Deficiency Leads to Premature Ovarian Failure.

Tet enzymes participate in DNA demethylation and play critical roles in stem cell pluripotency and differentiation. DNA methylation alters with age. We find that deficiency reduces fertility and leads to accelerated reproductive failure with age. Noticeably, -deficient mice at young age exhibit dramatically reduced follicle reserve and the follicle reserve further decreases with age, phenomenon consistent with premature ovarian failure (POF) syndrome. Consequently, deficient mice become infertile by reproductive middle age, while age matched wild-type mice still robustly reproduce. Moreover, by single cell transcriptome analysis of oocytes, deficiency elevates organelle fission, associated with defects in ubiquitination and declined autophagy, and also upregulates signaling pathways for Alzheimer's diseases, but down-regulates X-chromosome linked genes, such as , which is known to be implicated in POF. Additionally, is aberrantly upregulated and endogenous retroviruses also are altered in deficient oocytes. These molecular changes are consistent with oocyte senescence and follicle atresia and depletion found in premature ovarian failure or insufficiency. Our data suggest that enzyme plays roles in maintaining oocyte quality as well as oocyte number and follicle reserve and its deficiency can lead to POF.