Nomenclature: Rev-Erb-α

Systematic Nomenclature: NR1D1

Family: 1D. Rev-Erb receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 614 17q11.2 NR1D1 nuclear receptor subfamily 1, group D, member 1 12-14
Mouse 615 11D Nr1d1 nuclear receptor subfamily 1, group D, member 1 21
Rat 615 10q31 Nr1d1 nuclear receptor subfamily 1, group D, member 1 11
Previous and Unofficial Names
ear-1
Rev-ErbAα
Rev-erbα
EAR1
hRev
THRAL
Rev-ErbAalpha
THRA1
V-erbA-related protein 1
V-erbA-related protein EAR-1
nuclear receptor subfamily 1 group D member 1
rev-erb alpha
rev-erbA-alpha
REV-ERBalpha
rev-erbA(alpha)
R75201
A530070C09Rik
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
NURSA Receptor
OMIM
PharmGKB Gene
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Rev-Erbα ligand-binding domain in complex with coregulator (NCoR) ID1 peptide
PDB Id:  3N00
Resolution:  2.6Å
Species:  Human
References:  15
Natural/Endogenous Ligands
Comments: Orphan
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
GSK4112 Hs Agonist 6.4 pEC50 7
pEC50 6.4 (EC50 4x10-7 M) [7]
GSK4112 Hs Agonist 5.64 pIC50 10
pIC50 5.64 (IC50 2.3x10-6 M) [10]
heme Hs Agonist - - 17,25
[17,25]
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
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
SR8278 Hs Antagonist 6.3 pEC50 10
pEC50 6.3 [10]
SR8278 Hs Antagonist 6.5 pIC50 10
pIC50 6.5 [10]
DNA Binding
Structure:  Monomer, Homodimer
HRE core sequence:  A/T A A/T N T PuGGTCA
Response element:  DR2, Half site
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
Name Interaction Effect Reference
Thyroid hormone receptor-α Physical, Functional DNA binding 1
Main Co-regulators
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. 24
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. 26
Main Target Genes
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 16,22
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. 23
Tissue Distribution
Ubiquitous
Species:  Human
Technique:  Northern blotting, RT-PCR, immunocytochemistry and Western blotting.
References:  2-3,6,8-9,12-13,16
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
NR1D1 knock-out homozygote mice
Species:  Mouse
Tissue: 
Technique: 
References:  6
NR1D1 null mice.
Species:  Mouse
Tissue:  Purkinje cells, neurons
Technique: 
References:  8
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].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr1d1tm1Schb Nr1d1tm1Schb/Nr1d1tm1Schb
involves: 129/Sv
MGI:2444210  MP:0005365 abnormal bile salt homeostasis PMID: 19721697 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0004098 abnormal cerebellar granule cell morphology PMID: 10704394 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0000889 abnormal cerebellar molecular layer PMID: 10704394 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0000854 abnormal cerebellum development PMID: 10704394 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0000872 abnormal cerebellum external granule cell layer morphology PMID: 10704394 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0000849 abnormal cerebellum morphology PMID: 10704394 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0008572 abnormal Purkinje cell dendrite morphology PMID: 10704394 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0008579 abnormal Purkinje cell differentiation PMID: 10704394 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0009409 abnormal skeletal muscle fiber type ratio PMID: 15374821 
Nr1d1tm1Schb Nr1d1tm1Schb/Nr1d1tm1Schb
involves: 129/Sv * C57BL/6J
MGI:2444210  MP:0002564 advanced circadian phase PMID: 12150932 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0001262 decreased body weight PMID: 15374821 
Nr1d1tm1Schb Nr1d1tm1Schb/Nr1d1tm1Schb
involves: 129/Sv * C57BL/6J
MGI:2444210  MP:0001935 decreased litter size PMID: 12150932 
Nr1d1tm1Schb Nr1d1tm1Schb/Nr1d1tm1Schb
involves: 129/Sv
MGI:2444210  MP:0010026 decreased liver cholesterol level PMID: 19721697 
Nr1d1tm1Schb Nr1d1tm1Schb/Nr1d1tm1Schb
involves: 129/Sv
MGI:2444210  MP:0009356 decreased liver triglyceride level PMID: 19721697 
Nr1d1tm1Schb Nr1d1tm1Schb/Nr1d1tm1Schb
involves: 129/Sv
MGI:2444210  MP:0001556 increased circulating HDL cholesterol level PMID: 19721697 
Nr1d1tm1Schb Nr1d1tm1Schb/Nr1d1tm1Schb
involves: 129/Sv
MGI:2444210  MP:0000182 increased circulating LDL cholesterol level PMID: 19721697 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0009399 increased skeletal muscle fiber size PMID: 15374821 
Nr1d1tm1Ven Nr1d1tm1Ven/Nr1d1tm1Ven
Not Specified
MGI:2444210  MP:0001923 reduced female fertility PMID: 10704394 
Nr1d1tm1Schb Nr1d1tm1Schb/Nr1d1tm1Schb
involves: 129/Sv * C57BL/6J
MGI:2444210  MP:0002563 shortened circadian period PMID: 12150932 
Biologically Significant Variants
Type:  Alternative promoters.
Species:  Mouse
Description:  Rev_erb alpha 2 (mouse)
Amino acids:  576
References:  22
Type:  Alternative promoters.
Species:  Human
Description:  Rev erb alpha 2: This isoform is encoded by a mRNA transcribed from an alternative promoter. It lacks the first 114 aa in the N-Terminal domain of the protein.
Amino acids:  504
Protein accession: 
References:  22
Type:  Alternative promoters.
Species:  Rat
Description:  Rev erb alpha 2 (rat)
Amino acids:  508
Protein accession: 
References:  22

REFERENCES

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. U.S.A.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. Development127 (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 T, Burris TP. (2010) Identification of SR8278, a Synthetic Antagonist of the Nuclear Heme Receptor REV-ERB. ACS Chem Biol,  [Epub ahead of print]. [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. Cell57 (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. Cell110 (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. 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. U.S.A.99 (26): 16899-903. [PMID:12477932]

22. 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]

23. 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]

24. 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]

25. 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. Science318 (5857): 1786-9. [PMID:18006707]

26. 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. U.S.A.94 (26): 14400-5. [PMID:9405624]

To cite this database page, please use the following:

1D. Rev-Erb receptors: Rev-Erb-α. Last modified on 13/12/2013. Accessed on 26/10/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=596.

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