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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-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.

Pubmed ID: 22460952

Authors

  • Cho H
  • Zhao X
  • Hatori M
  • Yu RT
  • Barish GD
  • Lam MT
  • Chong LW
  • DiTacchio L
  • Atkins AR
  • Glass CK
  • Liddle C
  • Auwerx J
  • Downes M
  • Panda S
  • Evans RM

Journal

Nature

Publication Data

May 3, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK057978
  • Agency: NIDDK NIH HHS, Id: DK062434
  • Agency: NIDDK NIH HHS, Id: DK090962
  • Agency: NIDDK NIH HHS, Id: DK091618
  • Agency: NHLBI NIH HHS, Id: HL105278
  • Agency: NCI NIH HHS, Id: P30 CA014195
  • Agency: NIDDK NIH HHS, Id: R01 DK091618
  • Agency: NHLBI NIH HHS, Id: R01 HL105278
  • Agency: NHLBI NIH HHS, Id: R01 HL105278-21
  • Agency: NIDDK NIH HHS, Id: R24 DK090962
  • Agency: NIDDK NIH HHS, Id: R24 DK090962-02
  • Agency: NIDDK NIH HHS, Id: R37 DK057978
  • Agency: NIDDK NIH HHS, Id: R37 DK057978-34
  • Agency: NHLBI NIH HHS, Id: T32 HL007770
  • Agency: NHLBI NIH HHS, Id: T32 HL007770-15
  • Agency: NHLBI NIH HHS, Id: T32-HL007770
  • Agency: NIDDK NIH HHS, Id: U19 DK062434
  • Agency: NIDDK NIH HHS, Id: U19 DK062434-10
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Biological Clocks
  • Circadian Rhythm
  • Cryptochromes
  • Energy Metabolism
  • Feedback, Physiological
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Homeostasis
  • Lipid Metabolism
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Motor Activity
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Period Circadian Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • Transcriptome