Circadian clock genes cause activation of the human PAI-1 gene promoter with 4G/5G allelic preference.
Increased plasminogen activator inhibitor-1 (PAI-1) activity is associated with greater risk of myocardial infarction. PAI-1 expression is regulated by a 4G/5G promoter polymorphism. The 4G allele is associated with higher PAI-levels and greater circadian variation. Here we show that clock protein heterodimers BMAL/CLOCK cause greater activation (approximately 2-fold, P<0.05) of the 4G allele. Site-directed mutagenesis studies suggest that clock genes act on two canonical E-boxes to regulate PAI-1 promoter activity. These results identify a potential novel mechanism whereby allele-specific clock genes - mediated modulation of PAI-1 expression may contribute to circadian variation in cardiac risk.
Chong
Nelson W
NW
Cardiology Group, Department of Cardiovascular Sciences, Glenfield General Hospital, Clinical Sciences Wing, University of Leicester, Leicester LE3 9QP, UK. nc69@le.ac.uk
Codd
Veryan
V
Chan
Danny
D
Samani
Nilesh J
NJ
D000483:Alleles; D000818:Animals; D056926:CLOCK Proteins; D019556:COS Cells; D002522:Chlorocebus aethiops; D002940:Circadian Rhythm / Q000235:genetics; D024721:E-Box Elements; D006801:Humans; D016297:Mutagenesis, Site-Directed; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation
D017395:Plasminogen Activator Inhibitor 1; D015534:Trans-Activators; D056926:CLOCK Proteins; C538943:CLOCK protein, human