Global DNA methylation analysis of human atherosclerotic plaques reveals extensive genomic hypomethylation and reactivation at imprinted locus 14q32 involving induction of a miRNA cluster

被引：99

作者：

Aavik, Einari ^{[1
]}

Lumivuori, Henri ^{[1
]}

Leppanen, Olli ^{[2
]}

Wirth, Thomas ^{[1
]}

Hakkinen, Sanna-Kaisa ^{[1
]}

Braesen, Jan-Hinrich ^{[3
]}

Beschorner, Ulrich ^{[4
]}

Zeller, Thomas ^{[4
]}

Braspenning, Maarten ^{[5
]}

van Criekinge, Wim ^{[6
]}

Makinen, Kimmo ^{[7
]}

Yla-Herttuala, Seppo ^{[1
,8
,9
]}

机构：

[1] Univ Eastern Finland, Dept Biotechnol & Mol Med, AI Virtanen Inst Kuopio, FIN-70211 Kuopio, Finland

[2] Uppsala Univ, Cty Council Gavleborg, Ctr R&D, Gavle, Sweden

[3] Hannover Med Sch, Inst Pathol, D-30623 Hannover, Germany

[4] Univ Herzzentrum Freiburg Bad Krozingen, Dept Angiol, Bad Krozingen, Germany

[5] NXT Dx, Ghent, Belgium

[6] Univ Ghent, Lab Bioinformat & Computat Genom, B-9000 Ghent, Belgium

[7] Kuopio Univ Hosp, Vasc Surg Unit, SF-70210 Kuopio, Finland

[8] Kuopio Univ Hosp, Sci Serv Ctr, SF-70210 Kuopio, Finland

[9] Kuopio Univ Hosp, Gene Therapy Unit, SF-70210 Kuopio, Finland

来源：

EUROPEAN HEART JOURNAL | 2015年 / 36卷 / 16期

基金：

芬兰科学院;

关键词：

Atherosclerosis; DNA methylation; Epigenetics; Peripheral vascular disease; GENE-EXPRESSION; GROWTH; CELLS; REPRESSION; ARTERIES; DISEASE; LESIONS; TUMOR;

D O I：

10.1093/eurheartj/ehu437

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Genetics can explain just above 10% of the observed heritability in cardiovascular diseases. Epigenetics is about to provide some further explanations, but the information needed for that is in the accumulation phase. Genome-wide DNA methylation analysis has revealed thousands of genes, which are epigenetically differentially regulated in atherosclerotic plaques. Our results point to an additional level of complexity that needs to be integrated into the aetiology of atherogenesis.We conducted a genome-wide analysis to identify differentially methylated genes in atherosclerotic lesions. Methods DNA methylation at promoters, exons and introns was identified by massive parallel sequencing. Gene expression was analysed by microarrays, qPCR, immunohistochemistry and western blots. Results Globally, hypomethylation of chromosomal DNA predominates in atherosclerotic plaques and two-thirds of genes showing over 2.5-fold differential in DNA methylation are up-regulated in comparison to healthy mammary arteries. The imprinted chromatin locus 14q32 was identified for the first time as an extensively hypomethylated area in atherosclerosis with highly induced expression of miR127, -136, -410, -431, -432, -433 and capillary formation-associated gene RTL1. The top 100 list of hypomethylated promoters exhibited over 1000-fold enrichment for miRNAs, many of which mapped to locus 14q32. Unexpectedly, also gene body hypermethylation was found to correlate with stimulated mRNA expression. Conclusion Significant changes in genomic methylation were identified in atherosclerotic lesions. The most prominent gene cluster activated via hypomethylation was detected at imprinted chromosomal locus 14q32 with several clustered miRNAs that were up-regulated. These results suggest that epigenetic changes are involved in atherogenesis and may offer new potential therapeutic targets for vascular diseases.

引用

页码：993 / U23

页数：9

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