The study investigates the role of REV-ERBα and REV-ERBβ in regulating circadian behavior and metabolism. Using genome-wide cistromic analysis, the researchers identified shared binding sites for both REV-ERB isoforms, which overlap significantly with the master circadian regulator BMAL1. These findings suggest a direct connection between Bmal1 and REV-ERBα and β regulatory circuits. Genes within the intersection of the BMAL1, REV-ERBα, and REV-ERBβ cistromes are enriched for both clock and metabolic functions. Double knockout mice (DKOs) with impaired REV-ERB function showed disrupted circadian expression of core clock and lipid homeostatic gene networks, leading to altered circadian wheel-running behavior and deregulated lipid metabolism. These results indicate that REV-ERBα and β are integral to the coordination of circadian rhythm and metabolism. The circadian clock is a transcriptional mechanism that coordinates behavioral and physiological processes. The mammalian core clock involves a negative feedback loop where the transactivation of E-box-containing genes by CLOCK and BMAL1 is inhibited by PER1 and CRY1. REV-ERBα, β, and RORα, β, γ bind to a common response element (RORE), and their activities establish rhythmic expression of target genes such as Bmal1. However, the partial penetrance and mild period phenotype of Rev-erba−/− mice suggest they are not essential for core clock function. Instead, REV-ERBs are proposed to form an accessory feedback loop that stabilizes the clock. The study used isoform-specific antibodies and determined genome-wide binding sites (cistromes) of REV-ERBα and β in the liver. De novo motif analysis revealed that in vivo, in addition to the classic REV-ERB DR2 motifs, other nuclear receptor binding sites are predominant in the peaks bound by both REV-ERBα and β. Pathway analyses showed that REV-ERBα and β binding peaks are enriched for lipid metabolism genes and circadian clock genes. The overlap between REV-ERBα/β and BMAL1 cistromes suggests that both REV-ERBs are directly linked with clock function. The study generated genetically modified mouse lines with global, tissue-specific, or conditional knockouts of REV-ERBα and β. Global Rev-erba−/− and β−/− single knockout mice showed frequent postnatal lethality, while Rev-erba−/− mice on a mixed background had reduced fertility. Liver-specific double knockout mice (L-DKO) showed disrupted circadian expression of core clock genes and output genes. Microarray analysis revealed that over 90% of circadianly expressed genes were perturbed in L-DKO mice. The gene ontology of the Rev-erba/β-dependent circadian transcriptome mirrored that of their cistThe study investigates the role of REV-ERBα and REV-ERBβ in regulating circadian behavior and metabolism. Using genome-wide cistromic analysis, the researchers identified shared binding sites for both REV-ERB isoforms, which overlap significantly with the master circadian regulator BMAL1. These findings suggest a direct connection between Bmal1 and REV-ERBα and β regulatory circuits. Genes within the intersection of the BMAL1, REV-ERBα, and REV-ERBβ cistromes are enriched for both clock and metabolic functions. Double knockout mice (DKOs) with impaired REV-ERB function showed disrupted circadian expression of core clock and lipid homeostatic gene networks, leading to altered circadian wheel-running behavior and deregulated lipid metabolism. These results indicate that REV-ERBα and β are integral to the coordination of circadian rhythm and metabolism. The circadian clock is a transcriptional mechanism that coordinates behavioral and physiological processes. The mammalian core clock involves a negative feedback loop where the transactivation of E-box-containing genes by CLOCK and BMAL1 is inhibited by PER1 and CRY1. REV-ERBα, β, and RORα, β, γ bind to a common response element (RORE), and their activities establish rhythmic expression of target genes such as Bmal1. However, the partial penetrance and mild period phenotype of Rev-erba−/− mice suggest they are not essential for core clock function. Instead, REV-ERBs are proposed to form an accessory feedback loop that stabilizes the clock. The study used isoform-specific antibodies and determined genome-wide binding sites (cistromes) of REV-ERBα and β in the liver. De novo motif analysis revealed that in vivo, in addition to the classic REV-ERB DR2 motifs, other nuclear receptor binding sites are predominant in the peaks bound by both REV-ERBα and β. Pathway analyses showed that REV-ERBα and β binding peaks are enriched for lipid metabolism genes and circadian clock genes. The overlap between REV-ERBα/β and BMAL1 cistromes suggests that both REV-ERBs are directly linked with clock function. The study generated genetically modified mouse lines with global, tissue-specific, or conditional knockouts of REV-ERBα and β. Global Rev-erba−/− and β−/− single knockout mice showed frequent postnatal lethality, while Rev-erba−/− mice on a mixed background had reduced fertility. Liver-specific double knockout mice (L-DKO) showed disrupted circadian expression of core clock genes and output genes. Microarray analysis revealed that over 90% of circadianly expressed genes were perturbed in L-DKO mice. The gene ontology of the Rev-erba/β-dependent circadian transcriptome mirrored that of their cist