LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62
LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62
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LSD1 通过调节自噬接头 SQSTM1/p62 的转录导致程序性卵母细胞死亡
DOI：
10.1111/acel.13102
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发表时间：
2020-02-19
期刊：
影响因子：
7.8
通讯作者：
Wang, Chao
中科院分区：
文献类型：
--
作者：
He, Meina;Zhang, Tuo;Wang, Chao
在雌性哺乳动物中，卵巢内最初建立的原始卵泡（PF）池的大小决定了雌性的生殖寿命。有趣的是，由于不明原因，PF池的建立伴随着显著的程序性卵母细胞丢失。虽然细胞凋亡和自噬参与了卵母细胞丢失的过程，但其潜在的机制需要大量的研究。在这里，我们发现了赖氨酸特异性去甲基酶1 （LSD1）通过调节自噬水平来控制围产期小鼠卵母细胞命运的新作用。我们的研究结果表明，胎儿卵巢中相对较高的LSD1水平从性交后18.5 （dpc）开始急剧下降。同时，自噬水平升高，卵母细胞开始程序性死亡。与对照组相比，特异性破坏LSD1导致自噬显著增加，卵母细胞数量明显减少。相反，卵巢中过表达Lsd1可显著增加卵母细胞数量。我们进一步证明LSD1通过其H3K4me2去甲基化酶活性调节p62转录并影响自噬水平发挥作用。最后，在生理条件下，当大量卵母细胞丢失时，LSD1水平降低导致卵母细胞自噬水平升高。综上所述，LSD1可能是一种不可缺少的表观遗传分子，通过在特定的时间内抑制自噬水平来保护卵母细胞免受过早死亡。表观遗传调节通过调节小鼠自噬参与卵母细胞程序性死亡。
In female mammals, the size of the initially established primordial follicle (PF) pool within the ovaries determines the reproductive lifespan of females. Interestingly, the establishment of the PF pool is accompanied by a remarkable programmed oocyte loss for unclear reasons. Although apoptosis and autophagy are involved in the process of oocyte loss, the underlying mechanisms require substantial study. Here, we identify a new role of lysine-specific demethylase 1 (LSD1) in controlling the fate of oocytes in perinatal mice through regulating the level of autophagy. Our results show that the relatively higher level of LSD1 in fetal ovaries sharply reduces from 18.5 postcoitus (dpc). Meanwhile, the level of autophagy increases while oocytes are initiating programmed death. Specific disruption of LSD1 resulted in significantly increased autophagy and obviously decreased oocyte number compared with the control. Conversely, the oocyte number is remarkably increased by the overexpression of Lsd1 in ovaries. We further demonstrated that LSD1 exerts its role by regulating the transcription of p62 and affecting autophagy level through its H3K4me2 demethylase activity. Finally, in physiological conditions, a decrease in LSD1 level leads to an increased level of autophagy in the oocyte when a large number of oocytes are being lost. Collectively, LSD1 may be one of indispensible epigenetic molecules who protects oocytes against preterm death through repressing the autophagy level in a time-specific manner. And epigenetic modulation contributes to programmed oocyte death by regulating autophagy in mice.