Abstract:
The trophoblast epithelial-to-mesenchymal transition (EMT) is a procedure related to embryo implantation, spiral artery establishment and fetal-maternal communication, which is a key event for successful pregnancy. Inadequate EMT is one of the pathological mechanisms of recurrent miscarriage (RM). Whole-exome sequencing revealed that the mutation of bromodomain PHD-finger transcription factor (BPTF) was strongly associated with RM. In the present study, the effects of BPTF on EMT and the underlying mechanism were investigated. We found that the expression of BPTF in the villi of RM patients was significantly downregulated. Gene Ontology (GO) analysis revealed that BPTF participated in cell adhesion. The knockdown of BPTF prevented EMT and attenuated trophoblast invasion in vitro. BPTF activated Slug transcription by binding directly to the promoter region of the Slug gene. Interestingly, the protein levels of both Slug and BPTF were decreased in the villous cytotrophoblasts (VCTs) of RM villi. In conclusion, BPTF participates in the regulation of trophoblast EMT by activating Slug expression, suggesting that BPTF defects are an important factor in RM pathogenesis.
摘要:
滋养细胞上皮-间质转化(EMT)是一个与胚胎植入相关的过程,螺旋动脉建立和胎母交流,这是成功怀孕的关键事件。EMT不足是复发性流产(RM)的病理机制之一。全外显子组测序显示溴结构域PHD指转录因子(BPTF)的突变与RM密切相关。在本研究中,研究了BPTF对EMT的影响及其机制。我们发现RM患者绒毛中BPTF的表达明显下调。基因本体论(GO)分析显示BPTF参与细胞粘附。BPTF的敲减阻止了EMT并减弱了滋养细胞的体外侵袭。BPTF通过直接结合Slug基因的启动子区域来激活Slug转录。有趣的是,RM绒毛绒毛滋养细胞(VCT)中Slug和BPTF的蛋白水平均降低。总之,BPTF通过激活Slug表达参与滋养层EMT的调节,提示BPTF缺陷是RM发病的重要因素。