PRMT5促进Nur77蛋白精氨酸甲基化修饰抑制胚胎种植的机制研究

Decidualization of endometrial stromal cells plays an important role in the establishment and maintenance of embryo implantation. We have demonstrated that orphan nuclear receptor Nur77 is a critical regulator of embryo implantation and decidualization, but the factors regulating Nur77 expression and function are largely unknown. Recently, we show that PRMT5, identified as a physiological binding partner of Nur77, is significantly increased in the endometrium of infertile women, and suppresses endometrial stromal cells decidualization and embryo implantation. PRMT5 induces symmetric dimethylation of Nur77 and inhibits its transcriptional capacity. Based on these strong preliminary data, we hypothesized that augment PRMT5 expression in the endometrium of infertile women may contribute to impaired decidualization or endometrial receptivity by promoting arginine methylation of Nur77, which leads to embryo implantation failure. In this project, we will define the molecular mechanisms underlying the influence of PRMT5-dependent arginine methylation of Nur77 on reduced embryo implantation and decidualization in vitro and in a uterine-specific Prmt5 knock-in mouse model. It's hoped that these studies will provide novel insights into the molecular mechanism of embryo implantation failure, and may develop new therapies to improve the outcome of embryos implant following in vitro fertilization-embryo transfer (IVF-ET).

子宫内膜间质细胞蜕膜化对胚胎的成功植入和妊娠的建立至关重要。我们已证实核受体Nur77是子宫内膜蜕膜化和胚胎种植的重要调控分子，但其功能调控机制不清。我们新发现临床不孕患者子宫内膜组织中表达异常增高的蛋白质精氨酸甲基转移酶5（PRMT5）明显抑制子宫内膜间质细胞蜕膜化和小鼠胚胎种植；PRMT5与Nur77生理性相互结合，促进Nur77蛋白精氨酸对称性双甲基化修饰，并抑制Nur77对靶基因的转录激活作用。由此推测不孕患者子宫内膜组织中异常高表达的PRMT5通过增加Nur77蛋白精氨酸对称性双甲基化修饰，导致子宫内膜间质细胞蜕膜化受损和胚胎不能正常植入，这可能是胚胎种植失败的新机制。本研究将重点从Nur77蛋白甲基化修饰角度探讨PRMT5对胚胎种植的影响；并利用Prmt5子宫特异性敲入小鼠研究PRMT5调控胚胎植入的分子新机制，以期阐明临床不孕患者IVF-ET周期治疗时胚胎种植率低下的机制。

胚胎植入是胚胎和母体子宫内膜相互甄别并接纳的过程，是成功妊娠的基础，而母体子宫内膜间质细胞蜕膜化是决定胚胎植入成功的关键。本研究以蛋白质精氨酸甲基化修饰为切入点，以基因工程小鼠为模型，研究PRMT5介导的Nur77蛋白精氨酸对称性双甲基化（SDMA）修饰在子宫内膜间质细胞蜕膜化和胚胎种植过程中的作用机制。我们证实：PRMT5在子宫内膜生理病理情况下的表达模式；子宫间质细胞特异性敲除PRMT5导致间质细胞蜕膜化障碍和胚胎种植异常；PRMT5介导的Nur77蛋白精氨酸对称性双甲基化修饰促进子宫内膜间质细胞的蜕膜化和胚胎种植。此外我们还发现子宫特异性敲除PRMT5导致腺体发育障碍；子宫内膜异位症患者子宫内膜中PRMT5的低表达激活NF-κB通路，抑制子宫内膜蜕膜化。我们的研究为子宫内膜蜕膜化障碍患者的治疗提供了新靶点，为提高不孕症患者的妊娠率探索了新方法。