Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence
Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence
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DOI：
10.1111/j.1530-0277.2006.00068.x
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发表时间：
2006-04-01
影响因子：
3.2
通讯作者：
Bönsch, D
中科院分区：
文献类型：
--
作者：
Bleich, S;Lenz, B;Bönsch, D
背景：血浆同型半胱氨酸浓度升高可影响外周血细胞基因组和基因特异性DNA甲基化。本研究的目的是探讨在酒精依赖患者，谁表现出慢性升高的同型半胱氨酸水平，是否DNA甲基化模式内的HERP（同型半胱氨酸诱导的内质网蛋白）启动子区域和表达的HERP在RNA中的altered.Methods：HERP mRNA表达水平测定在血液中的66名男性酒精患者和55名非饮酒健康对照。表观遗传基因组DNA甲基化状态和HERP启动子甲基化用非放射性延伸分析测量。我们观察到在酒精依赖患者中，HERP启动子DNA甲基化率为7.6%，（t检验，t=-2.45，p < 0.02）与健康对照组相比，（80.4%，SD 14.5），这与他们的同型半胱氨酸水平升高显著相关（多元线性回归，p < 0.007）。此外，我们发现，与健康对照组（-6.04 Delta CT; SD 2.41）相比，酒精依赖患者（t检验，-7.61 Delta CT; SD 1.87，p < 0.001）的HERP mRNA表达显著降低。酒精中毒患者中HERP mRNA表达的降低最好由调节HERP基因启动子的超甲基化解释（回归分析，p = 0.004）.结论：据我们所知，这是第一项评估酒精中毒患者HERE mRNA表达及其特异性基因启动子甲基化的研究。由于DNA的超甲基化是基因表达下调中的重要表观遗传因素，并且由于HERP被认为在细胞内防御系统中发挥重要作用，因此这些发现可能有助于理解和治疗与酒精依赖相关的不同疾病。
Background: Elevated plasma homocysteine concentrations can influence genomic and gene-specific DNA methylation in peripheral blood cells. The aim of this study was to investigate in patients with alcohol dependence, who show chronically elevated homocysteine levels, whether DNA methylation pattern within the HERP (homocysteine-induced endoplasmic reticulum protein) promoter region and expression of HERP in RNA is altered.Methods: The HERP mRNA expression level was measured by quantitative PCR in the blood of 66 male alcoholic patients and 55 nondrinking healthy controls. Epigenetic genomic DNA methylation status and HERP promoter methylation were measured with a nonradioactive elongation assay.Results: We observed a significant increase (7.6%) in the HERP promoter DNA methylation in patients with alcohol dependence (t test, t=-2.45, p < 0.02) when compared with healthy controls (80.4%, SD 14.5), which was significantly associated with their elevated homocysteine levels (multiple linear regression, p < 0.007). Furthermore, we found,t significantly lower HERP mRNA expression in patients with alcohol dependence (t test, -7.61 Delta CT; SD 1.87, p < 0.001) when compared with healthy controls (-6.04 Delta CT; SD 2.41). The lowered HERP mRNA expression in alcoholic patients was best explained by the hypermethylation of the regulatory HERP gene promoter (regression analysis, p = 0.004).Conclusions: To our knowledge, this is the first study evaluating HERE mRNA expression and its specific gene promoter methylation in alcoholic patients. As hypermethylation of DNA is an important epigenetic factor in the down-regulation of gene expression, and as HERP has been considered to play an essential role within the intracellular defense system, these findings may be useful in the understanding and treatment of different disease conditions associated with alcohol dependence.