MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
Vascular Surgery Department, Zhongshan Xiamen Hospital, Fudan University, Xiamen, People's Republic of China.
Clin Epigenetics. 2021 Jun 8;13(1):124. doi: 10.1186/s13148-021-01110-9.
Thoracic aortic dissection (TAD) is a severe disease with limited understandings in its pathogenesis. Altered DNA methylation has been revealed to be involved in many diseases etiology. Few studies have examined the role of DNA methylation in the development of TAD. This study explored alterations of the DNA methylation landscape in TAD and examined the potential role of cell-free DNA (cfDNA) methylation as a biomarker in TAD diagnosis.
Ascending aortic tissues from TAD patients (Stanford type A; n = 6) and healthy controls (n = 6) were first examined via whole-genome bisulfite sequencing (WGBS). While no obvious global methylation shift was observed, numerous differentially methylated regions (DMRs) were identified, with associated genes enriched in the areas of vasculature and heart development. We further confirmed the methylation and expression changes in homeobox (Hox) clusters with 10 independent samples using bisulfite pyrosequencing and quantitative real-time PCR (qPCR). Among these, HOXA5, HOXB6 and HOXC6 were significantly down-regulated in TAD samples relative to controls. To evaluate cfDNA methylation pattern as a biomarker in TAD diagnosis, cfDNA from TAD patients (Stanford type A; n = 7) and healthy controls (n = 4) were examined by WGBS. A prediction model was built using DMRs identified previously from aortic tissues on methylation data from cfDNA. Both high sensitivity (86%) and specificity (75%) were achieved in patient classification (AUC = 0.96).
These findings showed an altered epigenetic regulation in TAD patients. This altered epigenetic regulation and subsequent altered expression of genes associated with vasculature and heart development, such as Hox family genes, may contribute to the loss of aortic integrity and TAD pathogenesis. Additionally, the cfDNA methylation in TAD was highly disease specific, which can be used as a non-invasive biomarker for disease prediction.
胸主动脉夹层（TAD）是一种严重的疾病，其发病机制尚不完全清楚。已发现 DNA 甲基化的改变与许多疾病的病因有关。很少有研究探讨 DNA 甲基化在 TAD 发展中的作用。本研究探讨了 TAD 中 DNA 甲基化图谱的改变，并研究了细胞游离 DNA（cfDNA）甲基化为 TAD 诊断的生物标志物的潜在作用。
首先通过全基因组亚硫酸氢盐测序（WGBS）检测 TAD 患者（斯坦福 A 型；n=6）和健康对照者（n=6）的升主动脉组织。虽然没有观察到明显的整体甲基化变化，但鉴定出了许多差异甲基化区域（DMR），与血管和心脏发育相关的基因富集在这些区域。我们进一步使用亚硫酸氢盐焦磷酸测序和定量实时 PCR（qPCR）在 10 个独立样本中验证了同源盒（Hox）簇的甲基化和表达变化。其中，HOXA5、HOXB6 和 HOXC6 在 TAD 样本中相对于对照组显著下调。为了评估 cfDNA 甲基化模式作为 TAD 诊断的生物标志物，我们通过 WGBS 检测 TAD 患者（斯坦福 A 型；n=7）和健康对照者（n=4）的 cfDNA。使用先前从主动脉组织中鉴定的 DMR 基于 cfDNA 甲基化数据构建了一个预测模型。在患者分类中，均取得了较高的敏感性（86%）和特异性（75%）（AUC=0.96）。
这些发现表明 TAD 患者存在异常的表观遗传调控。这种异常的表观遗传调控以及随后与血管和心脏发育相关的基因的表达改变，如 Hox 家族基因，可能导致主动脉完整性的丧失和 TAD 的发病机制。此外，TAD 中的 cfDNA 甲基化具有高度的疾病特异性，可作为疾病预测的非侵入性生物标志物。
Zotero 插件
