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

Nature. 2012 Mar 29;485(7396):123-7. doi: 10.1038/nature11048.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Cryptochromes
  • Nr1d1 protein, mouse
  • Nr1d2 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Period Circadian Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins

Associated data

  • GENBANK/GSE34020