, member 1 | 22 |
| Rat | 615 | 10q31 | Nr1d1 | nuclear receptor subfamily 1, group D, member 1 | 11 |
| Previous and Unofficial Names |
| ear-1 | EAR1 | THRA1 | THRAL | V-erbA-related protein EAR-1 | nuclear receptor subfamily 1, group D, member 1 | nuclear receptor subfamily 1 |
| Database Links |
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| Alphafold | P20393 (Hs), Q3UV55 (Mm), Q63503 (Rn) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL1961783 (Hs) |
| Ensembl Gene | ENSG00000126368 (Hs), ENSMUSG00000020889 (Mm), ENSRNOG00000009329 (Rn) |
| Entrez Gene | 9572 (Hs), 217166 (Mm), 252917 (Rn) |
| Human Protein Atlas | ENSG00000126368 (Hs) |
| KEGG Gene | hsa:9572 (Hs), mmu:217166 (Mm), rno:252917 (Rn) |
| OMIM | 602408 (Hs) |
| Pharos | P20393 (Hs) |
| RefSeq Nucleotide | NM_021724 (Hs), NM_145434 (Mm), NM_001113422 (Rn), NM_145775 (Rn) |
| RefSeq Protein | NP_001138897 (Hs), NP_068370 (Hs), NP_663409 (Mm), NP_665718 (Rn) |
| UniProtKB | P20393 (Hs), Q3UV55 (Mm), Q63503 (Rn) |
| Wikipedia | NR1D1 (Hs) |
| Selected 3D Structures |
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| Natural/Endogenous Ligands |
| heme |
| Comments: Orphan |
Download all structure-activity data for this target as a CSV file 
| Agonists |
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No ligand identified. Homology modeling of the putative LBDs of the NR1D subgroup suggested that the pocket is occupied by bulky side chains, and the small residual cavity could not accommodate a classical ligand [19]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonists |
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Immuno Process Associations | ||
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| DNA Binding |
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| DNA Binding Comments | |||||||
| The Rev-erbα gene product was shown to bind to DNA as a monomer to response element called RevRE which contains an AGGTCA motif linked in 5’ to an A/T rich sequence harbouring the following consensus : A/T A A/T N T. The RevRE is nearly identical to the RORE bound by ROR. Later on, it was shown by site selection experiments as well as by the study of a natural RevRE found in the human Rev-erbα promoter that it is able to homodimerize on RevDR2 elements that are composed of one classical RevRE followed in 3’ by an AGGTCA motif. While Rev-erbα homodimers bind and repress cooperatively at the RevDR2 element, the monomers can repress transcription at two separated RevREs provided the monomers are simultaneously bound . | |||||||
| Co-binding Partners |
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| Name | Interaction | Effect | Reference |
| Thyroid hormone receptor-α | Physical, Functional | DNA binding | 1 |
| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| NCOR1 | Co-repressor | No | No | No | NR1D1 lacks the canonical AF-2 found in many nuclear receptor. Its LBD is not able to interact with coactivator protein but only with corepressor, in line with its constitutive repressor activity. | 5 |
| NCOA5 | Other | No | No | No | This cofactor encompasses both repressor and activator functions | 20 |
| HDAC3 | Co-repressor | No | No | No | NR1D1 recruits the NCoR/HDAC3 complex at the promoter level of its target gene. | 25 |
| C1D | Co-repressor | No | No | No | SUN-CoR is a highly basic, 16-kDa nuclear protein which represses transcription when fused to a heterologous DNA binding domain, and interacts with RevErb in vitro. | 27 |
| Main Target Genes |
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| Name | Species | Effect | Technique | Comments | References |
| NR1D1 | Human | Repressed | ChIP, Transient transfection, EMSA | In human and all other species NR1D1 (Rev-erba) repress its own expression. | 1 |
| ARNTL | Human | Repressed | ChIP, Transient transfection, EMSA | This ARNTL (aryl hydrocarbon receptor nuclear translocator-like, Bmal1) repression is seen in all other species | 16,23 |
| APOC3 | Human | Repressed | Transient transfection, EMSA, Other | Expression of APOC3 (Apolipoprotein C-III) is repressed by Rev-erba in all other species studied | 4,18 |
| Apoa1 | Rat | Repressed | Transient transfection, EMSA, Others | Apoa1 (Apolipoprotein A) in rat, but not human, is repressed by the nuclear receptor Rev-erbalpha, which binds to a negative response element adjacent to the TATA box of the rat apoA-I promoter. | 24 |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| Rev-erbα is expressed in a wide variety of tissues as a single mRNA of 3 kb. Strong expression is observed in skeletal muscles, brown fat, liver, heart, and brain, modest levels in pituitary and kidney and very low levels in testis, lung and hypothalamus. Rev-erbα was shown to be expressed in cell lines of the B lymphocyte lineage. During development, Rev-erbα expression start in the heart at E 10.5, extend to the eyes one day after and then increase during the second week of life. In brain, a high expression in Purkinje cells of the cerebellum, olfactory granule cells, cerebral cortex and hippocampus was observed. It was shown that Rev-erbα expression increαses during adipocytes differentiation and decreases during myogenic differentiation. Recently, Rev-erbα was shown to be involved in the molecular pacemaker supporting circadian rhythms generation. Consequently, Rev-erbα exhibit a strong circadian expression. | ||||||||
| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| NR1D1 null mice do not show any obvious phenotype in either fat tissue or skeletal muscle, despite the known regulation of rev-erbA(alpha) expression during adipocyte and myotube differentiation in vitro. During the second week of life, the cerebellum of rev-erbA(alpha) mutants presents several unexpected abnormalities, such as alterations in the development of Purkinje cells, delay in the proliferation and migration of granule cells from the external granule cell layer and increased apoptosis of neurons in the internal granule cell layer. Interestingly, the expression pattern of rev-erbA(alpha) suggests that the abnormalities observed in the external granule cell layer could be secondary to Purkinje cell alterations [8]. NR1D1 knockout mouse strain: showed no difference between wild-type and NR1D1 null mice. However, they clearly show that homozygote mice exhibit defects in their circadian rhythm (period length and phase shifting properties of the clock) [6]. |
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Biologically Significant Variants
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1. Adelmant G, Bègue A, Stéhelin D, Laudet V. (1996) A functional Rev-erb alpha responsive element located in the human Rev-erb alpha promoter mediates a repressing activity. Proc Natl Acad Sci USA, 93 (8): 3553-8. [PMID:8622974]
2. Chawla A, Lazar MA. (1993) Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation. J Biol Chem, 268 (22): 16265-9. [PMID:8344913]
3. Chomez P, Neveu I, Mansén A, Kiesler E, Larsson L, Vennström B, Arenas E. (2000) Increased cell death and delayed development in the cerebellum of mice lacking the rev-erbA(alpha) orphan receptor. Development, 127 (7): 1489-98. [PMID:10704394]
4. Coste H, Rodríguez JC. (2002) Orphan nuclear hormone receptor Rev-erbalpha regulates the human apolipoprotein CIII promoter. J Biol Chem, 277 (30): 27120-9. [PMID:12021280]
5. Downes M, Burke LJ, Bailey PJ, Muscat GE. (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 Res, 24 (22): 4379-86. [PMID:8948627]
6. Downes M, Carozzi AJ, Muscat GE. (1995) Constitutive expression of the orphan receptor, Rev-erbA alpha, inhibits muscle differentiation and abrogates the expression of the myoD gene family. Mol Endocrinol, 9 (12): 1666-78. [PMID:8614403]
7. Grant D, Yin L, Collins JL, Parks DJ, Orband-Miller LA, Wisely GB, Joshi S, Lazar MA, Willson TM, Zuercher WJ. (2010) GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbα. ACS Chem Biol, 5 (10): 925-32. [PMID:20677822]
8. Hastings ML, Milcarek C, Martincic K, Peterson ML, Munroe SH. (1997) Expression of the thyroid hormone receptor gene, erbAalpha, in B lymphocytes: alternative mRNA processing is independent of differentiation but correlates with antisense RNA levels. Nucleic Acids Res, 25 (21): 4296-300. [PMID:9336460]
9. Kainu T, Enmark E, Gustafsson JA, Pelto-Huikko MP. (1996) Localization of the Rev-ErbA orphan receptors in the brain. Brain Res, 743 (1-2): 315-9. [PMID:9017260]
10. Kojetin D, Wang Y, Kamenecka TM, Burris TP. (2011) Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS Chem Biol, 6 (2): 131-4. [PMID:21043485]
11. Lazar MA, Hodin RA, Darling DS, Chin WW. (1989) A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit. Mol Cell Biol, 9 (3): 1128-36. [PMID:2542765]
12. Lazar MA, Jones KE, Chin WW. (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 Cell Biol, 9 (2): 77-83. [PMID:1971514]
13. Miyajima N, Horiuchi R, Shibuya Y, Fukushige S, Matsubara K, Toyoshima K, Yamamoto T. (1989) Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus. Cell, 57 (1): 31-9. [PMID:2539258]
14. Miyajima N, Kadowaki Y, Fukushige S, Shimizu S, Semba K, Yamanashi Y, Matsubara K, Toyoshima K, Yamamoto T. (1988) Identification of two novel members of erbA superfamily by molecular cloning: the gene products of the two are highly related to each other. Nucleic Acids Res, 16 (23): 11057-74. [PMID:2905047]
15. Phelan CA, Gampe RT, Lambert MH, Parks DJ, Montana V, Bynum J, Broderick TM, Hu X, Williams SP, Nolte RT, Lazar MA. (2010) Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of nuclear receptor-co-repressor interaction. Nat Struct Mol Biol, 17 (7): 808-14. [PMID:20581824]
16. Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U. (2002) The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell, 110 (2): 251-60. [PMID:12150932]
17. Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F. (2007) Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta. Nat Struct Mol Biol, 14 (12): 1207-13. [PMID:18037887]
18. Raspé E, Duez H, Mansén A, Fontaine C, Fiévet C, Fruchart JC, Vennström B, Staels B. (2002) Identification of Rev-erbalpha as a physiological repressor of apoC-III gene transcription. J Lipid Res, 43 (12): 2172-9. [PMID:12454280]
19. Renaud JP, Harris JM, Downes M, Burke LJ, Muscat GE. (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. Mol Endocrinol, 14 (5): 700-17. [PMID:10809233]
20. Sauvé F, McBroom LD, Gallant J, Moraitis AN, Labrie F, Giguère V. (2001) CIA, a novel estrogen receptor coactivator with a bifunctional nuclear receptor interacting determinant. Mol Cell Biol, 21 (1): 343-53. [PMID:11113208]
21. Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ, Lundasen T, Shin Y, Liu J, Cameron MD, Noel R et al.. (2012) Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature, 485 (7396): 62-8. [PMID:22460951]
22. Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF et al.. (2002) Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci USA, 99 (26): 16899-903. [PMID:12477932]
23. Triqueneaux G, Thenot S, Kakizawa T, Antoch MP, Safi R, Takahashi JS, Delaunay F, Laudet V. (2004) The orphan receptor Rev-erbalpha gene is a target of the circadian clock pacemaker. J Mol Endocrinol, 33 (3): 585-608. [PMID:15591021]
24. Vu-Dac N, Chopin-Delannoy S, Gervois P, Bonnelye E, Martin G, Fruchart JC, Laudet V, Staels B. (1998) The nuclear receptors peroxisome proliferator-activated receptor alpha and Rev-erbalpha mediate the species-specific regulation of apolipoprotein A-I expression by fibrates. J Biol Chem, 273 (40): 25713-20. [PMID:9748239]
25. Yin L, Lazar MA. (2005) The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Mol Endocrinol, 19 (6): 1452-9. [PMID:15761026]
26. Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB et al.. (2007) Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science, 318 (5857): 1786-9. [PMID:18006707]
27. Zamir I, Dawson J, Lavinsky RM, Glass CK, Rosenfeld MG, Lazar MA. (1997) Cloning and characterization of a corepressor and potential component of the nuclear hormone receptor repression complex. Proc Natl Acad Sci USA, 94 (26): 14400-5. [PMID:9405624]
1D. Rev-Erb receptors: Rev-Erb-α. Last modified on 05/11/2015. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=596.
