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

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 - Nature (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.

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.

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Broad disruption of circadian transcriptome in the absence of Rev-erbα and Rev-erbβa, Heatmap of genes with circadian expression in wild-type (left panel) and L-DKO (right panel) livers. 1227 unique accession numbers were selected based on fdr < 0.05. b, Genes expressed in a circadian manner that lose rhythm are highly associated with circadian and energy homeostasis functions as assessed by KEGG Pathway analysis.
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Figure 3: Broad disruption of circadian transcriptome in the absence of Rev-erbα and Rev-erbβa, Heatmap of genes with circadian expression in wild-type (left panel) and L-DKO (right panel) livers. 1227 unique accession numbers were selected based on fdr < 0.05. b, Genes expressed in a circadian manner that lose rhythm are highly associated with circadian and energy homeostasis functions as assessed by KEGG Pathway analysis.

Mentions: Microarray analysis of gene expression over a 24 hr time course (presented as Zeitgeber Time) revealed massive differences between the wildtype and L-DKO liver. Using CircWave v3.3 17 software, we determined that of the ~900 circadianly expressed genes in wildtype liver, the rhythmicity of more than 90% was perturbed in the L-DKO (Fig. 3a). The severity of the circadian disruption was comparable to that described for mice deficient in core clock components 18,19, emphasizing the functional impact associated with the extensive intersection between Rev-erbα/β and Bmal1 cistromes. Furthermore, the gene ontology of the Rev-erbα/β-dependent circadian transcriptome (those genes that lose rhythm in L-DKO; Fig. 3b) also mirrors that of their cistromes (Fig. 1c and Supplementary Table 1). This is of interest as the disrupted oscillation of these genes in the liver occurred in vivo in the presence of otherwise wildtype entraining signals and fully intact extra-hepatic clockwork (Supplementary Fig. 5). Notably, residual rhythmic expression of some genes were maintained in the L-DKO mice, indicating that they may be controlled by systemic cues, as suggested by Kornmann et al. 20.


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

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 - Nature (2012)

Broad disruption of circadian transcriptome in the absence of Rev-erbα and Rev-erbβa, Heatmap of genes with circadian expression in wild-type (left panel) and L-DKO (right panel) livers. 1227 unique accession numbers were selected based on fdr < 0.05. b, Genes expressed in a circadian manner that lose rhythm are highly associated with circadian and energy homeostasis functions as assessed by KEGG Pathway analysis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3367514&req=5

Figure 3: Broad disruption of circadian transcriptome in the absence of Rev-erbα and Rev-erbβa, Heatmap of genes with circadian expression in wild-type (left panel) and L-DKO (right panel) livers. 1227 unique accession numbers were selected based on fdr < 0.05. b, Genes expressed in a circadian manner that lose rhythm are highly associated with circadian and energy homeostasis functions as assessed by KEGG Pathway analysis.
Mentions: Microarray analysis of gene expression over a 24 hr time course (presented as Zeitgeber Time) revealed massive differences between the wildtype and L-DKO liver. Using CircWave v3.3 17 software, we determined that of the ~900 circadianly expressed genes in wildtype liver, the rhythmicity of more than 90% was perturbed in the L-DKO (Fig. 3a). The severity of the circadian disruption was comparable to that described for mice deficient in core clock components 18,19, emphasizing the functional impact associated with the extensive intersection between Rev-erbα/β and Bmal1 cistromes. Furthermore, the gene ontology of the Rev-erbα/β-dependent circadian transcriptome (those genes that lose rhythm in L-DKO; Fig. 3b) also mirrors that of their cistromes (Fig. 1c and Supplementary Table 1). This is of interest as the disrupted oscillation of these genes in the liver occurred in vivo in the presence of otherwise wildtype entraining signals and fully intact extra-hepatic clockwork (Supplementary Fig. 5). Notably, residual rhythmic expression of some genes were maintained in the L-DKO mice, indicating that they may be controlled by systemic cues, as suggested by Kornmann et al. 20.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.

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.

Show MeSH
Related in: MedlinePlus