Collaborative study of Xu Guoliang's group reveals that maternal TET3 deficiency mediates female gamete-derived adult diseases

Epidemiological studies have shown that adverse environmental exposures during pregnancy can affect offspring health, so health management during pregnancy is critic.

In order to solve the above problems, the researchers first used streptozocin (STZ)-induced diabetic female mice as a model to expose the oocytes to a hyperglycemic environment; then, the oocytes were harvested with normal male sperm for in vitro fertilization; The obtained two-cell embryos were transplanted into healthy pseudopregnant dams to produce offspri.

To further investigate the molecular mechanism by which hyperglycemia-exposed oocytes lead to impaired glucose tolerance in offspring, the researchers analyzed the transcriptome of MII oocytes from diabetic female mice and found that the expression level of the maternal factor Tet3 was significantly decreas.

The researchers then performed whole-genome methylation sequencing on the offspring of pancreatic islets from diabetic female mi.

In order to clarify that the altered DNA methylation profiles of genes related to the abnormal glucose tolerance phenotype and insulin secretion pathway in the offspring were caused by the decreased expression of TET3 in oocytes, we further analyzed the oocyte-specific homozygous or heterozygous knockout Tet3 mouse progeny, it was found that these progeny mice also showed the phenotype of Gck promoter DNA hypermethylation and impaired glucose toleran.

Notably, GV-stage oocytes from diabetic patients and blastocysts cultured in vitro also showed decreased TET3 expression levels and DNA hypermethylation in the GCK promoter region, respectively, suggesting that human oocytes exposed to hyperglycemic environments are Metabolic syndrome may also develop in offspring produced after fertilizati.

In conclusion, this study used mouse oocytes to be exposed to maternal hyperglycemia to simulate human exposure to pre-pregnancy hyperglycemia, and to further explore the molecular mechanism of oocyte TET3-mediated abnormal glucose tolerance in offspring, suggesting that oocyte developmental period It is a window period that is sensitive to environmental factors; maternal TET3 and its expression level in fertilized eggs and its normal function will affect the health of offspri.

Professor Huang Hefeng from the Institute of Reproduction and Development of Fudan University and researcher Xu Guoliang from the Center of Excellence for Molecular Cells are the co-corresponding authors of the pap.

Article link: https://

Link to News & views in the same period: https://

Hyperglycemia exposure resulted in decreased expression of DNA dioxygenase TET3 in egg cells, and its deficiency attenuated DNA demethylation of insulin secretion pathway-related genes in the male pronucleus of fertilized eggs, thereby increasing the risk of metabolic dysfunction in offspri.