Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency

Bin Chen, Ya-Rui Du, Hong Zhu, Mei-Ling Sun, Chao Wang, Yi Cheng, Haiyan Pang, Guolian Ding, Juan Gao, Yajing Tan, Xiaomei Tong, Pingping Lv, Feng Zhou, Qitao Zhan, Zhi-Mei Xu, Li Wang, Donghao Luo, Yinghui Ye, Li Jin, Songying Zhang, Yimin Zhu, Xiaona Lin, Yanting Wu, Luyang Jin, Yin Zhou, Caochong Yan, Jianzhong Sheng, Peter R. Flatt, Guo-Liang Xu () and Hefeng Huang ()
Additional contact information
Bin Chen: Zhejiang University School of Medicine
Ya-Rui Du: Chinese Academy of Sciences
Hong Zhu: Fudan University
Mei-Ling Sun: Chinese Academy of Sciences
Chao Wang: Chinese Academy of Sciences
Yi Cheng: Fudan University
Haiyan Pang: Zhejiang University School of Medicine
Guolian Ding: Fudan University
Juan Gao: Chinese Academy of Sciences
Yajing Tan: Shanghai Jiao Tong University
Xiaomei Tong: Zhejiang University, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province
Pingping Lv: Zhejiang University School of Medicine
Feng Zhou: Zhejiang University, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province
Qitao Zhan: Zhejiang University School of Medicine
Zhi-Mei Xu: Chinese Academy of Sciences
Li Wang: Shanghai Jiao Tong University
Donghao Luo: Zhejiang University, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province
Yinghui Ye: Zhejiang University School of Medicine
Li Jin: Fudan University
Songying Zhang: Zhejiang University, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province
Yimin Zhu: Zhejiang University School of Medicine
Xiaona Lin: Zhejiang University, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province
Yanting Wu: Fudan University
Luyang Jin: Zhejiang University School of Medicine
Yin Zhou: Zhejiang University
Caochong Yan: Zhejiang University School of Medicine
Jianzhong Sheng: Zhejiang University School of Medicine
Peter R. Flatt: Ulster University
Guo-Liang Xu: Chinese Academy of Sciences
Hefeng Huang: Zhejiang University School of Medicine

Nature, 2022, vol. 605, issue 7911, 761-766

Abstract: Abstract Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated1. Gestational diabetes has profound and enduring effects on the long-term health of the offspring2,3. However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote4, is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring.

Date: 2022
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DOI: 10.1038/s41586-022-04756-4

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