YTHDF3通过m1A表观修饰调控滋养细胞功能诱导自然流产的机制研究

母胎界面中滋养细胞的侵袭能力不足是导致妊娠相关疾病的重要因素，而精确调控滋养细胞生物学功能的RNA表观修饰机制却知之甚少。我们新近发现低氧能诱导滋养细胞mRNA的m1A表观修饰水平发生显著下调，且发现m1A修饰的reader蛋白为YTHDF3，同时胎盘特异性过表达YTHDF3后胚胎吸收率明显高于对照野生型小鼠。在此基础上，我们拟描绘正常和自然流产组织中滋养细胞的m1A表观修饰图谱，分析YTHDF3对人滋养细胞及蜕膜免疫细胞等生物学功能及妊娠的影响。通过iCLIP和转录组测序寻找与YTHDF3结合并受其调控的靶标基因，结合滋养细胞中m1A表观修饰图谱，从而探索YTHDF3通过结合哪些m1A修饰的关键基因并调控该靶标基因的表达进而调控滋养细胞生物学功能的分子机制，以期从m1A表观修饰的角度阐明调控滋养细胞迁移侵袭的新机制，为临床滋养细胞侵袭不足导致自然流产等妊娠相关疾病的治疗提供新思路。

The poor invasiveness of trophoblasts at the maternal-fetal interface is an important factor leading to pregnancy associated diseases, but the mechanism of RNA epigenetic modification that precisely regulates the biological function of trophoblasts is poorly understood. Recently, we found that hypoxia can induce a significant downregulation of m1A modification level of trophoblast mRNA, and found that YTHDF3 act as the m1A reader protein, and found that the embryo absorption rate after YTHDF3 specific overexpression in placenta is significantly higher than that of in the control wildtype. On this basis, we intend to describe the m1A modification map of trophoblasts from normal and spontaneous abortion tissue, and analyze the effect of YTHDF3 on the pregnancy outcome and biological functions of human trophoblasts and decidual immune cells. Through iCLIP and transcriptome deep sequencing, and combine with the results of m1A modification map in trophoblast, we will find the target genes which bound and regulated by YTHDF3, so as to explore the molecular mechanism of the biological function of trophoblast regulated by YTHDF3 via binding which key genes modified by m1A and regulating the expression of the target genes, we intend to clarify the regulation mechanism of trophoblast migration and invasion from the perspective of m1A modification. The new mechanism will provide new ideas for the treatment of pregnancy associated diseases such as spontaneous abortion due to the insufficient of trophoblast invasion.