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Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq]

ABSTRACT: The circadian clock acts at the genomic level to coordinate internal behavioral and physiologic rhythms via the CLOCK-BMAL transcriptional heterodimer. Although the nuclear receptors REV-ERBα and β have been proposed to contribute to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential we generated comparative cistromes of both Rev-erb isoforms, which revealed shared recognition at over ~50% of their total sites and extensive overlap with the master clock regulator Bmal. While Rev-erbα has been shown to directly regulate Bmal expression, the cistromic analysis reveals a more profound connection between Bmal and Rev-erbα and β regulatory circuits than previously suspected. Genes within the intersection of the Bmal and Rev-erb cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erbα/β function by creating double-knockout mice (DKOs) profoundly disrupted circadian expression of core clock and lipid homeostatic genes. As a result, DKOs show strikingly altered circadian wheel-running behavior and deregulated lipid metabolism. These data reveal an integral role of Rev-erbα/β in clock function as well as provide a cistromic basis for the integration of circadian rhythm and metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE34019 | GEO | 2012/03/29

SECONDARY ACCESSION(S): PRJNA156459

REPOSITORIES: GEO

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Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq]

Project description:The circadian clock acts at the genomic level to coordinate internal behavioral and physiologic rhythms via the CLOCK-BMAL transcriptional heterodimer. Although the nuclear receptors REV-ERBα and β have been proposed to contribute to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential we generated comparative cistromes of both Rev-erb isoforms, which revealed shared recognition at over ~50% of their total sites and extensive overlap with the master clock regulator Bmal. While Rev-erbα has been shown to directly regulate Bmal expression, the cistromic analysis reveals a more profound connection between Bmal and Rev-erbα and β regulatory circuits than previously suspected. Genes within the intersection of the Bmal and Rev-erb cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erbα/β function by creating double-knockout mice (DKOs) profoundly disrupted circadian expression of core clock and lipid homeostatic genes. As a result, DKOs show strikingly altered circadian wheel-running behavior and deregulated lipid metabolism. These data reveal an integral role of Rev-erbα/β in clock function as well as provide a cistromic basis for the integration of circadian rhythm and metabolism. Identification of Reverb alpha and Reverb beta binding sites in mouse liver at ZT8

2012-03-28 | E-GEOD-34019 | biostudies-arrayexpress

Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [Expression array]

2012-03-29 | GSE34018 | GEO

Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [Expression array]

Project description:The circadian clock acts at the genomic level to coordinate internal behavioral and physiologic rhythms via the CLOCK-BMAL transcriptional heterodimer. Although the nuclear receptors REV-ERB? and ? have been proposed to contribute to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential we generated comparative cistromes of both Rev-erb isoforms, which revealed shared recognition at over ~50% of their total sites and extensive overlap with the master clock regulator Bmal. While Rev-erb? has been shown to directly regulate Bmal expression, the cistromic analysis reveals a more profound connection between Bmal and Rev-erb? and ? regulatory circuits than previously suspected. Genes within the intersection of the Bmal and Rev-erb cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb?/? function by creating double-knockout mice (DKOs) profoundly disrupted circadian expression of core clock and lipid homeostatic genes. As a result, DKOs show strikingly altered circadian wheel-running behavior and deregulated lipid metabolism. These data reveal an integral role of Rev-erb?/? in clock function as well as provide a cistromic basis for the integration of circadian rhythm and metabolism. Total RNA was obtained from livers of wild-type and Liver-specific Reverb alpha/beta double knockout mice at ZT 0, 4, 8, 12, 16, and 20.

2012-03-28 | E-GEOD-34018 | biostudies-arrayexpress

Myocardial Rev-erb regulates metabolic diurnal rhythm in heart failure

Project description:Rev-erbα/β are druggable components of the molecular circadian clock. Rev-erb agonists can mitigate pressure overload-induced cardiac hypertrophy and myocardial infarction in mice, while Rev-erb antagonist increases myocardial ischemia-reperfusion tolerance ex vivo at the sleep-to-wake transitionHow cardiac Rev-erb regulates heart function has not been studied in vivo. ChIP-seq of Rev-erbα in the heart confirmed the robust diurnal rhythmicity of Rev-erbα genome binding with about 5 times more binding at ZT9 than at ZT21.

2021-12-08 | GSE153150 | GEO

Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function

Project description:This SuperSeries is composed of the following subset Series: GSE34018: Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [Expression array] GSE34019: Integral roles for Rev-erb alpha and Rev-erb beta in the circadian clock function [ChIP_seq] Refer to individual Series

2012-03-28 | E-GEOD-34020 | biostudies-arrayexpress

SR9009 has REV-ERB-independent effects on cell proliferation and metabolism

Project description:The nuclear receptors (NRs) REV-ERBα and β, encoded by Nr1d1 and Nr1d2, link circadian rhythms and metabolism. REV-ERB lacks the canonical NR activation domain, and thus functions as a transcriptional repressor. Like other NRs, REV-ERBs can be regulated by ligands, including naturally occurring heme, which potentiate their repressive activity. Attempts to pharmacologically target REV-ERBs by the use of putatively specific synthetic agonists, particularly SR90096, have suggested a wide range of beneficial effects in healthy as well as diseased animal models and cell systems. For instance, Sulli et al. recently reported that REV-ERB activation by SR9009 is specifically lethal to cancer (stem) cells but not other cell types. Because REV-ERBs are core components of the molecular clock, the results were interpreted as a link between the body’s circadian timekeeping system and cancer. Moreover, increased energy expenditure after SR9009 administration decreases obesity in mice, and the reported activity of SR9009 as an exercise mimetic in skeletal muscle have resulted in online sales of the compound as a performance-enhancing drug, with advertisements reassuringly highlighting REV-ERBs as the molecular target (https://www.evolutionary.org/stenabolic-sr9009-review; https://www.simplyanabolics.com/sarms/sr9009-stenabolic/).

2019-05-08 | GSE123312 | GEO

Myocardial Rev-erb-mediated diurnal metabolic rhythm( Part1/3)

Project description:Agonists and antagonists of nuclear receptor Rev-erbα/β, key components of the circadian clock, can benefit the heart. Here, we show that mice with cardiomyocyte-specific knockout (KO) of Rev-erbα/β display progressive cardiac dilation and lethal heart failure. Inducible ablation of Rev-erbα/β in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, particularly in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, particularly in the dark cycle. These findings delineate temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism.

2021-09-10 | ST001915 | MetabolomicsWorkbench

Myocardial Rev-erb-mediated diurnal metabolic rhythm (Part 2/3)

2021-09-10 | ST001916 | MetabolomicsWorkbench

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα deletion in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deficient enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

2023-08-09 | PXD043877 | Pride

Rev-erb(alpha) and (beta) Coordinately Protect the Circadian Clock and Normal Metabolic Function

Project description:We report the genomic regions enriched for Rev-erb(beta) binding in WT mouse liver, in addition to the false positive regions enriched by ChIP for Rev-erb(alpha) in Rev-erb(alpha) KO liver. In conjunction with previously published data for Rev-erb(alpha) in GSE26345 (GSM647029, GSM647033, and GSM647034), we report the common and subtype specific cistromes for Rev-erb using a quantitative analysis method.

2012-03-09 | GSE36375 | GEO

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