Optimized chemical probes for REV-ERB?.
Ontology highlight
ABSTRACT:
SUBMITTER: Trump RP
PROVIDER: S-EPMC4347663 | biostudies-literature | 2013 Jun
REPOSITORIES: biostudies-literature
Publications
Optimized chemical probes for REV-ERBα.
Trump Ryan P RP Bresciani Stefano S Cooper Anthony W J AW Tellam James P JP Wojno Justyna J Blaikley John J Orband-Miller Lisa A LA Kashatus Jennifer A JA Boudjelal Mohamed M Dawson Helen C HC Loudon Andrew A Ray David D Grant Daniel D Farrow Stuart N SN Willson Timothy M TM Tomkinson Nicholas C O NC
Journal of medicinal chemistry 20130523 11
REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either iv ...[more]
Similar Datasets
Project description:The circadian clock acts at the genomic level to coordinate internal behavioural and physiological rhythms via the CLOCK-BMAL1 transcriptional heterodimer. Although the nuclear receptors REV-ERB-? and REV-ERB-? have been proposed to form an accessory feedback loop that contributes to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential, we determined the genome-wide cis-acting targets (cistromes) 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-? has been shown to regulate Bmal1 expression directly, our cistromic analysis reveals a more profound connection between BMAL1 and the REV-ERB-? and REV-ERB-? genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-? and REV-ERB-? cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb-? and Rev-erb-? 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 show markedly altered circadian wheel-running behaviour and deregulated lipid metabolism. These data now unite REV-ERB-? and REV-ERB-? with PER, CRY and other components of the principal feedback loop that drives circadian expression and indicate a more integral mechanism for the coordination of circadian rhythm and metabolism.
| S-EPMC3367514 | biostudies-literature
Project description:The circadian clock regulates behavioural and physiological processes in a 24-h cycle. The nuclear receptors REV-ERB? and REV-ERB? are involved in the cell-autonomous circadian transcriptional/translational feedback loops as transcriptional repressors. A number of studies have also demonstrated a pivotal role of REV-ERBs in regulation of metabolic, neuronal, and inflammatory functions including bile acid metabolism, lipid metabolism, and production of inflammatory cytokines. Given the multifunctional role of REV-ERBs, it is important to elucidate the mechanism through which REV-ERBs exert their functions. To this end, we established a Rev-erb?/Rev-erb? double-knockout mouse embryonic stem (ES) cell model and analyzed the circadian clock and clock-controlled output gene expressions. A comprehensive mRNA-seq analysis revealed that the double knockout of both Rev-erb? and Rev-erb? does not abrogate expression rhythms of E-box-regulated core clock genes but drastically changes a diverse set of other rhythmically-expressed output genes. Of note, REV-ERB?/? deficiency does not compromise circadian expression rhythms of PER2, while REV-ERB target genes, Bmal1 and Npas2, are significantly upregulated. This study highlight the relevance of REV-ERBs as pivotal output mediators of the mammalian circadian clock.
| S-EPMC6629614 | biostudies-literature
Project description:The nuclear receptor Rev-erb? regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Rev-erb? together with closely related Rev-erb? has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erb? mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erb?, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.
| S-EPMC3323877 | biostudies-literature
Project description:The nuclear receptors REV-ERB? and REV-ERB? have been demonstrated to be core members of the circadian clock and participate in the regulation of a diverse set of metabolic functions. Due to their overlapping tissue expression patterns and gene expression profiles, REV-ERB? is thought to be redundant to REV-ERB?. Recent work has highlighted REV-ERB?'s role in the regulation of skeletal muscle oxidative capacity and mitochondrial biogenesis. Considering the similarity between the REV-ERBs and the hypothesized overlap in function, we sought to determine whether REV-ERB?-deficiency presented with a similar skeletal muscle phenotype as REV-ERB?-deficiency. Ectopic overexpression in C2C12 cells demonstrated that REV-ERB? drives mitochondrial biogenesis and the expression of genes involved in fatty acid oxidation. Intriguingly, knock down of REV-ERB? in C2C12 cultures also resulted in mitochondrial biogenesis and increased expression of genes involved in fatty acid ?-oxidation. To determine whether these effects occurred in vivo, we examined REV-ERB?-deficient mice and observed a similar increase in expression of genes involved in mitochondrial biogenesis and fatty acid ?-oxidation. Consistent with these results, REV-ERB?-deficient mice exhibited an altered metabolic phenotype compared to wild-type littermate controls when measured by indirect calorimetry. This likely compensated for the increased food consumption that occurred, possibly aiding in the maintenance of their weight over time. Since feeding behaviors are a direct circadian output, this study suggests that REV-ERB? may have more subtle effects on circadian behaviors than originally identified. Furthermore, these data implicate REV-ERB? in the control of skeletal muscle metabolism and energy expenditure and suggest that development of REV-ERB? versus REV-ERB? selective ligands may have therapeutic utility in the treatment of metabolic syndrome.
| S-EPMC5933789 | biostudies-literature
Project description:Rev-erb alpha belongs to the nuclear receptor superfamily, which contains receptors for steroids, thyroid hormones, retinoic acid, and vitamin D, as well as "orphan" receptors. No ligand has been found for Rev-erb alpha to date, making it one of these orphan receptors. Similar to some other orphan receptors, Rev-erb alpha has been shown to bind DNA as a monomer on a specific sequence called a Rev-erb alpah responsive element (RevRE), but its transcriptional activity remains unclear. In this paper, we characterize a functional RevRE located in the human Rev-erb alpha promoter itself. We also present evidence that (i) Rev-erb alpha mediates transcriptional repression of its own promoter in vitro, (ii) this repressing effect strictly depends on the binding of Rev-erb alpha to its responsive element and is transferable to a heterologous promoter; and (iii) Rev-erb alpha binds to this responsive sequence as a homodimer.
| S-EPMC39648 | biostudies-other
Project description:ROR?t is well recognized as the lineage-defining transcription factor for T helper 17 (TH17) cell development. However, the cell-intrinsic mechanisms that negatively regulate TH17 cell development and autoimmunity remain poorly understood. Here, we demonstrate that the transcriptional repressor REV-ERB? is exclusively expressed in TH17 cells, competes with ROR?t for their shared DNA consensus sequence, and negatively regulates TH17 cell development via repression of genes traditionally characterized as ROR?t dependent, including Il17a. Deletion of REV-ERB? enhanced TH17-mediated pro-inflammatory cytokine expression, exacerbating experimental autoimmune encephalomyelitis (EAE) and colitis. Treatment with REV-ERB-specific synthetic ligands, which have similar phenotypic properties as ROR? modulators, suppressed TH17 cell development, was effective in colitis intervention studies, and significantly decreased the onset, severity, and relapse rate in several models of EAE without affecting thymic cellularity. Our results establish that REV-ERB? negatively regulates pro-inflammatory TH17 responses in vivo and identifies the REV-ERBs as potential targets for the treatment of TH17-mediated autoimmune diseases.
| S-EPMC6400287 | biostudies-literature
Project description:The nuclear receptor REV-ERB? is a potent, constitutive transcriptional repressor critical for the regulation of key circadian and metabolic genes. Recently, REV-ERB?'s involvement in learning, neurogenesis, mood, and dopamine turnover was demonstrated suggesting a specific role in central nervous system functioning. We have previously shown that the brain expression of several core clock genes, including Rev-erb?, is modulated by sleep loss. We here test the consequences of a loss of REV-ERB? on the homeostatic regulation of sleep.EEG/EMG signals were recorded in Rev-erb? knockout (KO) mice and their wild type (WT) littermates during baseline, sleep deprivation, and recovery. Cortical gene expression measurements after sleep deprivation were contrasted to baseline.Although baseline sleep/wake duration was remarkably similar, KO mice showed an advance of the sleep/wake distribution relative to the light-dark cycle. After sleep onset in baseline and after sleep deprivation, both EEG delta power (1-4 Hz) and sleep consolidation were reduced in KO mice indicating a slower increase of homeostatic sleep need during wakefulness. This slower increase might relate to the smaller increase in theta and gamma power observed in the waking EEG prior to sleep onset under both conditions. Indeed, the increased theta activity during wakefulness predicted delta power in subsequent NREM sleep. Lack of Rev-erb? increased Bmal1, Npas2, Clock, and Fabp7 expression, confirming the direct regulation of these genes by REV-ERB? also in the brain.Our results add further proof to the notion that clock genes are involved in sleep homeostasis. Because accumulating evidence directly links REV-ERB? to dopamine signaling the altered homeostatic regulation of sleep reported here are discussed in that context.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2012-03-29 | GSE34020 | GEO
Project description:Chikungunya virus (CHIKV), an alphavirus spread by Aedes spp. mosquitos, causes severe inflammation and joint pain, progressing to a chronic arthralgic state in a subset of patients. Due to recent global epidemics of CHIKV and the potential for related viruses to cause outbreaks, multiple approaches to combat these pathogens are of interest. We report that SR9009, a synthetic agonist of nuclear receptors Rev-erb ?/?, inhibits replication of multiple alphaviruses (CHIKV and O'nyong'nyong virus) mainly by suppressing structural protein synthesis, although viral RNA accumulation is relatively unimpeded. Furthermore, SR9009 reduces the inflammatory response in cultured murine macrophages exposed to alphavirus-infected cells.
| S-EPMC6293476 | biostudies-literature
Project description:Circadian oscillation of body temperature is a basic, evolutionarily conserved feature of mammalian biology. In addition, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure. However, the mechanism responsible for coordinating daily body temperature rhythm and adaptability to environmental challenges is unknown. Here we show that the nuclear receptor Rev-erb? (also known as Nr1d1), a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue (BAT) function. Mice exposed to cold fare considerably better at 05:00 (Zeitgeber time?22) when Rev-erb? is barely expressed than at 17:00 (Zeitgeber time?10) when Rev-erb? is abundant. Deletion of Rev-erb? markedly improves cold tolerance at 17:00, indicating that overcoming Rev-erb?-dependent repression is a fundamental feature of the thermogenic response to cold. Physiological induction of uncoupling protein 1 (Ucp1) by cold temperatures is preceded by rapid downregulation of Rev-erb? in BAT. Rev-erb? represses Ucp1 in a brown-adipose-cell-autonomous manner and BAT Ucp1 levels are high in Rev-erb?-null mice, even at thermoneutrality. Genetic loss of Rev-erb? also abolishes normal rhythms of body temperature and BAT activity. Thus, Rev-erb? acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands.
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