BMI1 Deficiency Results in Female Infertility by Activating p16/p19 Signaling and Increasing Oxidative Stress

摘要

The polycomb repressor B lymphoma Mo-MLV insertion region 1 (BMI1) is a core composition of polycomb repressive complex 1 (PRC1) and contributes to diverse fundamental cellular processes including cell senescence, apoptosis and proliferation. To investigate the role and mechanism of BMI1 in maintaining normal female reproductive function, we compared the differences in reproductive phenotypes between Bmi1-deficient and wild-type female mice. The Bmi1-deficient female mice were then supplemented with N-acetylcysteine in their drinking water to explore whether antioxidant supplementation could improve reproductive dysfunction caused by BMI1 deficiency. The results revealed that Bmi1 deletion resulted in complete infertility in female mice, estrous cycle disorder, and follicular developmental disorders. The reactive oxygen species levels in the ovarian tissue were increased; the ability of antioxidant enzymes was downregulated; the expression levels of p19 and p53 proteins were significantly upregulated. We also found that oocytes derived from Bmi1-deficient mice could not develop into embryos by in vitro fertilization and in vitro culture of embryos. Furthermore, supplementation with the antioxidant NAC not only improved the reproductive defects caused by Bmi1 deletion, but also largely rescued the ability of Bmi1-deficient oocytes to develop into embryos in vitro. These results indicated that cells lacking Bmi1 resulted in female infertility by activating the p16/p19 signaling pathway, increasing oxidative stress and DNA damage, inhibiting granulosa cell proliferation, and inducing granulosa cell apoptosis. Thus, BMI1 may be a novel potential target for the clinical treatment of female infertility.