Rev-erbα is transcribed from the opposite strand of the thyroid receptor α (c-erbAα) gene on chromosome 17, with a 269-nucleotide overlap between the two transcripts. The other mammalian isoform of the receptor, Rev-erbβ is encoded by another gene on chromosome 3. In addition, there is one non-mammalian homolog, the ecdysone-regulated gene E75, which is present in Drosophila and C. elegans. The Rev-erbα gene itself has multiple transcripts. Two promoters govern the expression of the Rev-erbα gene in human and rat, generating two mRNA isoforms. The full-length isoform encodes a 614-amino acid protein, while a second isoform is generated from an internal promoter and produces a protein that is shorter by 106 amino acids. Both Rev-erbα mRNA isoforms contain E-boxes as well as Rev-erbα response elements, which means that they can be regulated in a circadian manner by the BMAL and Rev-erba proteins. In fact, both transcripts exhibit rhythmic expression in serum-synchronized fibroblasts.
The Rev-erbα protein is structurally unique from other nuclear receptors, in that it lacks helix 12 (H12) in its ligand-binding domain, which is usually responsible for forming the ligand binding pocket in other nuclear receptors. In place of the missing H12, Rev-erbα displays a hydrophobic interface that binds the corepressor N-CoR, making it a potent transcriptional repressor. Interestingly, all members of the Rev-erb family bind heme, which may act as a ligand to regulate their transcriptional activity.
Rev-erbα regulates gene transcription by directly binding to target response elements (RevREs), and comprises an A/T-rich flank followed by AGGTCA. Rev-erbα mediates repression by recruiting the corepressor N-CoR, which then activates the histone deacetylase (HDAC) 3. A number of target genes have been identified for Rev-erbα, including the lipoproteins ApoA1 and ApoCIII, hydratase dehydrogenase, the circadian factor BMAL, and the anti-fibrinolytic factor PAI-1. Many of these genes are coordinately regulated by Rev-erbα and the RAR-related orphan receptor RORα, which share the same response elements but exert opposite effects on gene transcription. Crosstalk between Rev-erbα and RORα likely acts to fine-tune their target physiologic networks, such as circadian rhythms, metabolic homeostasis, and inflammation.
Rev-erbα mRNA is induced during adipogenesis and is highly expressed in adipose tissue. One study reported that overexpression of Rev-erbα may enhance adipogenesis in cultured mouse adipocytes, but the mechanism of this effect remains to be elucidated. More recently, a study showed that the deletion of Rev-erbα in mice alters glucose and lipid metabolism and leads to obesity.
Rev-erbα expression is also regulated at the post-translational level: it is phosphorylated on the amino terminus by glycogen synthase kinase (GSK 3β), which contributes to its protein stability. It has been shown that lithium, which inhibits GSK3β, can de-stabilize Rev-erbα protein and affect its function in the circadian clock. This may partly explain lithium’s therapeutic effect on circadian diseases such as bipolar disorder.
^Lazar MA, Jones KE, Chin WW (March 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. doi:10.1089/dna.1990.9.77. PMID1971514.
^Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (2002). "The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator". Cell110 (2): 251–60. doi:10.1016/S0092-8674(02)00825-5. PMID12150932.
^Triqueneaux G, Thenot S, Kakizawa T, Antoch MP, Safi R, Takahashi JS, Delaunay F, Laudet V (2004). "The orphan receptor Rev-erbα gene is a target of the circadian clock pacemaker". J. Mol. Endocrinol.33 (3): 585–608. doi:10.1677/jme.1.01554. PMID15591021.
^Woo EJ, Jeong DG, Lim MY, Jun Kim S, Kim KJ, Yoon SM, Park BC, Eon Ryu S (2007). "Structural Insight into the Constitutive Repression Function of the Nuclear Receptor Rev-erbβ". J. Mol. Biol.373 (3): 735–44. doi:10.1016/j.jmb.2007.08.037. PMID17870090.
^Forman BM, Chen J, Blumberg B, Kliewer SA, Henshaw R, Ong ES, Evans RM (1994). "Cross-talk among ROR α 1 and the Rev-erb family of orphan nuclear receptors". Mol. Endocrinol.8 (9): 1253–61. doi:10.1210/me.8.9.1253. PMID7838158.
^Fontaine C, Dubois G, Duguay Y, Helledie T, Vu-Dac N, Gervois P, Soncin F, Mandrup S, Fruchart JC, Fruchart-Najib J, Staels B (2003). "The orphan nuclear receptor Rev-Erbα is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation". J. Biol. Chem.278 (39): 37672–80. doi:10.1074/jbc.M304664200. PMID12821652.
^Yin L, Wang J, Klein PS, Lazar MA (2006). "Nuclear receptor Rev-erbα is a critical lithium-sensitive component of the circadian clock". Science311 (5763): 1002–5. doi:10.1126/science.1121613. PMID16484495.
Miyajima N, Horiuchi R, Shibuya Y, et al. (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. doi:10.1016/0092-8674(89)90169-4. PMID2539258.
Burke LJ, Downes M, Laudet V, Muscat GE (1998). "Identification and characterization of a novel corepressor interaction region in RVR and Rev-erbA alpha". Mol. Endocrinol.12 (2): 248–62. doi:10.1210/me.12.2.248. PMID9482666.
Raspè E, Mautino G, Duval C, et al. (2003). "Transcriptional regulation of human Rev-erbalpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha". J. Biol. Chem.277 (51): 49275–81. doi:10.1074/jbc.M206215200. PMID12377782.
Raspé E, Duez H, Mansén A, et al. (2003). "Identification of Rev-erbalpha as a physiological repressor of apoC-III gene transcription". J. Lipid Res.43 (12): 2172–9. doi:10.1194/jlr.M200386-JLR200. PMID12454280.
Chopin-Delannoy S, Thénot S, Delaunay F, et al. (2004). "A specific and unusual nuclear localization signal in the DNA binding domain of the Rev-erb orphan receptors". J. Mol. Endocrinol.30 (2): 197–211. doi:10.1677/jme.0.0300197. PMID12683943.
Fontaine C, Dubois G, Duguay Y, et al. (2003). "The orphan nuclear receptor Rev-Erbalpha is a peroxisome proliferator-activated receptor (PPAR) gamma target gene and promotes PPARgamma-induced adipocyte differentiation". J. Biol. Chem.278 (39): 37672–80. doi:10.1074/jbc.M304664200. PMID12821652.
Johnson JM, Castle J, Garrett-Engele P, et al. (2004). "Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays". Science302 (5653): 2141–4. doi:10.1126/science.1090100. PMID14684825.