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Circadian clock genes cause activation of the human PAI‐1 gene promoter with 4G/5G allelic preference
Author(s) -
Chong Nelson W.,
Codd Veryan,
Chan Danny,
Samani Nilesh J.
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.07.014
Subject(s) - circadian rhythm , allele , biology , circadian clock , gene , genetics , activator (genetics) , clock , promoter , gene expression , endocrinology
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 (≈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.