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

H Cho, X Zhao, M Hatori, RT Yu, GD Barish, MT Lam… - Nature, 2012 - nature.com
H Cho, X Zhao, M Hatori, RT Yu, GD Barish, MT Lam, LW Chong, L DiTacchio, AR Atkins…
Nature, 2012nature.com
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 …
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.
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