TY - JOUR AU - Xin, Qiliang AU - Kong, Shuangbo AU - Yan, Junhao AU - Qiu, Jingtao AU - He, Bo AU - Zhou, Chan AU - Ni, Zhangli AU - Bao, Haili AU - Huang, Lin AU - Lu, Jinhua AU - Xia, Guoliang AU - Liu, Xicheng AU - Chen, Zi-Jiang AU - Wang, Chao AU - Wang, Haibin T1 - Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation PY - 2018/01/02/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI92862 VL - 128 IS - 1 UR - https://doi.org/10.1172/JCI92862 SP - 175 EP - 189 PB - The American Society for Clinical Investigation ER -