胚胎染色体非整倍体是早期自然流产(First trimester miscarriage, FTM)发生的最主要病因，而卵子非整倍体异常是胚胎非整倍体发生的主要原因。申请人的前期研究发现，FTM患者的卵巢储备下降及生发泡期卵子STAG3基因表达下降，而STAG3与联会复合体形成，Cohesin以及纺锤体微管的稳定性相关。因此我们提出“低水平的STAG3是导致FTM患者卵子非整倍体升高的原因”的科学假说。本项目拟通过观察FTM患者不同发育阶段卵子的STAG3表达水平以及采用 siRNA干扰STAG3后观察小鼠卵子非整倍体和FTM发生，验证所提出的科学假说；该研究还将通过敲降STAG3的上游抑制基因E2F6和添加Ezh2抑制剂使STAG3出现过表达，探索STAG3下降的表观遗传调控机制。该项目的完成有望从STAG3表观遗传学调控方面找到治疗FTM的新靶点。

Embryonic aneuploidy is a primary reason for first trimester miscarriage (FTM), and the most embryonic aneuploidy comes from oocyte aneuploidy. Our previous studies have shown that women with history of FTM have an inferior ovarian reserve and a lower mRNA level of STAG3 in GV-stage oocyte compared with normal women. As STAG3 is closely related to Cohesion loading, chromosome synaptonemal complex formation and microtubule stability. We hypothesize that the lower level of STAG3 might be the key factor for aneuploidy oocyte of women with history of FTM. In this project, we will verify our hypothesize by observing the STAG3 expression in MI and GV stage oocyte from FTM women and by establishing the mice miscarriage model by siRNA interference. Furthermore, we will endeavor to explore the epigenetically regulatory mechanism of STAG3 by knocking down STAG3 inhibitor E2F6 and adding the inhibitor of Ezh2. The accomplishment of this project will shed light on the mechanism of oocyte development and help us find new ways to treat patients with first trimester miscarriage by the new knowledge on STAG3 epigenetic mechanism.