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J. Biol. Chem., Vol. 279, Issue 28, 29147-29154, July 9, 2004
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DNA Methylation Polymorphisms Precede Any Histological Sign of Atherosclerosis in Mice Lacking Apolipoprotein E*
From the
Institute of Plant Biology, Department of Plant Biochemistry, Royal Veterinary and Agricultural College, 1871 Frederiksberg, Denmark, Experimental Cardiovascular Research, Department of Medicine, University of Lund, 205 02 Malmö, Sweden, the ¶Cancer Epigenetics Laboratory, Spanish National Cancer Centre, 28029 Madrid, Spain, and the ||Department of Clinical Biochemistry, Rigshospitalet, 2100 Copenhagen, Denmark
The present work investigates the occurrence and significance of aberrant DNA methylation patterns during early stages of atherosclerosis. To this end, we asked whether the genetically atherosclerosis-prone APOE-null mice show any changes in DNA methylation patterns before the appearance of histologically detectable vascular lesion. We exploited a combination of various techniques: DNA fingerprinting, in vitro methyl-accepting assay, 5-methylcytosine quantitation, histone post-translational modification analysis, Southern blotting, and PCR. Our results show that alterations in DNA methylation profiles, including both hyper- and hypomethylation, were present in aortas and PBMC of 4-week-old mutant mice with no detectable atherosclerotic lesion. Sequencing and expression analysis of 60 leukocytic polymorphisms revealed that epigenetic changes involve transcribed genic sequences, as well as repeated interspersed elements. Furthermore, we showed for the first time that atherogenic lipoproteins promote global DNA hypermethylation in a human monocyte cell line. Taken together, our results unequivocally show that alterations in DNA methylation profiles are early markers of atherosclerosis in a mouse model and may play a causative role in atherogenesis.
Received for publication, April 1, 2004 , and in revised form, May 3, 2004.
* This work was supported by the Swedish Research Council, the Swedish Heart and Lung Foundation, the Crafoordska Stiftelsen, and Danish Research Council Grant 22-02-0578 (to S. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY606848–AY606871 (in the order listed in Table II).
** To whom all correspondence should be addressed. Tel.: 45-35452934; Fax: 45-35454640; E-mail: silvio.zaina{at}rh.dk.
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