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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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Cry-deficient mice show arrhythmic Angptl2 expression.Relative levels of Angptl2, Per2, and Rev-erbα mRNA expression in WAT of Cry-deficient or wild-type mice at CT 2 and CT 12 (n  =  4 for each data point). The expression level in wild-type mice at CT 12 was set to 100%. Data are expressed as means ± S.E.M. **p < 0.01. n.s., no statistical difference.
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pone-0057921-g006: Cry-deficient mice show arrhythmic Angptl2 expression.Relative levels of Angptl2, Per2, and Rev-erbα mRNA expression in WAT of Cry-deficient or wild-type mice at CT 2 and CT 12 (n  =  4 for each data point). The expression level in wild-type mice at CT 12 was set to 100%. Data are expressed as means ± S.E.M. **p < 0.01. n.s., no statistical difference.

Mentions: Finally, to determine the importance of a molecular clock in regulating rhythmic ANGPTL2 expression in vivo, we examined periodic expression of Angptl2 mRNA in mice lacking both Cry1 and Cry2 genes (Cry-deficient mice) [18] by real-time PCR analysis. Cry-deficient mice show disruption of periodic expression of clock-controlled genes and exhibit abnormal rhythmicity of metabolic and behavioral activities [18], [24]-[26]. Wild-type mice showed significantly increased Angptl2 expression in WAT at circadian time (CT) 12 compared to CT 2 (Figure 6). However, we observed no significant differences in Angptl2 expression levels at these time points in Cry-deficient mice (Figure 6). Rhythmicity of both Per2 and Rev-erbα was also abolished in WAT of Cry-deficient mice (Figure 6). Interestingly, periodic Angptl2 expression was also abolished in the aorta of Cry-deficient mice (Figure S3). These results indicate that components of a molecular clock are essential to regulate rhythmic Angptl2 expression in WAT and aorta.


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)

Cry-deficient mice show arrhythmic Angptl2 expression.Relative levels of Angptl2, Per2, and Rev-erbα mRNA expression in WAT of Cry-deficient or wild-type mice at CT 2 and CT 12 (n  =  4 for each data point). The expression level in wild-type mice at CT 12 was set to 100%. Data are expressed as means ± S.E.M. **p < 0.01. n.s., no statistical difference.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585275&req=5

pone-0057921-g006: Cry-deficient mice show arrhythmic Angptl2 expression.Relative levels of Angptl2, Per2, and Rev-erbα mRNA expression in WAT of Cry-deficient or wild-type mice at CT 2 and CT 12 (n  =  4 for each data point). The expression level in wild-type mice at CT 12 was set to 100%. Data are expressed as means ± S.E.M. **p < 0.01. n.s., no statistical difference.
Mentions: Finally, to determine the importance of a molecular clock in regulating rhythmic ANGPTL2 expression in vivo, we examined periodic expression of Angptl2 mRNA in mice lacking both Cry1 and Cry2 genes (Cry-deficient mice) [18] by real-time PCR analysis. Cry-deficient mice show disruption of periodic expression of clock-controlled genes and exhibit abnormal rhythmicity of metabolic and behavioral activities [18], [24]-[26]. Wild-type mice showed significantly increased Angptl2 expression in WAT at circadian time (CT) 12 compared to CT 2 (Figure 6). However, we observed no significant differences in Angptl2 expression levels at these time points in Cry-deficient mice (Figure 6). Rhythmicity of both Per2 and Rev-erbα was also abolished in WAT of Cry-deficient mice (Figure 6). Interestingly, periodic Angptl2 expression was also abolished in the aorta of Cry-deficient mice (Figure S3). These results indicate that components of a molecular clock are essential to regulate rhythmic Angptl2 expression in WAT and aorta.

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