DNA Methylation Profiling in Aneurysm and Comorbid Atherosclerosis of the Ascending Aorta

Abstract

Atherosclerosis and aneurysm of the aorta are relatively common pathological conditions that remain asymptomatic for a long period of time and have life-threatening and disabling complications. DNA methylation profiling in several regions (a dilated area, a nondilated area, and an atherosclerotic plaque) of the ascending aorta was carried out in patients with aortic aneurysm. DNA methylation was analyzed by reduced representation bisulfite sequencing (RRBS). Differences in methylation level between dilated and normal aortic tissues were detected for two CpG sites of the NR2F1-AS1 gene (|Δβ| ≥ 0.2 and FDR < 0.05). In total, 586/480 differentially methylated CpG sites (DMSs) were identified by comparing atherosclerotic plaque samples with dilated/normal aortic tissues; 323/234 of the DMSs were hypermethylated and 263/246 were hypomethylated in atherosclerotic plaques. Most DMSs were in introns and intergenic regions; 88.2% of the DMSs were in the binding sites of transcription factors, among which ZNf263, ZFP148, PATZ1, NRF1, TCF12, and EGR1 play a role in the pathogenesis of atherosclerosis of various arteries and ELK1, ETS1, and KLF15 play a role in aortic aneurysms. Sixteen DMSs were found in the regions of the genes CMIP, RPH3AL, XRCC1, GATA5, EXD3, KCNC2, HIVEP3, ADCY9, CDCP2, FOLR1, WT1, MGMT, GAS2, CA1, PRSS16, and ANK3, whose protein products are involved in both aortic dissection and atherosclerosis in various arterial circulation regions. The protein products of the genes are involved in a wide range of biological processes, including mesenchyme development (GO:0060485; FOLR1, WT1, GATA5, HIVEP3, and KCNC2) and positive regulation of DNA metabolic processes (GO:0051054; MGMT, WT1, and XRCC1).