Lower Methylation of the ANGPTL2 Gene in Leukocytes from Post-Acute Coronary Syndrome Patients.
Lower Methylation of the ANGPTL2 Gene in Leukocytes from Post-Acute Coronary Syndrome Patients.
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DOI：
10.1371/journal.pone.0153920
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Thorin E
中科院分区：
文献类型：
--
作者：
Nguyen A;Mamarbachi M;Turcot V;Lessard S;Yu C;Luo X;Lalongé J;Hayami D;Gayda M;Juneau M;Thorin-Trescases N;Lettre G;Nigam A;Thorin E
DNA甲基化被认为可以调节成年期的基因表达，以应对环境的不断变化。因此，甲基化组被认为是随年龄变化的健康生物标志物。 ANGPTL2 是一种循环促炎蛋白，其随着年龄的增长而增加，并且在患有冠状动脉疾病的患者中会过早增加；整合启动子的甲基化模式可能有助于区分其表达中与年龄相关的变化和与疾病相关的变化。我们认为，在促炎症环境中，ANGPTL2 被差异甲基化，从而调节 ANGPTL2 的表达。为了检验这一假设，我们研究了急性后冠脉综合征 (ACS) 患者白细胞中 ANGPTL2 基因启动子甲基化的变化。 DNA 是从具有心血管危险因素的 ACS 后患者以及健康年轻人和年龄匹配的对照者的循环白细胞中提取的。 ANGPTL2 基因中发现的甲基化位点 (CpG) 被用于特定 DNA 甲基化定量。通过体外荧光素酶测定评估 ANGPTL2 甲基化的功能。与健康对照相比，ACS 后患者的 C 反应蛋白和 ANGPTL2 循环水平显着升高。在 ANGPTL2 启动子中发现特定 CpG 的甲基化减少，并允许区分年龄与疾病相关的甲基化。体外特定 CpG 的 DNA 甲基化会导致 ANGPTL2 启动子活性受到抑制。 ANGPTL2 启动子区域白细胞 DNA 甲基化减少与促炎环境相关，该环境是 ACS 后患者与年龄匹配的健康对照者不同的特征。 ANGPTL2 基因中不同 CpG 的甲基化可能被证明是冠状动脉疾病的可靠生物标志物。
DNA methylation is believed to regulate gene expression during adulthood in response to the constant changes in environment. The methylome is therefore proposed to be a biomarker of health through age. ANGPTL2 is a circulating pro-inflammatory protein that increases with age and prematurely in patients with coronary artery diseases; integrating the methylation pattern of the promoter may help differentiate age- vs. disease-related change in its expression. We believe that in a pro-inflammatory environment, ANGPTL2 is differentially methylated, regulating ANGPTL2 expression. To test this hypothesis we investigated the changes in promoter methylation of ANGPTL2 gene in leukocytes from patients suffering from post-acute coronary syndrome (ACS). DNA was extracted from circulating leukocytes of post-ACS patients with cardiovascular risk factors and from healthy young and age-matched controls. Methylation sites (CpGs) found in the ANGPTL2 gene were targeted for specific DNA methylation quantification. The functionality of ANGPTL2 methylation was assessed by an in vitro luciferase assay. In post-ACS patients, C-reactive protein and ANGPTL2 circulating levels increased significantly when compared to healthy controls. Decreased methylation of specific CpGs were found in the promoter of ANGPTL2 and allowed to discriminate age vs. disease associated methylation. In vitro DNA methylation of specific CpG lead to inhibition of ANGPTL2 promoter activity. Reduced leukocyte DNA methylation in the promoter region of ANGPTL2 is associated with the pro-inflammatory environment that characterizes patients with post-ACS differently from age-matched healthy controls. Methylation of different CpGs in ANGPTL2 gene may prove to be a reliable biomarker of coronary disease.