Liu Linlin, Wang Huasong, Xu Guo Liang, Liu Lin
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, China.
State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
Front Cell Dev Biol. 2021 Mar 23;9:644135. doi: 10.3389/fcell.2021.644135. eCollection 2021.
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.
Tet酶参与DNA去甲基化，并在干细胞多能性和分化中发挥关键作用。DNA甲基化随年龄而改变。我们发现，（该酶）缺乏会降低生育能力，并随着年龄增长导致加速的生殖功能衰竭。值得注意的是，年轻的（该酶）缺乏小鼠表现出显著减少的卵泡储备，并且卵泡储备随着年龄进一步减少，这种现象与卵巢早衰（POF）综合征一致。因此，（该酶）缺乏的小鼠在生殖中年时变得不育，而年龄匹配的野生型小鼠仍能强劲繁殖。此外，通过对卵母细胞的单细胞转录组分析，（该酶）缺乏会提高细胞器裂变，与泛素化缺陷和自噬下降相关，并且还会上调阿尔茨海默病的信号通路，但下调X染色体连锁基因，如已知与POF有关的（某个基因）。此外，（某个基因）在（该酶）缺乏的卵母细胞中异常上调，内源性逆转录病毒也发生改变。这些分子变化与在卵巢早衰或功能不全中发现的卵母细胞衰老、卵泡闭锁和耗竭一致。我们的数据表明，（该）酶在维持卵母细胞质量以及卵母细胞数量和卵泡储备中发挥作用，其缺乏可导致POF。
