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 function1,2, 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-α has been shown to regulate Bmal1 expression directly1,2, 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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We thank S. Kaufman, J. Alvarez, E. Banayo, H. Juguilon, S. Jacinto and H. Le for technical assistance; and L. Ong and S. Ganley for administrative assistance. We also thank L. Pei for discussion. R.M.E is an Investigator of the Howard Hughes Medical Institute at The Salk Institute for Biological Studies and March of Dimes Chair in Molecular and Developmental Biology. H.C. is a recipient of National Research Service Award (T32-HL007770). This work was supported by National Institutes of Health Grants (DK062434, DK057978, DK090962, DK091618 and HL105278), National Health and Medical Research Council of Australia Project Grants (NHMRC 512354 and 632886), the Helmsley Charitable Trust, the Glenn Foundation and the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
This file contains Supplementary Materials and Methods, Supplementary Figure 1-8 and Supplementary Tables 1-7. This file was replaced on 26 September 2012 to correct errors in Supplementary Figure 4. (PDF 3369 kb)
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Cho, H., Zhao, X., Hatori, M. et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 485, 123–127 (2012). https://doi.org/10.1038/nature11048
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