BMI1 Deficiency Results in Female Infertility by Activating p16/p19 Signaling and Increasing Oxidative Stress
BMI1 Deficiency Results in Female Infertility by Activating p16/p19 Signaling and Increasing Oxidative Stress
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DOI：
10.7150/ijbs.30488
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发表时间：
2019-03
影响因子：
9.2
通讯作者：
Rong Wang;Xian Xue;Yang Wang;Hai-feng Zhao;Yuling Zhang;Hui Wang;D. Miao
中科院分区：
文献类型：
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作者：
Rong Wang;Xian Xue;Yang Wang;Hai-feng Zhao;Yuling Zhang;Hui Wang;D. Miao
多梳状阻遏物B淋巴瘤Mo-MLV插入区1（BMI 1）是多梳状阻遏复合物1（PRC 1）的核心组成部分，并有助于多种基本细胞过程，包括细胞衰老、凋亡和增殖。为了探讨BMI 1在维持雌性正常生殖功能中的作用和机制，我们比较了BMI 1缺陷型和野生型雌性小鼠生殖表型的差异。然后在Bmi 1缺陷的雌性小鼠的饮用水中补充N-乙酰半胱氨酸，以探索抗氧化剂补充是否可以改善Bmi 1缺陷引起的生殖功能障碍。结果表明，Bmi 1缺失导致雌性小鼠完全不育，发情周期紊乱和卵泡发育障碍。卵巢组织中活性氧水平升高，抗氧化酶能力下调，p19和p53蛋白表达水平显著上调。我们还发现，来自Bmi 1缺陷小鼠的卵母细胞不能通过体外受精和胚胎体外培养发育成胚胎。此外，补充抗氧化剂NAC不仅改善了Bmi 1缺失引起的生殖缺陷，而且在很大程度上挽救了Bmi 1缺陷卵母细胞在体外发育成胚胎的能力。这些结果表明，缺乏Bmi 1的细胞通过激活p16/p19信号通路，增加氧化应激和DNA损伤，抑制颗粒细胞增殖，诱导颗粒细胞凋亡而导致女性不育。因此，BMI 1可能成为女性不孕症临床治疗的一个新的潜在靶点。
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.