Bmi-1 Directs Normal Uterine Receptivity For Embry Implantation Via Regulating The PR Ubiquitinate Modification

Implantation involves an intricate discourse between the embryo and uterus and is a gateway to further embryonic development.Synchronizing embryonic development until the blastocyst stage with the uterine differentiation that takes place to produce the receptive state is crucial to successful implantation,and therefore to pregnancy outcome.These developmental events are synchronized with the proliferation and differentiation of specific uterine cell types,primarily under the direction of ovarian oestrogen(E2)and progesterone(P4).These hormones make the uterus conducive('receptive')to accept a blastocyst for implantation.Progesterone is known as pregnancy hormone essential for embryo implantation and subsequent pregnancy maintenance.Natural and synthetic progestogens have been commonly used for prevention of recurrent pregnancy loss in women with inadequate progesterone secretion or reduced progesterone sensitivity.However,it remained controversial whether progesterone supplementation in the first trimester of pregnancy would increase the chance of successful implantation and ongoing pregnancy among women with a history of unexplained recurrent miscarriages.Particularly,it remained largely unknown yet regarding the underlying cause for impaired endometrial progesterone responsiveness during early pregnancy.Employing multiple approaches,we demonstrated herein that uterine-selective depletion of mouse B cell-specific Mo-MLV integration site 1(Bmi-1)hampers uterine progesterone responsiveness and thus derails normal uterine receptivity resulting in implantation failure in mice.Searching for the underlying mechanism,we provided here genetic and biochemical evidence that Bmi-1,a key component of the polycomb repressive complex-1,via interacting with progesterone receptor PR and E3 ligase E6-AP in a polycomb complex independent manner regulates PR ubiquitination essential for normal progesterone responsiveness.Most importantly,this essentiality of Bmi-1 for endometrial PR function is conserved from mouse to human,since we observed a close association of aberrantly low endometrial BMI-1 expression with restrained PR responsiveness in miscarriage women.Besides uncovering a novel regulatory mechanism of BMI-1 ensuring normal endometrial progesterone responsiveness at periimplantation,our findings help to better understand the underlying causes of spontaneous pregnancy loss in women.