Hypermethylation of endoplasmic reticulum disulfide oxidase 1alpha leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia.
Hypermethylation of endoplasmic reticulum disulfide oxidase 1alpha leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia.
复制标题
先兆子痫中内质网二硫化物氧化酶 1α 的高甲基化通过内质网应激导致滋养层细胞凋亡。
DOI：
10.1002/jcb.27101
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发表时间：
2018
影响因子：
4
通讯作者：
Jiang Yideng
中科院分区：
文献类型：
--
作者：
Xiong Jiantuan;Ding Ning;Gao Tingting;Wang Yanhua;Guo Wei;Zhang Hui;Ma Xiaoli;Li Fan;Sun Jianmin;Yang Xiaoling;Wu Kai;Zhang Huiping;Jiang Yideng
异常的滋养层细胞凋亡与包括先兆子痫（PE）在内的妊娠相关疾病的发病机制有关，而内质网（ER）应激被认为是调节细胞凋亡的新途径。在这项研究中，我们观察到缺氧条件下的滋养层细胞以及PE大鼠的胎盘中都会触发凋亡和内质网应激。定量聚合酶链反应和Western blot分析表明，缺氧条件下滋养层细胞中内质网二硫化物氧化酶1α（ERO1α）的表达由于ERO1α启动子区的高甲基化而受到抑制，ERO1α表达的抑制在ER应激和滋养层细胞凋亡中发挥重要作用。此外，我们发现DNA甲基转移酶1（DNMT1）是调节ERO1α表达的DNA甲基化的关键甲基转移酶，尽管DNMT1表达受到缺氧抑制，但DNMT1与ERO1α启动子区的结合水平在缺氧下显着升高，这表明DNMT1与ERO1α启动子区的结合水平而不是低氧条件下的结合水平。 DNMT1 表达水平有助于 ERO1α 的高甲基化。总而言之，这些结果表明，DNMT1 与 ERO1α 启动子结合增加介导的 ERO1α 高甲基化通过 PE 大鼠胎盘中的 ER 应激导致滋养层细胞凋亡，这有助于深入了解 PE 的病因，并可能为 PE 的治疗提供有效的治疗靶点。
Abnormal trophoblast cell apoptosis is implicated in the pathogenesis of pregnancy‐related disorders including preeclampsia (PE), and endoplasmic reticulum (ER) stress has been considered as a novel pathway in the regulation of cell apoptosis. In this study, we observed that both apoptosis and ER stress are triggered in trophoblast cells under hypoxia as well as in the placenta of PE rats. Quantitative polymerase chain reaction and Western blot analysis showed that the expression of endoplasmic reticulum disulfide oxidase 1α (ERO1α) is suppressed in trophoblast cells under hypoxia due to the hypermethylation of the ERO1α promoter region, and the inhibition of ERO1α expression plays an important role in ER stress and trophoblast cell apoptosis. Furthermore, we found that DNA methyltransferase 1 (DNMT1) is a key methyltransferase for DNA methylation in the regulation of ERO1α expression, and the binding level of DNMT1 to the ERO1α promoter is markedly elevated under hypoxia although DNMT1 expression is inhibited by hypoxia, suggesting that the binding level of DNMT1 to the ERO1α promoter region rather than the DNMT1 expression level contributes to the hypermethylation of ERO1α. Taken together, these results demonstrate that the hypermethylation of ERO1α mediated by increased binding of DNMT1 to the ERO1α promoter leads to trophoblast cell apoptosis through ER stress in the placenta of PE rats, which shed insight into the etiology of PE and might present a validated therapeutic target for the treatment of PE.