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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 November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):175-189. https://doi.org/10.1172/JCI92862.
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Research Article Reproductive biology Article has an altmetric score of 1

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 3

Epithelium-selective Bmi1-knockout mice exhibit normal embryo implantation and uterine expression of receptivity marker genes.

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Epithelium-selective Bmi1-knockout mice exhibit normal embryo implantati...
(A) Immunohistochemical analysis shows the specific deletion of epithelial BMI1 in Bmi1fl/fl LtfCre/+ mouse uteri. Black scale bar: 100 μm. (B) Number of implantation sites and representative uteri in Bmi1fl/fl and Bmi1fl/fl LtfCre/+ mice. Number within the bar indicates the number of mice with implantation sites per total tested mice. (C) The comparable expression level of COX2 indicates normal attachment reaction in Bmi1fl/fl and Bmi1fl/fl LtfCre/+ mice. Black scale bar: 100 μm. (D and E) In situ hybridization analysis of receptivity marker genes reveal normal uterine receptivity in Bmi1fl/fl LtfCre/+ females on day 4 (D4) of pregnancy. Black scale bar: 100 μm. Bl, blastocyst; Ge, glandular epithelium; Le, luminal epithelium; S, stroma.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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