Alternative titles; symbols
HGNC Approved Gene Symbol: NR1D2
Cytogenetic location: 3p24.2 Genomic coordinates (GRCh38) : 3:23,945,286-23,980,617 (from NCBI)
NR1D1 (602408) and NR1D2 are key components of the circadian clock machinery (Ding et al., 2021).
Dumas et al. (1994) used PCR with primers from conserved regions of nuclear hormone receptor superfamily genes to identify a new member of this superfamily, which they called BD73. The amino acid sequence of BD73 is 96% identical to Rev-ErbA-alpha in the DNA-binding domain and 72% identical in the ligand-binding domain. Northern blot analysis showed a 4.5-kb transcript present in variable amounts in a variety of tissues and cell lines.
Dumas et al. (1994) showed that, in vitro, the BD73 protein has DNA-binding activity to a specific A/T-rich sequence.
Toward a system-level understanding of the transcriptional circuitry regulating circadian clocks, Ueda et al. (2005) identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of the transcriptional dynamics. Ueda et al. (2005) found that E boxes (CACGTG) and E-prime boxes (CACGTT) controlled the expression of Per1 (602260), Nr1d2, Per2 (603426), Nr1d1, Dbp (124097), Bhlhb2 (604256), and Bhlhb3 (606200) transcription following a repressor-precedes-activator pattern, resulting in delayed transcriptional activity. RevErbA/ROR (600825)-binding elements regulated the transcriptional activity of Arntl (602550), Npas2 (603347), Nfil3 (605327), Clock (601851), Cry1 (601933), and Rorc (602943) through a repressor-precedes-activator pattern as well. DBP/E4BP4-binding elements controlled the expression of Per1, Per2, Per3 (603427), Nr1d1, Nr1d2, Rora, and Rorb (601972) through a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Ueda et al. (2005) suggested that regulation of E/E-prime boxes is a topologic vulnerability in mammalian circadian clocks, a concept that had been functionally verified using in vitro phenotype assay systems.
Using yeast 2-hybrid, pull-down, and coimmunoprecipitation analyses, Wang et al. (2007) showed that human ZNHIT1 (618617) interacted with REV-ERB-beta, with amino acids 72 to 110 of ZNHIT1 and the ligand-binding domain of REV-ERB-beta required for the interaction. Fluorescence-tagged ZNHIT1 and REV-ERB-beta colocalized in nucleus of HeLa cells. REV-ERB-beta bound to the promoter of APOC3 (107720) and repressed its expression, but this repression could be removed by recruitment of ZNHIT1 to the APOC3 promoter. ZNHIT1 did not affect binding of REV-ERB-beta to the APOC3 promoter, as it remained bound after recruitment of ZNHIT1.
Solt et al. (2012) identified potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behavior and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle, and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidemia and hyperglycemia.
Cho et al. (2012) determined the genomewide cis-acting targets of both REV-ERB isoforms in murine liver, which revealed shared recognition at over 50% of their total DNA binding sites and extensive overlap with the master circadian regulator BMAL1. Although REV-ERB-alpha has been shown to regulate BMAL1 expression directly, cistromic analysis revealed a more profound connection between BMAL1 and the REV-ERB-alpha and REV-ERB-beta genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-alpha, and REV-ERB-beta cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of REV-ERB-alpha and REV-ERB-beta function by creating double-knockout mice profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, double-knockout mice showed markedly altered circadian wheel-running behavior and deregulated lipid metabolism. Cho et al. (2012) concluded that their data united REV-ERB-alpha and REV-ERB-beta with PER, CRY, and other components of the principal feedback loop that drives circadian expression and indicated a more integral mechanism for the coordination of circadian rhythm and metabolism.
Lam et al. (2013) presented evidence that in mouse macrophages Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage lineage-determining factors, thereby establishing a macrophage-specific program of repression. The repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at 2 enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby mRNAs, suggesting a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a modified form of global run-on sequencing that quantifies nascent 5-prime ends, Lam et al. (2013) showed that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription factor binding and the specific sequences encoding the eRNA transcript. Lam et al. (2013) concluded that their studies provided evidence for a direct role of eRNAs in contributing to enhancer function and suggested that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription.
Sulli et al. (2018) showed that 2 agonists of REV-ERBs, SR9009 and SR9011, are specifically lethal to cancer cells and oncogene-induced senescent cells, including melanocytic nevi, and have no effect on the viability of normal cells or tissues. The anticancer activity of SR9009 and SR9011 affects a number of oncogenic drivers such as HRAS (190020), BRAF (164757), PIK3CA (171834), and others, and persists in the absence of p53 and under hypoxic conditions. The regulation of autophagy and de novo lipogenesis by SR9009 and SR9011 has a critical role in evoking an apoptotic response in malignant cells. Notably, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing overt toxicity in mice. Sulli et al. (2018) concluded that pharmacologic modulation of circadian regulators is an effective antitumor strategy, identifying a class of anticancer agents with a wide therapeutic window. Sulli et al. (2018) proposed that REV-ERB agonists are inhibitors of autophagy and de novo lipogenesis, with selective activity towards malignant and benign neoplasms.
Guan et al. (2020) showed that deletion of Rev-Erb-alpha and Rev-Erb-beta in adult mouse hepatocytes disrupted the diurnal rhythms of a subset of liver genes and altered the diurnal rhythm of de novo lipogenesis. In addition, loss of hepatocyte Rev-Erb-alpha and Rev-Erb-beta remodeled the rhythmic transcriptomes and metabolomes of multiple cell types within liver. Alteration of food availability demonstrated the hierarchy of the cell-intrinsic hepatocyte clock mechanism and the feeding environment. The studies revealed novel roles of the hepatocyte clock in physiologic coordination of nutritional signals and cell-cell communication controlling rhythmic metabolism.
Using YAC mapping and FISH, Koh and Moore (1999) mapped the NR1D2 gene to chromosome 3p24.3-p24.2.
Koh and Moore (1999) noted that the THRA (190120), NR1D1 (602408), and RARA (180240) genes are linked on chromosome 17q, and that the NR1D1 gene overlaps an exon of the THRA gene on the opposite strand. They found that THRB (190160), NR1D2, and RARB (180220) are similarly linked and oriented on chromosome 3p. The ancestral genes were duplicated before the divergence of vertebrates, since at least the TRs and RARs are also duplicated in birds and amphibians.
Ding et al. (2021) found that mice with GABA neuron-specific knockout of both Rev-erb-alpha and Rev-erb-beta were born at mendelian ratio and did not show developmental defects compared with wildtype. Knockout mice displayed normal diurnal rhythm, normal diurnal patterns of food intake, normal total daily food intake, and normal body weight on chow diet under regular light-dark conditions. However, knockout mice showed Zeitgeber time (ZT)-dependent abnormalities in glucose metabolism, with impairment of glucose tolerance and impaired insulin sensitivity. Expression of Rev-erb-alpha and Rev-erb-beta displayed robust diurnal rhythm in the SCN. The rhythmicity of the SCN GABA neural activity and Rev-erb expression regulated rhythmic glucose metabolism in mice, as Rev-erb regulated the diurnal rhythm of the SCN GABA neural activity by regulating SCN GABA neuron firing, and SCN firing regulated glucose metabolism by regulating the rhythmic hepatic insulin sensitivity. In support, type-2 diabetes (T2D; 125853) patients with 'extended dawn phenomenon' (DP) displayed differential temporal pattern of Rev-erb gene expression compared with T2D patients without DP.
Cho, H., Zhao, X., Hatori, M., Yu, R. T., Barish, G. D., Lam, M. T., Chong, L.-W., DiTacchio, L., Atkins, A. R., Glass, C. K., Liddle, C., Auwerx, J., Downes, M., Panda, S., Evans, R. M. Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta. Nature 485: 123-127, 2012. [PubMed: 22460952] [Full Text: https://doi.org/10.1038/nature11048]
Ding, G., Li, X., Hou, X., Zhou, W., Gong, Y., Liu, F., He, Y., Song, J., Wang, J., Basil, P., Li, W., Qian, S., and 10 others. REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity. Nature 592: 763-767, 2021. Note: Erratum: Nature 595: E2, 2021. [PubMed: 33762728] [Full Text: https://doi.org/10.1038/s41586-021-03358-w]
Dumas, B., Harding, H. P., Choi, H.-S., Lehmann, K. A., Chung, M., Lazar, M. A., Moore, D. D. A new orphan member of the nuclear hormone receptor superfamily closely related to Rev-Erb. Molec. Endocr. 8: 996-1005, 1994. [PubMed: 7997240] [Full Text: https://doi.org/10.1210/mend.8.8.7997240]
Guan, D., Xiong, Y., Trinh, T. M., Hu, W., Jiang, C., Dierickx, P., Jang, C., Rabinowitz, J. D., Lazar, M. A. The hepatocyte clock and feeding control chronophysiology of multiple liver cell types. Science 369: 1388-1394, 2020. [PubMed: 32732282] [Full Text: https://doi.org/10.1126/science.aba8984]
Koh, Y.-S., Moore, D. D. Linkage of the nuclear hormone receptor genes NR1D2, THRB, and RARB: evidence for an ancient, large-scale duplication. Genomics 57: 289-292, 1999. [PubMed: 10198169] [Full Text: https://doi.org/10.1006/geno.1998.5683]
Lam, M. T. Y., Cho, H., Lesch, H. P., Gosselin, D., Heinz, S., Tanaka-Oishi, Y., Benner, C., Kaikkonen, M. U., Kim, A. S., Kosaka, M., Lee, C. Y., Watt, A., Grossman, T. R., Rosenfeld, M. G., Evans, R. M., Glass, C. K. Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature 498: 511-515, 2013. [PubMed: 23728303] [Full Text: https://doi.org/10.1038/nature12209]
Solt, L. A., Wang, Y., Banerjee, S., Hughes, T., Kojetin, D. J., Lundasen, T., Shin, Y., Liu, J., Cameron, M. D., Noel, R., Yoo, S.-H., Takahashi, J. S., Butler, A. A., Kamenecka, T. M., Burris, T. P. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485: 62-68, 2012. [PubMed: 22460951] [Full Text: https://doi.org/10.1038/nature11030]
Sulli, G., Rommel, A., Wang, X., Kolar, M. J., Puca, F., Saghatelian, A., Plikus, M. V., Verma, I. M., Panda, S. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553: 351-355, 2018. [PubMed: 29320480] [Full Text: https://doi.org/10.1038/nature25170]
Ueda, H. R., Hayashi, S., Chen, W., Sano, M., Machida, M., Shigeyoshi, Y., Iino, M., Hashimoto, S. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nature Genet. 37: 187-192, 2005. [PubMed: 15665827] [Full Text: https://doi.org/10.1038/ng1504]
Wang, J., Li, Y., Zhang, M., Liu, Z., Wu, C., Yuan, H., Li, Y.-Y., Zhao, X., Lu, H. A zinc finger HIT domain-containing protein, ZNHIT-1, interacts with orphan nuclear hormone receptor Rev-erb-beta and removes Rev-erb-beta-induced inhibition of apoCIII transcription. FEBS J. 274: 5370-5381, 2007. [PubMed: 17892483] [Full Text: https://doi.org/10.1111/j.1742-4658.2007.06062.x]