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GENE REGULATION. Discrete functions of nuclear receptor Rev-erb? couple metabolism to the clock.

ABSTRACT: Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erb?, a transcription factor (TF) that functions both as a core repressive component of the cell-autonomous clock and as a regulator of metabolic genes. Here, we show that Rev-erb? modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erb? to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erb? regulates metabolic genes primarily by recruiting the HDAC3 co-repressor to sites to which it is tethered by cell type-specific transcription factors. Thus, direct competition between Rev-erb? and ROR TFs provides a universal mechanism for self-sustained control of the molecular clock across all tissues, whereas Rev-erb? uses lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4613749 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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GENE REGULATION. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock.

Zhang Yuxiang Y Fang Bin B Emmett Matthew J MJ Damle Manashree M Sun Zheng Z Feng Dan D Armour Sean M SM Remsberg Jarrett R JR Jager Jennifer J Soccio Raymond E RE Steger David J DJ Lazar Mitchell A MA

Science (New York, N.Y.) 20150604 6242

Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erbα, a transcription factor (TF) that functions both as a core repressive component of the cell-autonomous clock and as a regulator of metabolic genes. Here, we show that Rev-erbα modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erbα to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erbα regulates metab ...[more]

PMID: 26044300

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Project description:Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα-/- mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα-/- mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα-/- microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα-/- mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα-/- mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

Dataset Information

GENE REGULATION. Discrete functions of nuclear receptor Rev-erb? couple metabolism to the clock.

Publications

GENE REGULATION. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock.

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