title: 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 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.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Cho
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhao
authors.forename: Megumi
authors.initials: M
authors.lastname: Hatori
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barish
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lam
authors.forename: Ling-Wa
authors.initials: LW
authors.lastname: Chong
authors.forename: Luciano
authors.initials: L
authors.lastname: DiTacchio
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Satchidananda
authors.initials: S
authors.lastname: Panda
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D056931:Cryptochromes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056950:Period Circadian Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics
chemical_list: D056931:Cryptochromes; C498262:Nr1d1 protein, mouse; C499650:Nr1d2 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D056950:Period Circadian Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins