Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency

• Published in: Nature (London) Vol. 605; no. 7911; pp. 761 - 766
• Main Authors: Chen, Bin, Du, Ya-Rui, Zhu, Hong, Sun, Mei-Ling, Wang, Chao, Cheng, Yi, Pang, Haiyan, Ding, Guolian, Gao, Juan, Tan, Yajing, Tong, Xiaomei, Lv, Pingping, Zhou, Feng, Zhan, Qitao, Xu, Zhi-Mei, Wang, Li, Luo, Donghao, Ye, Yinghui, Jin, Li, Zhang, Songying, Zhu, Yimin, Lin, Xiaona, Wu, Yanting, Jin, Luyang, Zhou, Yin, Yan, Caochong, Sheng, Jianzhong, Flatt, Peter R., Xu, Guo-Liang, Huang, Hefeng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-05-2022; Nature Publishing Group
• Subjects: 13; 13/51; 14/19; 14/35; 38; 38/1; 38/22; 38/23; 38/77; 38/90; 631/136/2435; 631/208/176/1988; 64/60; 692/163/2743/2815; Abnormalities; Adult; Age; Animals; Demethylation; Diabetes; Diabetes mellitus; Dioxygenase; Dioxygenases - metabolism; DNA damage; Embryos; Epigenetics; Female; Females; Gametocytes; Gene deletion; Gene expression; Glucokinase; Glucose; Glucose - metabolism; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; Glucose tolerance; Health risks; Homeostasis; Humanities and Social Sciences; Humans; Hyperglycemia; Hyperglycemia - complications; Hyperglycemia - genetics; Hyperglycemia - metabolism; In vitro fertilization; Insulin; Insulin resistance; Insulin secretion; Intolerance; Males; Mammals; Maternal Inheritance; Metabolism; Mice; Mothers; mRNA; multidisciplinary; Offspring; Oocytes; Oocytes - metabolism; Oxidation; Perturbation; Science; Science (multidisciplinary); Secretion; Womens health; Zygotes
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-04756-4

Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated
1
. Gestational diabetes has profound and enduring effects on the long-term health of the offspring
2
,
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 zygote
4
, 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.
Pregestational hyperglycaemia in mothers increases the probability of glucose intolerance in the offspring, an effect controlled by TET3-dependent DNA demethylation of genes involved in insulin secretion.