Pan, S;
Lai, H;
Shen, Y;
Breeze, C;
Beck, S;
Hong, T;
Wang, C;
(2017)
DNA methylome analysis reveals distinct epigenetic patterns of ascending aortic dissection and bicuspid aortic valve.
Cardiovascular Research
, 113
(6)
pp. 692-704.
10.1093/cvr/cvx050.
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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.
| Type: | Article |
|---|---|
| Title: | DNA methylome analysis reveals distinct epigenetic patterns of ascending aortic dissection and bicuspid aortic valve |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/cvr/cvx050 |
| Publisher version: | http://dx.doi.org/10.1093/cvr/cvx050 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Aortic dissection, Bicuspid aortic valve, DNA methylation, Smooth muscle cell, Phenotype |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1554793 |
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