Abstract
Tet enzymes participate in DNA demethylation and play critical roles in stem cell pluripotency and differentiation. DNA methylation alters with age. We find that Tet1 deficiency reduces fertility and leads to accelerated reproductive failure with age. Noticeably, Tet1-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, Tet1-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, Tet1 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 Fmr1, which is known to be implicated in POF. Additionally, Line1 is aberrantly upregulated and endogenous retroviruses also are altered in Tet1-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 Tet1 enzyme plays roles in maintaining oocyte quality as well as oocyte number and follicle reserve and its deficiency can lead to POF.
Highlights
Ten-eleven translocation (Tet) methylcytosine dioxygenases play a major role in shaping DNA methylation patterns through demethylation (Wu and Zhang, 2017)
We show that Tet1 deficiency leads to premature ovarian failure (POF) by influencing the quality of oocytes, including aberrant X-chromosome inactivation, and increased expression of L1-mus, as well as the oocyte number and follicle reserve
We extended the study by evaluating age effects on the fertility and oocytes in adult mice deficient in Tet1
Summary
Ten-eleven translocation (Tet) methylcytosine dioxygenases play a major role in shaping DNA methylation patterns through demethylation (Wu and Zhang, 2017). Tet1-mediated 5 hmC signals play important role in DNA demethylation during primordial germ cell (PGC) development and meiosis (Yamaguchi et al, 2012, 2013a; Hill et al, 2018). Tet deficiency results in meiotic defects of PGCs, including impaired homologous pairing and recombination in meiotic germ cells (meiocytes) during fetal development, probably due to insufficient demethylation and failed activation of meiotic genes (Yamaguchi et al, 2013a), such that Tet1-deficient mice at young age already exhibit reduced number of oocytes in the ovary and subfertility (Yamaguchi et al, 2012, 2013a). It will be interesting to investigate whether Tet deficiency impacts reproductive aging of adult mice
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