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 behavioral and physiologic rhythms via the CLOCK-BMAL transcriptional heterodimer. Although the nuclear receptors REV-ERBα and 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 generated comparative cistromes of both REV-ERB isoforms, which revealed shared recognition at over 50% of their total sites and extensive overlap with the master circadian regulator BMAL1. While Rev-erbα has been shown to directly regulate Bmal1 expression1,2, the cistromic analysis reveals a direct connection between Bmal1 and Rev-erbα and β regulatory circuits than previously suspected. Genes within the intersection of the BMAL1, REV-ERBα and REV-ERBβ cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erbα/β function by creating double-knockout mice (DKOs) profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, DKOs show strikingly altered circadian wheel-running behavior and deregulated lipid metabolism. These data now ally Rev-erbα/β with Per, Cry and other components of the principal feedback loop that drives circadian expression and suggest a more integral mechanism for the coordination of circadian rhythm and metabolism.

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

“…***P < 0.001; *P < 0.05. also enriched in target genes of REV-ERB and REV-ERB (ref. 18), we believe that it is unlikely that the upregulation of these targets in Ho-1-and Ho-2-depleted hepatocytes was due to CO directly regulating the activity of REV-ERB and REV-ERB (discussion in Supplementary Note 2).…”

Circadian regulation of lipid metabolism

“…For example, thousands of DNAbinding sites in mouse liver are rhythmically occupied by BMAL1, including genes involved in sterol and TAG metabolic pathways (49,50) . Similarly, the circadian cistromes for REV-ERBα, nuclear receptor corepressor and histone deacetylase 3 overlap extensively and are enriched for genes involved in lipid metabolism (51)(52)(53) . Circadian rhythms in genome-wide occupancy for BMAL1, REV-ERBα and REV-ERBβ show strong overlap for metabolic pathways and transcriptional regulators in the liver (52) , and similar findings have been reported for other core clock proteins (BMAL1, CLOCK, NPAS2, PER1, PER2, CRY1 and CRY2) (54) .…”

“…Similarly, the circadian cistromes for REV-ERBα, nuclear receptor corepressor and histone deacetylase 3 overlap extensively and are enriched for genes involved in lipid metabolism (51)(52)(53) . Circadian rhythms in genome-wide occupancy for BMAL1, REV-ERBα and REV-ERBβ show strong overlap for metabolic pathways and transcriptional regulators in the liver (52) , and similar findings have been reported for other core clock proteins (BMAL1, CLOCK, NPAS2, PER1, PER2, CRY1 and CRY2) (54) . Importantly, the circadian clock can exert its widespread influence on energy metabolism by regulating ratelimiting steps in metabolic pathways (55) , as well as nuclear receptors, including REV-ERB and ROR proteins, and PPARα, PPARγ and PPARδ, which are key transcriptional regulators of lipid metabolism.…”

Horloges circadiennes et métabolisme : intégration des signaux métaboliques et environnementaux

“…Rev-erb et Rev-erb corégulent les gènes de la lipogenèse de façon circadienne permettant d'assurer l'homéostasie lipidique. Leur délétion spécifiquement dans le foie conduit à l'apparition d'une stéatose hépatique [35,36]. Rev-erb intervient aussi dans le développement du tissu adipeux et la synthèse des acides biliaires et du glucose [37].…”