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Cited by 1,037Circadian rhythm and melatoninPeroxisome Proliferator-Activated ReceptorsSirtuins and Resveratrol in Medicine

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

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Cho, Han, Zhao, Xuan, Hatori, Megumi, Yu, Ruth T., Barish, Grant D., Lam, Michael T., Chong, Ling-Wa, DiTacchio, Luciano +7 more·2012·Nature
DOI 10.1038/nature11048PMC PMC3367514
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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 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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Research works printed but not linked: 26

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Authors
Cho, H., Zhao, X., Hatori, M., Yu, R. T., Barish, G. D., Lam, M. T., Chong, L.-W., DiTacchio, L., Atkins, A. R., Glass, C. K., Liddle, C., Auwerx, J., Downes, M., Panda, S., & Evans, R. M.
Affiliations
  • Salk Institute for Biological Studies (US)
  • University of California San Diego (US)
  • The University of Sydney (AU)
  • École Polytechnique Fédérale de Lausanne (CH)
Corresponding author
Evans, Ronald M.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2012-03-29
Volume
485
Issue
7396
Pages
123-127
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature11048
PMC
PMC3367514
OpenAlex
W2011072921
Cited by
1,037
References
4
Citations by year
2026: 58 · 2025: 75 · 2024: 56 · 2023: 65 · 2022: 88 · 2021: 81 · 2020: 80 · 2019: 75 · 2018: 67 · 2017: 57 · 2016: 71 · 2015: 70 · 2014: 84 · 2013: 74 · 2012: 35
FWCI
35.60
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
Funders
  • Howard Hughes Medical Institute
  • National Heart, Lung, and Blood Institute (HL105278, T32HL007770, R01HL105278)
  • National Cancer Institute (P30CA014195)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, DK 091618, DK057978, DK062434, R01DK091618, R01DK057978, R24DK090962, DK090962, U19DK062434)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
NR1D1, circadian clock, clock genes, metabolic regulation, SR9009, hypothalamus, energy expenditure, diet-induced obesity, dyslipidemia, hyperglycemia, Bmal1, cistrome, lipid metabolism, circadian activity
MeSH terms
Animals, Biological Clocks, Circadian Rhythm, Energy Metabolism, Gene Expression Regulation, Homeostasis, Liver, Male, Mice, Inbred C57BL, Molecular Sequence Data, Motor Activity, Repressor Proteins, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Feedback, Physiological, Lipid Metabolism, Mice, Gene Regulatory Networks, Cryptochromes, Period Circadian Proteins, Nuclear Receptor Subfamily 1, Group D, Member 1, Transcriptome

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