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Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation
Qiliang Xin, … , Chao Wang, Haibin Wang
Qiliang Xin, … , Chao Wang, Haibin Wang
Published January 2, 2018; First published November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):175-189. https://doi.org/10.1172/JCI92862.
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Categories: Research Article Reproductive biology

Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation

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Abstract

Natural and synthetic progestogens have been commonly used to prevent recurrent pregnancy loss in women with inadequate progesterone secretion or reduced progesterone sensitivity. However, the clinical efficacy of progesterone and its analogs for maintaining pregnancy is variable. Additionally, the underlying cause of impaired endometrial progesterone responsiveness during early pregnancy remains unknown. Here, we demonstrated that uterine-selective depletion of BMI1, a key component of the polycomb repressive complex-1 (PRC1), hampers uterine progesterone responsiveness and derails normal uterine receptivity, resulting in implantation failure in mice. We further uncovered genetic and biochemical evidence that BMI1 interacts with the progesterone receptor (PR) and the E3 ligase E6AP in a polycomb complex–independent manner and regulates the PR ubiquitination that is essential for normal progesterone responsiveness. A close association of aberrantly low endometrial BMI1 expression with restrained PR responsiveness in women who had previously had a miscarriage indicated that the role of BMI1 in endometrial PR function is conserved in mice and in humans. In addition to uncovering a potential regulatory mechanism of BMI1 that ensures normal endometrial progesterone responsiveness during early pregnancy, our findings have the potential to help clarify the underlying causes of spontaneous pregnancy loss in women.

Authors

Qiliang Xin, Shuangbo Kong, Junhao Yan, Jingtao Qiu, Bo He, Chan Zhou, Zhangli Ni, Haili Bao, Lin Huang, Jinhua Lu, Guoliang Xia, Xicheng Liu, Zi-Jiang Chen, Chao Wang, Haibin Wang

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Figure 1

Uterine-selective depletion of Bmi1 results in embryo implantation failure.

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Uterine-selective depletion of Bmi1 results in embryo implantation failu...
(A) In situ hybridization analysis reveals a spatiotemporal expression of Bmi1 in mouse uteri on days 1–8 of pregnancy. White scale bar: 100 μm. (B–D) Quantitative real-time PCR (B), immunoblotting (C), and immunohistochemical analysis (D) of uterine Bmi1 mRNA and protein levels in Bmi1fl/fl and Bmi1d/d uteri on day 4 (D4). The values are shown as the mean ± SEM (n = 3). Black scale bar: 100 μm. (E) Number of ovulated eggs in Bmi1fl/fl and Bmi1d/d mice. Number within the bar indicates the number of mice tested. (F) Average litter sizes of Bmi1fl/fl versus Bmi1d/d females. Number within the bar indicates the number of mice tested. (G and H) A large portion of Bmi1d/d females exhibit implantation failure recovered with morphologically normal blastocysts upon flushing the uterine horn on days 5 (G) and 6 (H) of pregnancy. IS, implantation site. Number within the bar indicates the number of mice with implantation sites per total tested mice. Data represent the mean ± SEM. **P < 0.01, independent-samples Student’s t test. Bls, blastocysts; Em, embryo; Ge, glandular epithelium; Le, luminal epithelium; S, stroma.
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