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

Nature volume 485, pages 123–127 (2012)Cite this article

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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 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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Figure 1: Cistromic analyses of REV-ERB-α and REV-ERB-β in liver.
Figure 2: Circadian gene expression of many canonical core clock genes and output genes are disrupted in livers of Rev-erb-α lox/lox Rev-erb-β lox/lox albumin-Cre (L-DKO) mice.
Figure 3: Broad disruption of circadian transcriptome in the absence of Rev-erb-α and Rev-erb-β.
Figure 4: Loss of both Rev-erb-α and Rev-erb-β results in disrupted circadian wheel-running behaviour and metabolic shift.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray and ChIP-seq data sets have been deposited in the NCBI Gene Expression Omnibus with the accession number GSE34020.

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Acknowledgements

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.

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Authors and Affiliations

  1. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Han Cho, Xuan Zhao, Ruth T. Yu, Grant D. Barish, Ling-Wa Chong, Annette R. Atkins, Michael Downes & Ronald M. Evans

  2. Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Megumi Hatori, Luciano DiTacchio & Satchidananda Panda

  3. Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA,

    Michael T. Lam & Christopher K. Glass

  4. The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, 2145, New South Wales, Australia

    Christopher Liddle

  5. Ecole Polytechnique Fédérale in Lausanne CH-1015, Lausanne, Switzerland

    Johan Auwerx

  6. Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Ronald M. Evans

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Contributions

X.Z., G.D.B., R.T.Y., M.D. and C.L. performed and/or analysed the results from ChIP-seq. R.T.Y., M.D., M.T.L. and C.K.G. performed and/or analysed the results from the microarray experiment. M.H., L.D. and S.P. performed and/or analysed the wheel-running assay and the real-time luciferase assay. J.A. performed gene targeting. H.C. and L.-W.C. performed all experiments. H.C. and R.M.E. designed all experiments, analysed all results and H.C., R.T.Y., M.D., A.R.A., S.P. and R.M.E. wrote the manuscript.

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Correspondence to Ronald M. Evans.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

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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