Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation.
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.
['Xin|Qiliang|Q|', 'Kong|Shuangbo|S|', 'Yan|Junhao|J|', 'Qiu|Jingtao|J|', 'He|Bo|B|', 'Zhou|Chan|C|', 'Ni|Zhangli|Z|', 'Bao|Haili|H|', 'Huang|Lin|L|', 'Lu|Jinhua|J|', 'Xia|Guoliang|G|', 'Liu|Xicheng|X|', 'Chen|Zi-Jiang|ZJ|', 'Wang|Chao|C|', 'Wang|Haibin|H|']
D000022:Abortion, Spontaneous D000818:Animals D010064:Embryo Implantation D004717:Endometrium D005260:Female D006801:Humans D051379:Mice D008822:Mice, Transgenic D063150:Polycomb Repressive Complex 1 D011247:Pregnancy D011374:Progesterone D011518:Proto-Oncogene Proteins D011980:Receptors, Progesterone D044767:Ubiquitin-Protein Ligases
Fertility Mouse models Reproductive Biology Sex hormones