KIAA1429通过介导PIK3R1m6A修饰调控FoxO信号通路在单合子双胎选择性宫内生长受限中的机制研究

双胎选择性宫内生长受限（sIUGR）是常见的双胎严重并发症，其分子机制不清。以往研究仅证实sIUGR小胎胎盘小、血管密度减少。我们通过测序并验证发现小胎胎盘PIK3R1的m6A和表达水平异常。那么，PIK3R1异常的m6A及表达与sIUGR发病的关系和机制是什么？我们发现，在小胎胎盘中介导m6A修饰的KIAA1429表达降低；在细胞缺氧模型中KIAA1429表达异常，且与PIK3R1的m6A水平呈正相关，与表达呈负相关，并影响下游FoxO信号通路导致滋养细胞功能障碍。据此提出假设：KIAA1429可能通过介导PIK3R1的m6A修饰调控FoxO信号通路引起滋养细胞功能异常及血管发育障碍，最终导致sIUGR发生。本课题拟从临床相关性、生物学功能及分子机制三方面探讨KIAA1429调控PIK3R1的m6A修饰在sIUGR中的分子机制，为阐明表观遗传修饰机制与胎盘功能及胎儿发育的关系奠定基础。

Selective intrauterine growth restriction (sIUGR) is one of the most severe complications among monozygotic twins with adverse outcome, but the mechanism of which is still unclear. Previous studies have found that the smaller fetus of sIUGR shared less placenta and had sparser vasculature compared with the larger fetus. Our study showed that aberrant m6A and expression levels were both detected in the placenta of the small fetuses than that of the larger ones by sequencing technology and validation assays. What is the relationship and mechanism between aberrant m6A and expression level of PIK3R1 and sIUGR? Our further study showed that the expression of KIAA1429 was down-regulated in the smaller placental shares compared to the larger ones. Aberrant expression of KIAA1429 was detected in hypoxic trophoblast in vitro. And there was a positive correlation between KIAA1429 and the m6A level of PIK3R1, while there was a negative correlation between KIAA1429 and the expression of PIK3R1. Furthermore, FoxO signaling pathway and the functions of trophoblast were also affected by aberrant KIAA1429. Thus, we presume that aberrant KIAA1429 may induce dysplasias of trophoblasts and vasculature by mediating the FoxO signaling pathway via m6A modification of PIK3R1, leading to delayed growth in one fetus of sIUGR. The purpose of this study is to investigate the mechanism of KIAA1429-mediated m6A modification of PIK3R1 in placenta of sIUGR and try to lay the foundation for exploring the relationship between epigenetic mechanism and placental functions and fetal development.