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J Cell Biochem. 2018 Nov;119(10):8588-8599. doi: 10.1002/jcb.27101. Epub 2018 Jul 30.

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

Xiong J1, Ding N1,2, Gao T2,3, Wang Y1,2, Guo W1,2, Zhang H1,2, Ma X2,3, Li F1,2, Sun J1,4, Yang X1,2, Wu K1, Zhang H5, Jiang Y1,2.

Author information

1
School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia, China.
2
Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, Ningxia, China.
3
Department of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China.
4
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
5
Department of Prenatal Diagnosis Center, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.

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 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.

KEYWORDS:

DNA methylation; DNA methyltransferase (DNMT); apoptosis; endoplasmic reticulum (ER) stress; endoplasmic reticulum oxidoreductin 1α (ERO1α)

PMID:
30058081
DOI:
10.1002/jcb.27101

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