LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62

Abstract

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.

Inhibition of the NLRP3 inflammasome prevents ovarian aging

“…Blockade of autophagic flux and accumulation of nondegraded substrates in the form of autophagosome are linked to aging (12). Furthermore, apoptosis and autophagy are involved in the process of oocyte loss (13,14). Nlrp3 −/− female mice showed increased levels of ATG12, beclin 1, and LC3-II protein and reduced expression of p62/ SQSTM1 compared with an accumulation of LC3-I with p62-aged WT mice associated with an impairment of autophagy ( Fig.…”

Long non-coding RNA Xist regulates oocyte loss via suppressing miR-23b-3p/miR-29a-3p maturation and upregulating STX17 in perinatal mouse ovaries

“…2A ). As autophagy is also reported to be active during follicular assembly and contributes to perinatal oocyte loss 5 , we, therefore, tested whether Xist could induce autophagy in perinatal mouse ovaries. As the microtubule-associated protein light chain 3B (LC3B) is a marker of autophagosomes, we observed more LC3B puncta presented in the cytoplasm of Xist- overexpressed oocytes (Fig.…”

“…It is well accepted that cellular apoptosis and autophagy processes are responsible for programmed oocyte loss occurring briefly around the time of birth 5 , 31 , 40 . Meanwhile, lncRNAs are emerging as central regulators in controlling cell autophagy or apoptosis in various diseases 49 , 50 .…”

“…However, multiple factors can induce excessive loss or overactivation of PFs in the PF pool, which is closely related to primary premature ovarian insufficiency (POI) and even to female infertility 3 , 4 . A better understanding of the regulatory mechanisms underlying PF pool formation will provide us with deep insights into the potential pathogenic mechanism of POI 5 – 7 .…”

Inhibition of the NLRP3 inflammasome prevents ovarian aging

“…Blockade of autophagic flux and accumulation of non-degraded substrates in the form of autophagosome are linked to aging (11). Furthermore, apoptosis and autophagy are involved in the process of oocyte loss (12,13). Interestingly, Nlrp3 -/female mice showed increased levels of ATG12, beclin 1 and LC3II protein, and reduced expression of p62/SQSTM1 ( Figure 3C).…”