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

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

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 6

BMI1 ensures normal PR sensitivity via modulating E6AP-mediated PR ubiquitination.

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BMI1 ensures normal PR sensitivity via modulating E6AP-mediated PR ubiqu...
(A and B) Coimmunoprecipitation analysis reveals that BMI1 can physically interact with E6AP both in human Ishikawa cells (A) and mouse receptive day 4 (D4) uteri (B). (C) PRE-luciferase reporter assay shows a compromised PR transcriptional activity in E6AP-KO Ishikawa cells. pSV40-Renilla served as an internal control. The values are shown as the mean ± SEM (n = 3). (D) Mammalian 2-hybrid analysis reveals a significantly reduced physical association of SRC1/2 with PRB in E6AP-KO Ishikawa cells. Data shown represent the mean ± SEM (n = 3). (E) Cotransfection of SRC1 or SRC2 can partially improve PR transcriptional activity in E6AP-KO Ishikawa cells. The values are shown as the mean ± SEM (n = 3). (F) BMI1 promotes the physical interaction of E6AP with PRB. The values are shown as the mean ± SEM (n = 3). (G and H) Ubiquitination of PRB is greatly hampered in BMI1-mutant Ishikawa cells (G), as well as in day 4 Bmi1d/d mouse uteri (H). (I) PRE-luciferase reporter assay reveals a compromised PR transcriptional activity in WT Ishikawa cells transfected with a lysine-less Ub mutant (Ub-K0). Data represent the mean ± SEM (n = 3). *P < 0.05, independent-samples Student’s t test. P4, progesterone.