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

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-a and REV-ERB-b have been proposed to form an accessory feedback loop that contributes to clock function 1,2 , 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-a has been shown to regulate Bmal1 expression directly 1,2 , our cistromic analysis reveals a more profound connection between BMAL1 and the REV-ERB-a and REV-ERB-b genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-a and REV-ERB-b cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb-a and Rev-erb-b function by creating doubleknockout mice profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, double-knockout mice show markedly altered circadian wheelrunning behaviour and deregulated lipid metabolism. These data now unite REV-ERB-a and REV-ERB-b 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.