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Hypermethylation of endoplasmic reticulum disulfide oxidase 1α leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia

Xiong, Jiantuan; Ding, Ning; Gao, Tingting; Wang, Yanhua; Guo, Wei; Zhang, Hui; Ma, Xiaoli; Li, Fan; Sun, Jianmin LU and Yang, Xiaoling, et al. (2018) In Journal of Cellular Biochemistry
Abstract

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... (More)

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.

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keywords
Apoptosis, DNA methylation, DNA methyltransferase (DNMT), Endoplasmic reticulum (ER) stress, Endoplasmic reticulum oxidoreductin 1α (ERO1α)
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Journal of Cellular Biochemistry
publisher
Wiley-Blackwell
external identifiers
  • scopus:85051037291
ISSN
0730-2312
DOI
10.1002/jcb.27101
language
English
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yes
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0160fa73-9b7a-4fb4-892e-1356590acfe8
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2018-09-13 11:57:15
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2018-09-14 03:00:11
@article{0160fa73-9b7a-4fb4-892e-1356590acfe8,
  abstract     = {<p>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.</p>},
  author       = {Xiong, Jiantuan and Ding, Ning and Gao, Tingting and Wang, Yanhua and Guo, Wei and Zhang, Hui and Ma, Xiaoli and Li, Fan and Sun, Jianmin and Yang, Xiaoling and Wu, Kai and Zhang, Huiping and Jiang, Yideng},
  issn         = {0730-2312},
  keyword      = {Apoptosis,DNA methylation,DNA methyltransferase (DNMT),Endoplasmic reticulum (ER) stress,Endoplasmic reticulum oxidoreductin 1α (ERO1α)},
  language     = {eng},
  month        = {07},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Cellular Biochemistry},
  title        = {Hypermethylation of endoplasmic reticulum disulfide oxidase 1α leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia},
  url          = {http://dx.doi.org/10.1002/jcb.27101},
  year         = {2018},
}