Alternative titles; symbols
HGNC Approved Gene Symbol: NR1D1
Cytogenetic location: 17q21.1 Genomic coordinates (GRCh38) : 17:40,092,793-40,100,589 (from NCBI)
NR1D1 and NR1D2 (602304) are key components of the circadian clock machinery (Ding et al., 2021).
Cellular homologs of the viral oncogene v-erbA are members of the nuclear receptor superfamily, which provide a direct link between signaling molecules and the transcriptional response. Lazar et al. (1989) isolated a rat gene with homology to ERBA (190120) that is transcribed from the opposite strand of the ERBA gene. They designated the gene Rev-ERBA-alpha.
Miyajima et al. (1989) cloned both the human Rev-ERBA-alpha and the ERBA genes, referring to them as EAR1 and EAR7, respectively. The EAR1 gene encodes a predicted 614-amino acid protein. Northern blot analysis detected expression of the 2.9-kb EAR1 mRNA in all tissues tested.
By RNAscope analysis, Ding et al. (2021) showed that Rev-erb-alpha was the primary Rev-erb form compared with Rev-erb-beta, and was highly enriched in the suprachiasmatic nucleus (SCN), which is mainly composed of GABAergic neurons.
Zhao et al. (1998) described the crystal structure of the DNA-binding region of the Rev-ERBA-alpha receptor at 2.3-angstrom resolution.
Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 (602550) and CLOCK (601851), players of the positive limb, activate transcription of the cryptochrome (see 601933) and period (PER; see 602260) genes, components of the negative limb. BMAL1 and PER transcription cycles display nearly opposite phases and are thus governed by different mechanisms. Preitner et al. (2002) identified REV-ERB-alpha as the major regulator of cyclic BMAL1 transcription. Circadian REV-ERB-alpha expression is controlled by components of the general feedback loop. Thus, REV-ERB-alpha constitutes a molecular link through which components of the negative limb drive antiphasic expression of components of the positive limb. While REV-ERB-alpha influences the period length and affects the phase-shifting properties of the clock, it is not required for circadian rhythm generation.
Using a systems-biologic approach based on genomic, molecular, and cell biologic techniques, Ueda et al. (2002) profiled suprachiasmatic nuclei and liver genomewide expression patterns under light/dark cycles and constant darkness. Ueda et al. (2002) determined transcription start sites of human orthologs for newly identified cycling genes and then performed bioinformatic searches for relationships between time of day-specific expression and transcription factor response elements around transcription start sites. Ueda et al. (2002) demonstrated the role of the Rev-ErbA/ROR response element in gene expression during circadian night, which is in phase with BMAL1 and in antiphase to PER2 (603426) oscillations. Ueda et al. (2002) verified their observations using an in vitro validation system in which cultured fibroblasts transiently transfected with clock-controlled reporter vectors exhibited robust circadian bioluminescence. Ueda et al. (2002) found 7 cycling genes in the suprachiasmatic nucleus with putative cAMP response elements (CRE:TGACGT) in the promoter regions of their orthologs, the phases of which consolidate to subjective day. Ueda et al. (2002) also found 10 cycling genes in the suprachiasmatic nucleus with putative Rev-ErbA/ROR response elements (AGGTCA), to which Rev-ErbA and ROR family members bind, in the promoter regions of their orthologs. The 10 genes identified included BMAL1 and E4BP4 (605327), which displayed similar circadian expression antiphase to PER2 oscillations in both suprachiasmatic nucleus and liver. Ueda et al. (2002) found that Rev-ErbA, Rev-ErbA-beta, ROR-alpha (600825), and ROR-beta (601972) displayed similar circadian expression profiles in the suprachiasmatic nucleus, with peaks during the day and troughs during the night, whereas ROR-gamma (602943) was not detected in the suprachiasmatic nucleus throughout the 24-hour cycle.
REV-ERB-alpha is induced dramatically during adipogenesis (Chawla and Lazar, 1993). Coste and Rodriguez (2002) determined that REV-ERB-alpha transfected and expressed in human hepatic cells specifically repressed APOC3 (107720) promoter activity. By deletion and site-directed mutagenesis experiments, they showed that REV-ERB-alpha bound to an element in the proximal promoter of the APOC3 gene that is also a ROR-alpha-1 (600825) element. They provided evidence for cross-talk between REV-ERB-alpha and ROR-alpha-1 in modulating the APOC3 promoter.
Etchegaray et al. (2003) demonstrated that transcriptional regulation of the core clock mechanism in mouse liver is accompanied by rhythms in H3 histone (see 602810) acetylation, and that H3 acetylation is a potential target of the inhibitory action of Cry. The promoter regions of the Per1 (602260), Per2, and Cry1 genes exhibited circadian rhythms in H3 acetylation and RNA polymerase II (see 180660) binding that were synchronous with the corresponding steady-state mRNA rhythms. The histone acetyltransferase p300 (602700) precipitated with Clock in vivo in a time-dependent manner. Moreover, the Cry proteins inhibited a p300-induced increase in Clock/Bmal1-mediated transcription. Etchegaray et al. (2003) concluded that the delayed timing of the Cry1 mRNA rhythm, relative to the Per rhythms, was due to the coordinated activities of Rev-Erb-alpha and Clock/Bmal1, and defined a novel mechanism for circadian phase control.
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, Nr1d2, Per2, Nr1d1, Dbp (124097), Bhlhb2 (604256), and Bhlhb3 (606200) transcription following a repressor-precedes-activator pattern, resulting in delayed transcriptional activity. RevErbA/ROR-binding elements regulated the transcriptional activity of Arntl, Npas2 (603347), Nfil3, Clock, Cry1, and Rorc 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 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.
Yin et al. (2006) demonstrated that GSK3-beta (605004) phosphorylates and stabilizes the orphan nuclear receptor Rev-erb-alpha, a negative component of the circadian clock. Lithium treatment of cells led to rapid proteasomal degradation of Rev-erb-alpha and activation of clock gene Bmal1. A form of Rev-erb-alpha that is insensitive to lithium interfered with the expression of circadian genes. Yin et al. (2006) concluded that control of Rev-erb-alpha protein stability is thus a critical component of the peripheral clock and a biologic target of lithium therapy.
Yin et al. (2007) showed that heme binds reversibly to the orphan nuclear receptor Rev-erb-alpha, a critical negative component of the circadian core clock, and regulates its interaction with a nuclear receptor corepressor complex. Furthermore, heme suppresses hepatic gluconeogenic gene expression and glucose output through Rev-erb-alpha-mediated gene repression. Thus, Yin et al. (2007) concluded that Rev-erb-alpha serves as a heme sensor that coordinates the cellular clock, glucose homeostasis, and energy metabolism.
Feng et al. (2011) showed that histone deacetylase-3 (HDAC3; 605166) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Although amounts of HDAC3 are constant, its genomic recruitment in liver corresponds to the expression pattern of the circadian nuclear receptor Rev-erb-alpha. Rev-erb-alpha colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erb-alpha in mouse liver causes hepatic steatosis. Thus, Feng et al. (2011) concluded that genomic recruitment of HDAC3 by Rev-erb-alpha directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis.
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 (602550). 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 (NR1D2) genomic regulatory circuits than had been 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 (see 602260), CRY (601933), 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.
Gerhart-Hines et al. (2013) demonstrated that Rev-erb-alpha, a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue function. Mice exposed to cold fare considerably better at 05:00 (Zeitgeber time 22) when Rev-erb-alpha is barely expressed than at 17:00 (Zeitgeber time 10) when Rev-erb-alpha is abundant. Deletion of Rev-erb-alpha markedly improves cold tolerance at 17:00, indicating that overcoming Rev-erb-alpha-dependent repression is a fundamental feature of the thermogenic response to cold. Physiologic induction of uncoupling protein-1 (UCP1; 113730) by cold temperatures is preceded by rapid downregulation of Rev-erb-alpha in brown adipose tissue. Rev-erb-alpha represses Ucp1 in a brown adipose cell-autonomous manner and brown adipose tissue Ucp1 levels are high in Rev-erb-alpha-null mice, even at thermoneutrality. Genetic loss of Rev-erb-alpha also abolishes normal rhythms of body temperature and brown adipose tissue activity. Gerhart-Hines et al. (2013) concluded that Rev-erb-alpha acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands.
Yu et al. (2013) showed that the transcription factor NFIL3 (605327) suppresses TH17 cell development by directly binding and repressing the ROR-gamma-t (RORC; 602943) promoter. NFIL3 links TH17 cell development to the circadian clock network through the transcription factor REV-ERB-alpha. Accordingly, TH17 lineage specification varies diurnally and is altered in Rev-erb-alpha-null mice. Light-cycle disruption elevated intestinal TH17 cell frequencies and increased susceptibility to inflammatory disease. Yu et al. (2013) concluded that lineage specification of this key immune cell is under direct circadian control.
Zhang et al. (2015) showed that Rev-erb-alpha modulated a cell-autonomous clock and metabolism by different genomic mechanisms. Clock control requires Rev-erb-alpha to bind directly to the genome at its cognate sites, where it competes with activating ROR transcription factors (see 601972). By contrast, Rev-erb-alpha regulates metabolic genes primarily by recruiting the HDAC3 (605166) corepressor to sites to which it is tethered by cell type-specific transcription factors. Thus, direct competition between Rev-erb-alpha and ROR transcription factors provides a universal mechanism for self-sustained control of the molecular clock across all tissues, whereas Rev-erb-alpha uses lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue.
Kim et al. (2018) found that in mice, circadian gene expression in the liver is controlled by rhythmic chromatin interactions between enhancers and promoters. Rev-erb-alpha, a core repressive transcription factor of the clock, opposes functional loop formation between Rev-erb-alpha-regulated enhancers and circadian target gene promoters by recruitment of the NCoR (600849)-HDAC3 corepressor complex, histone deacetylation, and eviction of the elongation factor BRD4 (608749) and the looping factor MED1 (604311). Thus, Kim et al. (2018) concluded that a repressive arm of the molecular clock operates by rhythmically modulating chromatin loops to control circadian gene 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.
Miyajima et al. (1989) found that, as in rat, human EAR1 and EAR7 are transcribed from opposite strands and share 1 exon. The EAR1 gene comprises 3 exons. Adelmant et al. (1996) showed that Rev-ERBA-alpha mediates transcriptional repression of its own promoter by binding to a Rev-ERBA-alpha responsive element.
Miyajima et al. (1989) stated that the human EAR1 and EAR7 genes reside on chromosome 17q21.
Liu et al. (2007) showed that PGC1-alpha (604517), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC1-alpha stimulates the expression of clock genes, notably Bma11 (602550) and Rev-erb-alpha, through coactivation of the ROR family of orphan nuclear receptors. Liu et al. (2007) concluded that they identified PGC1-alpha as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism.
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.
Adelmant, G., Begue, A., Stehelin, D., Laudet, V. A functional Rev-erb-alpha responsive element located in the human Rev-erb-alpha promoter mediates a repressing activity. Proc. Nat. Acad. Sci. 93: 3553-3558, 1996. [PubMed: 8622974] [Full Text: https://doi.org/10.1073/pnas.93.8.3553]
Chawla, A., Lazar, M. A. 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: 16265-16269, 1993. [PubMed: 8344913]
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]
Coste, H., Rodriguez, J. C. Orphan nuclear hormone receptor Rev-erb-alpha regulates the human apolipoprotein CIII promoter. J. Biol. Chem. 277: 27120-27129, 2002. [PubMed: 12021280] [Full Text: https://doi.org/10.1074/jbc.M203421200]
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]
Etchegaray, J.-P., Lee, C., Wade, P. A., Reppert, S. M. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421: 177-182, 2003. [PubMed: 12483227] [Full Text: https://doi.org/10.1038/nature01314]
Feng, D., Liu, T., Sun, Z., Bugge, A., Mullican, S. E., Alenghat, T., Liu, X. S., Lazar, M. A. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331: 1315-1319, 2011. [PubMed: 21393543] [Full Text: https://doi.org/10.1126/science.1198125]
Gerhart-Hines, Z., Feng, D., Emmett, M. J., Everett, L. J., Loro, E., Briggs, E. R., Bugge, A., Hou, C., Ferrara, C., Seale, P., Pryma, D. A., Khurana, T. S., Lazar, M. A. The nuclear receptor Rev-erb-alpha controls circadian thermogenic plasticity. Nature 503: 410-413, 2013. [PubMed: 24162845] [Full Text: https://doi.org/10.1038/nature12642]
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]
Kim, Y. H., Marhon, S. A., Zhang, Y., Steger, D. J., Won, K.-J., Lazar, M. A. Rev-erb-alpha dynamically modulates chromatin looping to control circadian gene transcription. Science 359: 1274-1277, 2018. [PubMed: 29439026] [Full Text: https://doi.org/10.1126/science.aao6891]
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]
Lazar, M. A., Hodin, R. A., Darling, D. S., Chin, W. W. A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA-alpha transcriptional unit. Molec. Cell. Biol. 9: 1128-1136, 1989. [PubMed: 2542765] [Full Text: https://doi.org/10.1128/mcb.9.3.1128-1136.1989]
Liu, C., Li, S., Liu, T., Borjigin, J., Lin, J. D. Transcriptional coactivator PGC-1-alpha integrates the mammalian clock and energy metabolism. Nature 447: 477-481, 2007. [PubMed: 17476214] [Full Text: https://doi.org/10.1038/nature05767]
Miyajima, N., Horiuchi, R., Shibuya, S., Matsubara, K., Toyoshima, K., Yamamoto, T. Two erbA homologs encoding proteins with different T(3) binding capacities are transcribed from opposite DNA strands of the same genetic locus. Cell 57: 31-39, 1989. [PubMed: 2539258] [Full Text: https://doi.org/10.1016/0092-8674(89)90169-4]
Preitner, N., Damiola, F., Lopez-Molina, L., Zakany, J., Duboule, D., Albrecht, U., Schibler, U. The orphan nuclear receptor REV-ERB-alpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110: 251-260, 2002. [PubMed: 12150932] [Full Text: https://doi.org/10.1016/s0092-8674(02)00825-5]
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., Chen, W., Adachi, A., Wakamatsu, H., Hayashi, S., Takasugi, T., Nagano, M., Nakahama, K., Suzuki, Y., Sugano, S., Iino, M., Shigeyoshi, Y., Hashimoto, S. A transcription factor response element for gene expression during circadian night. Nature 418: 534-539, 2002. [PubMed: 12152080] [Full Text: https://doi.org/10.1038/nature00906]
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]
Yin, L., Wang, J., Klein, P. S., Lazar, M. A. Nuclear receptor Rev-erb-alpha is a critical lithium-sensitive component of the circadian clock. Science 311: 1002-1005, 2006. [PubMed: 16484495] [Full Text: https://doi.org/10.1126/science.1121613]
Yin, L., Wu, N., Curtin, J. C., Qatanani, M., Szwergold, N. R., Reid, R. A., Waitt, G. M., Parks, D. J., Pearce, K. H., Wisely, G. B., Lazar, M. A. Rev-erb-alpha, a heme sensor that coordinates metabolic and circadian pathways. Science 318: 1786-1789, 2007. [PubMed: 18006707] [Full Text: https://doi.org/10.1126/science.1150179]
Yu, X., Rollins, D., Ruhn, K. A., Stubblefield, J. J., Green, C. B., Kashiwada, M., Rothman, P. B., Takahashi, J. S., Hooper, L. V. TH17 cell differentiation is regulated by the circadian clock. Science 342: 727-730, 2013. [PubMed: 24202171] [Full Text: https://doi.org/10.1126/science.1243884]
Zhang, Y., Fang, B., Emmett, M. J., Damle, M., Sun, Z., Feng, D., Armour, S. M., Remsberg, J. R., Jager, J., Soccio, R. E., Steger, D. J., Lazar, M. A. Discrete functions of nuclear receptor Rev-erb-alpha couple metabolism to the clock. Science 348: 1488-1492, 2015. [PubMed: 26044300] [Full Text: https://doi.org/10.1126/science.aab3021]
Zhao, Q., Khorasanizadeh, S., Miyoshi, Y., Lazar, M. A., Rastinejad, F. Structural elements of an orphan nuclear receptor-DNA complex. Molec. Cell 1: 849-861, 1998. [PubMed: 9660968] [Full Text: https://doi.org/10.1016/s1097-2765(00)80084-2]