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

• Published in: Nature communications 2025-01, Vol.16 (1), p.127-17, Article 127
• Main Authors: Guo, Hong-Yan, Tang, Shou-Bin, Li, Li-Jun, Lin, Jing, Zhang, Ting-Ting, Chao, Shuo, Jin, Xiao-Wen, Xu, Kui-Peng, Su, Xiao-Feng, Yin, Shen, Zhao, Ming-Hui, Huang, Gui-An, Yang, Li-Jia, Shen, Wei, Zhang, Lei, Zhang, Cui-Lian, Sun, Qing-Yuan, Ge, Zhao-Jia
• Format: Article
• Language: English
• Subjects: 13/1; 13/89; 14/19; 14/32; 14/63; 38/22; 38/77; 38/91; 631/136/2442; 631/208/176/1988; 64/60; 692/163/2743/137/1926; Animals; Deoxyribonucleic acid; Diabetes mellitus; Diabetes, Gestational - genetics; Diabetes, Gestational - metabolism; DNA; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNA Methylation; DNMT1 protein; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; Epigenetics; Female; Gametocytes; Gene expression; Genomics; Gestational diabetes; Heredity; Humanities and Social Sciences; Humans; Male; Metabolic disorders; Mice; multidisciplinary; Offspring; Oocytes; Oocytes - metabolism; Pregnancy; Pregnancy complications; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-55499-x

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. Gestational diabetes milletus (GDM) may have impairments on offspring health. Here, the authors suggest that the increase of EZH2 is an important reason for the disrupted DNA methylome in oocytes exposed to GDM, which may be associated with the transgenerational inheritance of the metabolic disorders.