CDYL/AIF1信号通路异常抑制子宫内膜上皮细胞黏附致胚胎反复着床失败的机制研究

子宫内膜容受性低下所致胚胎反复着床失败（RIF）是辅助生殖临床难题，上皮细胞黏附功能下降是造成容受性降低的重要原因，机制不详。前期研究发现：表观调控因子CDYL在对照组分泌中期子宫内膜上皮细胞高表达，RIF组显著下调；条件性敲除Cdyl雌鼠，子宫内膜容受性受损、生育力下降；Ishikawa细胞转录组测序和验证发现AIF1是CDYL下游关键因子，在RIF组高表达；干扰CDYL表达，AIF1水平增加、启动子区组蛋白修饰模式改变，细胞黏附被抑制；过表达CDYL或敲低AIF1，黏附恢复。由此推测，RIF患者CDYL表达下降通过上调AIF1表达抑制上皮细胞黏附进而降低子宫内膜容受性。本项目拟借助临床标本、Cdyl条件性敲除小鼠等，系统分析CDYL、AIF1与RIF发生的相关性；阐述CDYL调控AIF1信号通路在维持子宫内膜容受性中的重要作用及机制；以期发现治疗RIF的新干预靶点。

Recurrent implantation failure (RIF) caused by low endometrial receptivity is a severely clinical problem in assisted reproduction. Impaired adhesion of endometrial epithelial cells is one of the major causes of decreased endometrial receptivity, which mechanism is unknown. Our previous studies found that Chromodomain Y like (CDYL) was highly expressed in the endometrium at mid-secretory phase during the normal menstrual cycles. However, the expression of CDYL was down-regulated in RIF group. Mice with Cdyl conditional deficiency in endometrial epithelial cells showed decreased implantation sites and impaired endometrial receptivity. Using RNA-seq analysis after shRNA-mediated knockdown of CDYL in Ishikawa cells, we found allograft inflammatory factor 1 (AIF1) expression was dramatically up-regulated responding to the CDYL inhibition, with changes in epigenetic modification of AIF1 promoter region. AIF1 expression was increased in the endometrial epithelial cells from RIF patients. Moreover, the cell adhesion was impaired by CDYL-knockdown in Ishikawa cells, which could be rescued by CDYL-overexpression or AIF1-knockdown. Therefore, we suggest that the decreased expression of CDYL in RIF patients inhibits the adhesion function of endometrial epithelial cells and reduces endometrial receptivity by promoting AIF1 levels. This project will analyze the correlation between CDYL, AIF1 and the clinical occurrence of RIF; explore the mechanism of CDYL in regulating endometrial receptivity via epigenetic regulation of AIF1 expression; and elucidate new strategies to prevent embryo implantation failure by targeting CDYL and AIF1.