| First Author | Chen B | Year | 2022 |
| Journal | Nature | Volume | 605 |
| Issue | 7911 | Pages | 761-766 |
| PubMed ID | 35585240 | Mgi Jnum | J:338105 |
| Mgi Id | MGI:7367058 | Doi | 10.1038/s41586-022-04756-4 |
| Citation | Chen B, et al. (2022) Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency. Nature 605(7911):761-766 |
| abstractText | 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. |
