The Orphan Nuclear Receptor Rev-erbα Recruits the N-CoR/Histone Deacetylase 3 Corepressor to Regulate the Circadian Bmal1 Gene

William Penn University, Filadelfia, Pennsylvania, United States
Molecular Endocrinology (Impact Factor: 4.02). 07/2005; 19(6):1452-9. DOI: 10.1210/me.2005-0057
Source: PubMed


Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The orphan nuclear receptor Rev-erbalpha has recently been implicated as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of circadian rhythm in mammals, is negatively correlated with Rev-erbalpha mRNA level, but the molecular mechanism underlying this regulation is largely unknown. Here we show that Rev-erbalpha dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human. Rev-erbalpha directly binds to the mouse Bmal1 promoter and recruits the endogenous nuclear receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex, in association with a decrease in histone acetylation. The endogenous N-CoR/HDAC3 complex is also associated with the endogenous Bmal1 promoter in human HepG2 liver cells, where a reduction in cellular HDAC3 level markedly increases the expression of Bmal1 mRNA. These data demonstrate a new function for the N-CoR/HDAC3 complex in regulating the expression of genes involved in circadian rhythm by functioning as corepressor for Rev-erbalpha.

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Available from: Mitchell A Lazar, Jul 08, 2015
    • "It is widely accepted that the nuclear receptor REV- ERBa is an important clock component of integrating circadian clock and many physiological processes such as adipogenesis, immunity, and lipid metabolism (Feng et al., 2011; Fontaine et al., 2003; Gibbs et al., 2012; Laitinen et al., 2005; Preitner et al., 2002; Triqueneaux et al., 2004; Yin & Lazar, 2005). REV-ERBa usually functions as a transcriptional repressor for the lack of activation function (AF-2) domain present at the Cterminal of the ligand-binding domain (Crumbley & Burris, 2011; Phelan et al., 2010; Yin & Lazar, 2005). "
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    ABSTRACT: The nuclear receptor REV-ERBα links circadian rhythms and numerous physiological processes, but its physiological role in ovaries remains largely unknown. The aim of this study was to determine the potential role of REV-ERBα in the regulation of the transcription of its putative target genes in granulosa cells (GCs) prepared from Per2-destablized luciferase (dLuc) reporter gene transgenic rats. Alas1, Ppargc1a, and Il6 were chosen as representatives for genes analysis. A real-time monitoring system of Per2 promoter activity was performed to detect Per2-dLuc circadian oscillations. Two agonists (GSK4112, heme) and an antagonist (SR8278) of REV-ERBα as well as Rev-erbα siRNA knockdown were used to identify its target genes. Clear Per2-dLuc circadian oscillations were generated in matured GCs after synchronization with GSK4112 or SR8278. GSK4112 treatment lengthened and SR8278 treatment shortened the period of circadian oscillations in matured GCs stimulated with or without luteinizing hormone (LH). GSK4112 showed an inhibitory effect on the amplitude of circadian oscillations and caused an arrhythmic expression of canonical clock genes. SR8278 also had a subtle effect on their daily expression profiles, but the treatment resulted only in the arrhythmic expression of Rev-erbα. These findings indicate the functional biological activity of REV-ERBα in response to its ligands. Its natural ligand heme further elongated the period of circadian oscillations and alleviated their amplitudes in GCs cultured with LH. Heme treatment also repressed the expressions of clock genes, Alas1, Il6, and Ppargc1a. Rev-erbα knockdown up-regulated these transcript levels. Collectively, these data extend the recent finding to rat GCs and demonstrate that REV-ERBα represses the expressions of Alas1, Ppargc1a, and Il6, providing novel insights into the physiological significance of REV-ERBα in ovarian circadian oscillators.
    Chronobiology International 06/2015; 32(6):739-749. DOI:10.3109/07420528.2015.1042582 · 3.34 Impact Factor
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    • "REV-ERBa represses target gene transcription by recruiting histone deacetylase 3 (HDAC3) complexes to the promoter region (Yin and Lazar, 2005; Feng et al., 2011). Thus, we examined HDAC3 recruitment to the TH promoter region and its subsequent histone acetylation state. "
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    ABSTRACT: The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanisms are still unclear. Here, we show that the circadian nuclear receptor REV-ERBα, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erbα gene or pharmacological inhibition of REV-ERBα activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERBα repressed tyrosine hydroxylase (TH) gene transcription via competition with nuclear receptor-related 1 protein (NURR1), another nuclear receptor crucial for dopaminergic neuronal function, thereby driving circadian TH expression through a target-dependent antagonistic mechanism. In conclusion, we identified a molecular connection between the circadian timing system and mood regulation, suggesting that REV-ERBα could be targeting in the treatment of circadian rhythm-related affective disorders.
    Cell 05/2014; 157(4):858-68. DOI:10.1016/j.cell.2014.03.039 · 32.24 Impact Factor
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    • "Rev-erbα represses transcription of several genes that control these cellular processes. For instance, Rev-erbα is part of the core clock machinery and represses the expression of the transcription factors BMAL1 and CLOCK [4,5], key components of the mammalian circadian clock, and regulators of the circadian genes PERIOD and CRY [1]. In addition, Rev-erbα shows a strong circadian pattern in many tissues, and is important in the circadian control of metabolism [2]. "
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    ABSTRACT: The nuclear receptor Rev-erbα has been implicated as a major regulator of the circadian clock and integrates circadian rhythm and metabolism. Rev-erbα controls circadian oscillations of several clock genes and Rev-erbα protein degradation is important for maintenance of the circadian oscillations and also for adipocyte differentiation. Elucidating the mechanisms that regulates Rev-erbα stability is essential for our understanding of these processes. Here we report that the protein Deleted in Breast Cancer 1 (DBC1) is a novel regulator of Rev-erbα. Rev-erbα and DBC1 interact in cells and in vivo, and DBC1 modulates the Rev-erbα repressor function. Depletion of DBC1 by siRNA in cells or in DBC1 knockout mice produced a marked decrease in Rev-erbα protein levels, but not in mRNA levels. In contrast, DBC1 overexpression significantly enhanced Rev-erbα protein stability by preventing its ubiquitination and degradation. The regulation of Rev-erbα protein levels and function by DBC1 depends on both the N-terminal and C-terminal domains of DBC1. More importantly, in cells depleted of DBC1 there was a dramatic decrease in circadian oscillations of both Rev-erbα and Bmal1. In summary, our data identifies DBC1 as an important regulator of the circadian receptor Rev-erbα and proposes that Rev-erbα could be involved in mediating some of the physiological effects of DBC1.
    Biochemical Journal 02/2013; 451(Pt 3). DOI:10.1042/BJ20121085 · 4.40 Impact Factor
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