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

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.

References

  1. 1

    Preitner, N. et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002)

    CAS  Article  Google Scholar 

  2. 2

    Liu, A. C. et al. Redundant function of REV-ERBα and β and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS Genet. 4, e1000023 (2008)

    Article  Google Scholar 

  3. 3

    Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998)

    ADS  CAS  Article  Google Scholar 

  4. 4

    DeBruyne, J. P., Weaver, D. R. & Reppert, S. M. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nature Neurosci. 10, 543–545 (2007)

    CAS  Article  Google Scholar 

  5. 5

    Zheng, B. et al. Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105, 683–694 (2001)

    CAS  Article  Google Scholar 

  6. 6

    van der Horst, G. T. et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630 (1999)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Vitaterna, M. H. et al. Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc. Natl Acad. Sci. USA 96, 12114–12119 (1999)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Levi, F. & Schibler, U. Circadian rhythms: mechanisms and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 47, 593–628 (2007)

    CAS  Article  Google Scholar 

  9. 9

    Ukai-Tadenuma, M. et al. Delay in feedback repression by cryptochrome 1 is required for circadian clock function. Cell 144, 268–281 (2011)

    CAS  Article  Google Scholar 

  10. 10

    Yang, X. et al. Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801–810 (2006)

    CAS  Article  Google Scholar 

  11. 11

    Feng, D. et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 1315–1319 (2011)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Le Martelot, G. et al. REV-ERBα participates in circadian SREBP signaling and bile acid homeostasis. PLoS Biol. 7, e1000181 (2009)

    Article  Google Scholar 

  14. 14

    Rey, G. et al. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biol. 9, e1000595 (2011)

    CAS  Article  Google Scholar 

  15. 15

    Chomez, P. et al. Increased cell death and delayed development in the cerebellum of mice lacking the rev-erbAα orphan receptor. Development 127, 1489–1498 (2000)

    CAS  PubMed  Google Scholar 

  16. 16

    Postic, C. et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J. Biol. Chem. 274, 305–315 (1999)

    CAS  Article  Google Scholar 

  17. 17

    Oster, H., Damerow, S., Hut, R. A. & Eichele, G. Transcriptional profiling in the adrenal gland reveals circadian regulation of hormone biosynthesis genes and nucleosome assembly genes. J. Biol. Rhythms 21, 350–361 (2006)

    CAS  Article  Google Scholar 

  18. 18

    Miller, B. H. et al. Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc. Natl Acad. Sci. USA 104, 3342–3347 (2007)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Hatanaka, F. et al. Genome-wide profiling of the core clock protein BMAL1 targets reveals a strict relationship with metabolism. Mol. Cell. Biol. 30, 5636–5648 (2010)

    CAS  Article  Google Scholar 

  20. 20

    Kornmann, B. et al. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol. 5, e34 (2007)

    Article  Google Scholar 

  21. 21

    Hayashi, S. & McMahon, A. P. Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev. Biol. 244, 305–318 (2002)

    CAS  Article  Google Scholar 

  22. 22

    Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000)

    CAS  Article  Google Scholar 

  23. 23

    Huang, W. et al. Circadian rhythms, sleep, and metabolism. J. Clin. Invest. 121, 2133–2141 (2011)

    CAS  Article  Google Scholar 

  24. 24

    Raspé, E. et al. Identification of Rev-erbα as a physiological repressor of apoC-III gene transcription. J. Lipid Res. 43, 2172–2179 (2002)

    Article  Google Scholar 

  25. 25

    Kumar, N. et al. Regulation of adipogenesis by natural and synthetic REV-ERB ligands. Endocrinology 151, 3015–3025 (2010)

    CAS  Article  Google Scholar 

  26. 26

    Gibbs, J. E. et al. The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc. Natl Acad. Sci. USA 109, 582–587 (2012)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Huang, W., Ramsey, K. M., Marcheva, B. & Bass, J. Circadian rhythms, sleep, and metabolism. J. Clin. Invest. 121, 2133–2141 (2011)

    CAS  Article  Google Scholar 

  28. 28

    Lamia, K. A. et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437–440 (2009)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Lamia, K. A. et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480, 552–556 (2011)

    ADS  CAS  Article  Google Scholar 

  30. 30

    Kojetin, D., Wang, Y., Kamenecka, T. M. & Burris, T. P. Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS Chem. Biol. 6, 131–134 (2011)

    CAS  Article  Google Scholar 

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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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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.

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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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