Altered DNA methylation pattern reveals epigenetic regulation of Hox genes in thoracic aortic dissection and serves as a biomarker in disease diagnosis.
Altered DNA methylation pattern reveals epigenetic regulation of Hox genes in thoracic aortic dissection and serves as a biomarker in disease diagnosis.
复制标题
DNA甲基化模式的改变揭示了胸主动脉夹层中Hox基因的表观遗传调控，并可作为疾病诊断的生物标志物
DOI：
10.1186/s13148-021-01110-9
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发表时间：
2021-06-08
影响因子：
5.7
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Liu P;Zhang J;Du D;Zhang D;Jin Z;Qiu W;Zhou X;Dong S;Zhou M;Zhao H;Zhang W;Ma J;Sun S;Fu W;Liu Y;Wang L
背景
胸主动脉夹层（TAD）是一种严重的疾病，对其发病机制的了解有限。 DNA 甲基化的改变已被揭示与许多疾病的病因学有关。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 甲基化景观的变化，并检验了游离 DNA (cfDNA) 甲基化作为 TAD 诊断中生物标志物的潜在作用。
结果
首先通过全基因组亚硫酸氢盐测序 (WGBS) 检查 TAD 患者（斯坦福 A 型；n = 6）和健康对照（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，但发现了许多差异甲基化区域（DMR），相关基因在脉管系统和心脏发育区域富集。我们使用亚硫酸氢盐焦磷酸测序和定量实时 PCR (qPCR) 进一步证实了同源盒 (Hox) 簇中 10 个独立样本的甲基化和表达变化。其中，与对照相比，TAD 样本中的 HOXA5、HOXB6 和 HOXC6 显着下调。为了评估 cfDNA 甲基化模式作为 TAD 诊断中的生物标志物，通过 WGBS 检查了 TAD 患者（斯坦福 A 型；n = 7）和健康对照（n = 4）的 cfDNA。使用先前从主动脉组织中根据 cfDNA 甲基化数据鉴定的 DMR 建立了预测模型。患者分类实现了高灵敏度 (86%) 和特异度 (75%) (AUC = 0.96)。
结论
这些发现表明 TAD 患者的表观遗传调控发生了改变。这种表观遗传调控的改变以及随后与脉管系统和心脏发育相关的基因（例如 Hox 家族基因）表达的改变可能导致主动脉完整性的丧失和 TAD 发病机制。此外，TAD 中的 cfDNA 甲基化具有高度的疾病特异性，可用作疾病预测的非侵入性生物标志物。
Background
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.
Results
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).
Conclusions
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.
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通讯作者：
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