title: DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E.
abstract: 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.
authors.affiliation: Department of Plant Biochemistry, Royal Veterinary and Agricultural College, 1871 Frederiksberg, Denmark.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Lund
authors.forename: Linda
authors.initials: L
authors.lastname: Andersson
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Lauria
authors.forename: Marie
authors.initials: M
authors.lastname: Lindholm
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Ana
authors.initials: A
authors.lastname: Villar-Garea
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Silvio
authors.initials: S
authors.lastname: Zaina
mesh_terms: 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
chemical_list: D001057:Apolipoproteins E; D006657:Histones; D008074:Lipoproteins