Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-05

AUTHORS

Han Cho, Xuan Zhao, Megumi Hatori, Ruth T. Yu, Grant D. Barish, Michael T. Lam, Ling-Wa Chong, Luciano DiTacchio, Annette R. Atkins, Christopher K. Glass, Christopher Liddle, Johan Auwerx, Michael Downes, Satchidananda Panda, Ronald M. Evans

ABSTRACT

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-α and REV-ERB-β 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-α has been shown to regulate Bmal1 expression directly, our cistromic analysis reveals a more profound connection between BMAL1 and the REV-ERB-α and REV-ERB-β genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-α and REV-ERB-β cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb-α and Rev-erb-β 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-α and REV-ERB-β 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. More... »

PAGES

123

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature11048

DOI

http://dx.doi.org/10.1038/nature11048

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1014253136

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22460952


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