Gestational diabetes mellitus causes genome hyper-methylation of oocyte via increased EZH2

Hong-Yan Guo, Shou-Bin Tang, Li-Jun Li, Jing Lin, Ting-Ting Zhang, Shuo Chao, Xiao-Wen Jin, Kui-Peng Xu, Xiao-Feng Su, Shen Yin, Ming-Hui Zhao, Gui-An Huang, Li-Jia Yang, Wei Shen, Lei Zhang, Cui-Lian Zhang (luckyzcl@qq.com), Qing-Yuan Sun (sunqy@gd2h.org.cn) and Zhao-Jia Ge (gejdssd313@163.com)
Additional contact information
Hong-Yan Guo: Qingdao Agricultural University
Shou-Bin Tang: Qingdao Agricultural University
Li-Jun Li: Qingdao Agricultural University
Jing Lin: Qingdao Agricultural University
Ting-Ting Zhang: Henan Provincial People’s Hospital
Shuo Chao: Qingdao Agricultural University
Xiao-Wen Jin: Qingdao Agricultural University
Kui-Peng Xu: Qingdao Agricultural University
Xiao-Feng Su: Qingdao Agricultural University
Shen Yin: Qingdao Agricultural University
Ming-Hui Zhao: Qingdao Agricultural University
Gui-An Huang: Qingdao Agricultural University
Li-Jia Yang: Qingdao Agricultural University
Wei Shen: Qingdao Agricultural University
Lei Zhang: Tsinghua University
Cui-Lian Zhang: Henan Provincial People’s Hospital
Qing-Yuan Sun: Guangdong Second Provincial General Hospital
Zhao-Jia Ge: Qingdao Agricultural University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Gestational diabetes mellitus (GDM), a common pregnancy disease, has long-term negative effects on offspring health. Epigenetic changes may have important contributions to that, but the underlying mechanisms are not well understood. Here, we report the influence of GDM on DNA methylation of offspring (GDF1) oocytes and the possible mechanisms. Our results show that GDM induces genomic hyper-methylation of offspring oocytes, and at least a part of the altered methylation is inherited by F2 oocytes, which may be a reason for the inheritance of metabolic disorders. We further find that GDM exposure increases the expression of Ezh2 in oocytes. Ezh2 regulates DNA methylation via DNMT1, and Ezh2 knockdown reduces the genomic methylation level of GDF1 oocytes. These results suggest that GDM may induce oocyte genomic hyper-methylation of offspring via enhancing the Ezh2 expression recruiting more DNMT1 into nucleus.

Date: 2025
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DOI: 10.1038/s41467-024-55499-x

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