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Cardiovasc Res. 2017 May 1;113(6):692-704. doi: 10.1093/cvr/cvx050.

DNA methylome analysis reveals distinct epigenetic patterns of ascending aortic dissection and bicuspid aortic valve.

Author information

1
Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Xuhui District, 180 Fenglin Road, Shanghai 200032, China.
2
CAS Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
3
Medical Genomics, Paul O'Gorman Building, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
4
Statistical Cancer Genomics, Paul O'Gorman Building, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
5
Department of Women's Cancer, University College London, Medical School Building, Room 340, 74 Huntley Street, LondonWC1E 6AU, UK.

Abstract

Aims:

Epigenetics may mediate the effects of environmental risk factors on disease, including heart disease. Thus, measuring the DNA methylome offers the opportunity to identify novel disease biomarkers and novel insights into disease mechanisms. The DNA methylation landscape of ascending aortic dissection (AD) and bicuspid aortic valve (BAV) with aortic aneurysmal dilatation remain uncharacterized. The present study aimed to explore the genome-wide DNA methylation landscape underpinning these two diseases.

Methods and results:

We used Illumina 450k DNA methylation beadarrays to analyse 21 ascending aorta samples, including 10 cases with AD, 5 with BAV and 6 healthy controls. We adjusted for intra-sample cellular heterogeneity, providing the first unbiased genome-wide exploration of the DNA methylation landscape underpinning these two diseases. We discover that both diseases are characterized by loss of DNA methylation at non-CpG sites. We validate this non-CpG hypomethylation signature with pyrosequencing. In contrast to non-CpGs, AD and BAV exhibit distinct DNA methylation landscapes at CpG sites, with BAV characterized mainly by hypermethylation of EZH2 targets. In the case of AD, integrative DNA methylation gene expression analysis reveals that AD is characterized by a dedifferentiated smooth muscle cell phenotype. Our integrative analysis further reveals hypomethylation associated overexpression of RARA in AD, a pattern which is also seen in cells exposed to smoke toxins.

Conclusion:

Our data supports a model in which increased cellular proliferation in AD and BAV underpins loss of methylation at non-CpG sites. Our data further supports a model, in which AD is associated with an inflammatory vascular remodeling process, possibly mediated by the epigenome and linked to environmental risk factors such as smoking.

KEYWORDS:

Aortic dissection; Bicuspid aortic valve; DNA methylation; Phenotype; Smooth muscle cell

PMID:
28444195
DOI:
10.1093/cvr/cvx050
[Indexed for MEDLINE]

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