DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E.
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.
Lund
Gertrud
G
Department of Plant Biochemistry, Royal Veterinary and Agricultural College, 1871 Frederiksberg, Denmark.
Andersson
Linda
L
Lauria
Massimiliano
M
Lindholm
Marie
M
Fraga
Mario F
MF
Villar-Garea
Ana
A
Ballestar
Esteban
E
Esteller
Manel
M
Zaina
Silvio
S
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation; D004195:Disease Models, Animal; D006657:Histones / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000502:physiology; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011499:Protein Processing, Post-Translational
D001057:Apolipoproteins E; D006657:Histones; D008074:Lipoproteins