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A molecular clock regulates angiopoietin-like protein 2 expression.

Kadomatsu T, Uragami S, Akashi M, Tsuchiya Y, Nakajima H, Nakashima Y, Endo M, Miyata K, Terada K, Todo T, Node K, Oike Y - PLoS ONE (2013)

Bottom Line: Promoter activity of the human ANGPTL2 gene was significantly induced by CLOCK and BMAL1, an induction markedly attenuated by CRY co-expression.We also identified functional E-boxes in the ANGPTL2 promoter and observed occupancy of these sites by endogenous CLOCK in human osteosarcoma cells.Taken together, these data suggest that periodic expression of ANGPTL2 is regulated by a molecular clock.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. tkado@gpo.kumamoto-u.ac.jp

ABSTRACT
Various physiological and behavioral processes exhibit circadian rhythmicity. These rhythms are usually maintained by negative feedback loops of core clock genes, namely, CLOCK, BMAL, PER, and CRY. Recently, dysfunction in the circadian clock has been recognized as an important foundation for the pathophysiology of lifestyle-related diseases, such as obesity, cardiovascular disease, and some cancers. We have reported that angiopoietin-like protein 2 (ANGPTL2) contributes to the pathogenesis of these lifestyle-related diseases by inducing chronic inflammation. However, molecular mechanisms underlying regulation of ANGPTL2 expression are poorly understood. Here, we assess circadian rhythmicity of ANGPTL2 expression in various mouse tissues. We observed that ANGPTL2 rhythmicity was similar to that of the PER2 gene, which is regulated by the CLOCK/BMAL1 complex. Promoter activity of the human ANGPTL2 gene was significantly induced by CLOCK and BMAL1, an induction markedly attenuated by CRY co-expression. We also identified functional E-boxes in the ANGPTL2 promoter and observed occupancy of these sites by endogenous CLOCK in human osteosarcoma cells. Furthermore, Cry-deficient mice exhibited arrhythmic Angptl2 expression. Taken together, these data suggest that periodic expression of ANGPTL2 is regulated by a molecular clock.

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Temporal expression of Angptl2 and core clock genes in mouse epididymal white adipose tissue.Temporal expression of Angptl2 (A), Clock (B), Bmal1 (C), Cry1 (D), Per2 (E), Rev-erbα (F), and Rorα (G) mRNA in epididymal white adipose tissue (WAT) of mice housed under light/dark cycles. For light/dark cycles, Zeitgeber time (ZT) 0 or ZT 24 was designated as lights on and ZT 12 or ZT 36 as lights off. The average mRNA expression level across all time points was set to 1. Data are expressed as means ± S.E.M. (n  =  3 mice for each data point).
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pone-0057921-g001: Temporal expression of Angptl2 and core clock genes in mouse epididymal white adipose tissue.Temporal expression of Angptl2 (A), Clock (B), Bmal1 (C), Cry1 (D), Per2 (E), Rev-erbα (F), and Rorα (G) mRNA in epididymal white adipose tissue (WAT) of mice housed under light/dark cycles. For light/dark cycles, Zeitgeber time (ZT) 0 or ZT 24 was designated as lights on and ZT 12 or ZT 36 as lights off. The average mRNA expression level across all time points was set to 1. Data are expressed as means ± S.E.M. (n  =  3 mice for each data point).

Mentions: To determine whether Angptl2 shows circadian expression in vivo, we performed real-time PCR analysis and compared periodic Angptl2 expression with that of core clock genes, including Bmal1, Clock, Per2, Cry1, Rev-erbα, and Rorα in mouse epididymal WAT every 4 hours (Figure 1). Clock and Bmal1 mRNA expression dropped to trough levels between Zeitgeber time (ZT) 10 and ZT 14 and between ZT 34 and ZT 38 (Figure 1B and C), while Angptl2 expression and that of other core clock genes regulated by the CLOCK/BMAL1 complex [1] showed the opposite patterns. Angptl2, Per2, and Rorα mRNA expression levels peaked between ZT 10 and ZT 14 and between ZT 34 and ZT 38 (Figure 1A, E, and G), while Cry1 mRNA expression peaked between ZT 16 and ZT 20 and between ZT 40 and ZT 44 (Figure 1D). Rev-erbα mRNA expression levels peaked between ZT 4 and ZT 8 and between ZT 28 and ZT 32 (Figure 1F).


A molecular clock regulates angiopoietin-like protein 2 expression.

Kadomatsu T, Uragami S, Akashi M, Tsuchiya Y, Nakajima H, Nakashima Y, Endo M, Miyata K, Terada K, Todo T, Node K, Oike Y - PLoS ONE (2013)

Temporal expression of Angptl2 and core clock genes in mouse epididymal white adipose tissue.Temporal expression of Angptl2 (A), Clock (B), Bmal1 (C), Cry1 (D), Per2 (E), Rev-erbα (F), and Rorα (G) mRNA in epididymal white adipose tissue (WAT) of mice housed under light/dark cycles. For light/dark cycles, Zeitgeber time (ZT) 0 or ZT 24 was designated as lights on and ZT 12 or ZT 36 as lights off. The average mRNA expression level across all time points was set to 1. Data are expressed as means ± S.E.M. (n  =  3 mice for each data point).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585275&req=5

pone-0057921-g001: Temporal expression of Angptl2 and core clock genes in mouse epididymal white adipose tissue.Temporal expression of Angptl2 (A), Clock (B), Bmal1 (C), Cry1 (D), Per2 (E), Rev-erbα (F), and Rorα (G) mRNA in epididymal white adipose tissue (WAT) of mice housed under light/dark cycles. For light/dark cycles, Zeitgeber time (ZT) 0 or ZT 24 was designated as lights on and ZT 12 or ZT 36 as lights off. The average mRNA expression level across all time points was set to 1. Data are expressed as means ± S.E.M. (n  =  3 mice for each data point).
Mentions: To determine whether Angptl2 shows circadian expression in vivo, we performed real-time PCR analysis and compared periodic Angptl2 expression with that of core clock genes, including Bmal1, Clock, Per2, Cry1, Rev-erbα, and Rorα in mouse epididymal WAT every 4 hours (Figure 1). Clock and Bmal1 mRNA expression dropped to trough levels between Zeitgeber time (ZT) 10 and ZT 14 and between ZT 34 and ZT 38 (Figure 1B and C), while Angptl2 expression and that of other core clock genes regulated by the CLOCK/BMAL1 complex [1] showed the opposite patterns. Angptl2, Per2, and Rorα mRNA expression levels peaked between ZT 10 and ZT 14 and between ZT 34 and ZT 38 (Figure 1A, E, and G), while Cry1 mRNA expression peaked between ZT 16 and ZT 20 and between ZT 40 and ZT 44 (Figure 1D). Rev-erbα mRNA expression levels peaked between ZT 4 and ZT 8 and between ZT 28 and ZT 32 (Figure 1F).

Bottom Line: Promoter activity of the human ANGPTL2 gene was significantly induced by CLOCK and BMAL1, an induction markedly attenuated by CRY co-expression.We also identified functional E-boxes in the ANGPTL2 promoter and observed occupancy of these sites by endogenous CLOCK in human osteosarcoma cells.Taken together, these data suggest that periodic expression of ANGPTL2 is regulated by a molecular clock.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. tkado@gpo.kumamoto-u.ac.jp

ABSTRACT
Various physiological and behavioral processes exhibit circadian rhythmicity. These rhythms are usually maintained by negative feedback loops of core clock genes, namely, CLOCK, BMAL, PER, and CRY. Recently, dysfunction in the circadian clock has been recognized as an important foundation for the pathophysiology of lifestyle-related diseases, such as obesity, cardiovascular disease, and some cancers. We have reported that angiopoietin-like protein 2 (ANGPTL2) contributes to the pathogenesis of these lifestyle-related diseases by inducing chronic inflammation. However, molecular mechanisms underlying regulation of ANGPTL2 expression are poorly understood. Here, we assess circadian rhythmicity of ANGPTL2 expression in various mouse tissues. We observed that ANGPTL2 rhythmicity was similar to that of the PER2 gene, which is regulated by the CLOCK/BMAL1 complex. Promoter activity of the human ANGPTL2 gene was significantly induced by CLOCK and BMAL1, an induction markedly attenuated by CRY co-expression. We also identified functional E-boxes in the ANGPTL2 promoter and observed occupancy of these sites by endogenous CLOCK in human osteosarcoma cells. Furthermore, Cry-deficient mice exhibited arrhythmic Angptl2 expression. Taken together, these data suggest that periodic expression of ANGPTL2 is regulated by a molecular clock.

Show MeSH
Related in: MedlinePlus