on July 3, 2003
Published online before print July 3, 2003, doi: 10.1161/01.ATV.0000084637.01883.CA
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Submitted on February 24, 2003
Accepted on May 15, 2003
Regulation of the Expression of the Apolipoprotein(a) Gene. Evidence for a Regulatory Role of the 5' Distal Apolipoprotein(a) Transcription Control Region Enhancer in Yeast Artificial Chromosome Transgenic Mice
Thierry Huby *;
From Institut National de la Santé et de la Recherche Médicale (T.H., C.D., M.J.C., J.T.,), INSERM Unit 551, Dyslipemias and Atherosclerosis: Genetics, Metabolism and Therapeutics, Hôpital de la Pitié, Paris, France; Genome Sciences Department (V.A., E.L.G., E.M.R.), Lawrence Berkeley National Laboratory, Berkeley, Calif; and CV Therapeutics (R.M.L.), Palo Alto, Calif.
* To whom correspondence should be addressed. E-mail: thuby{at}infobiogen.fr.
Objective--The apolipoprotein(a) [apo(a)] gene locus is the major determinant of the circulating concentration of the atherothrombogenic lipoprotein Lp(a). In vitro analysis of the intergenic region between the apo(a) and plasminogen genes revealed the presence of a putative apo(a) transcription control region (ACR) approximately 20 kb upstream of the apo(a) gene that significantly increases the minimal promoter activity of the human apo(a) gene.
Methods and Results--To examine the function of the ACR in its natural genomic context, we used the Cre-loxP recombination system to generate 2 nearly identical apo(a)-yeast artificial chromosome transgenic mouse lines that possess a single integration site for the human apo(a) transgene in the mouse genome but differ by the presence or absence of the ACR enhancer. Analysis of the 2 groups of animals revealed that the deletion of the ACR was associated with 30% reduction in plasma and mRNA apo(a) levels. apo(a)-yeast artificial chromosome transgenic mice with and without the ACR sequence were similar in all other aspects of apo(a) regulation, including liver-specific apo(a) expression and alteration in expression levels in response to sexual maturation and a high-fat diet.
Conclusions--This study provides the first experimental in vivo evidence for a functional role of the ACR enhancer in determining levels of apo(a) expression.
Key words: apolipoprotein(a) • gene expression • enhancer • yeast artificial chromosome • transgenic mice
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