滋养细胞侵入不足是子痫前期(PE)发生的主要原因之一，而PE胎盘中DNA甲基化异常升高是导致这一问题的关键因素，但其作用机制尚不明确。我们之前报道了DNA甲基转移酶DNMT3A(3A)在胎盘中的异常低表达对PE发生具有重要作用。有趣的是，我们进一步研究发现与传统认识不同，敲降3A导致了滋养细胞基因组DNA甲基化升高，FAM46C(46C)基因body甲基化程度明显增加且其蛋白在PE胎盘中高表达。重要的是，敲降46C能完全恢复3A缺失对滋养细胞迁移侵袭的影响。这些结果提示3A介导的46C甲基化异常调控在PE中扮演了关键角色。在此基础上，本课题将利用滋养细胞、小鼠囊胚等模型深入探讨3A负调控46C基因body甲基化的功能和机制，鉴定46C作用于滋养细胞的关键下游通路，揭示3A介导的46C甲基化异常调控在PE中的重要作用。本项目有望提出3A负调控DNA甲基化的新模式，为PE临床诊治提供新的思路。

Preeclampsia is a multiple system disorder during human pregnancy, which has become the major causes of maternal and fetal morbidity and mortality. The invasion deficiency of trophoblast cells has been thought as one of the major reasons. It has been demonstrated that genomic DNA methylation is upregulated in preeclamptic placenta, which influences the migration and invasion of trophoblast cells. However, the underlying mechanisms still remain elusive up to now. In our previous work, we reported that DNMT3A downregulation is relevant to preeclampsia. Then, our recent results show that knockdown of DNMT3A obviously increases genomic DNA methylation in trophoblast cells, and FAM46C gene body methylation is negatively regulated by DNMT3A. Moreover, we detected high expression of FAM46C in the clinical samples of preeclamptic placenta. Importantly, FAM46C downregulation can rescue the defects caused by DNMT3A knockdown. Collectively, the findings of our recent study imply that DNMT3A-mediated aberrant FAM46C gene body methylation play important roles in preeclamspsia. Thus, by using trophoblast cell lines in vitro and mouse model in vivo, this project will elucidate the functions and mechanisms of DNMT3A-mediated negative regulation of FAM46C gene body methylation, identify downstream signal pathways regulated by FAM46C in trophoblast cells, clarify the function of DNMT3A and FAM46C in placentation and pregnancy outcome, reveal the correlation between DNMT3A-mediated aberrant FAM46C gene body methylation and preeclampsia. And this study will not only propose a new model for DNMT3A-mediated negative regulation of DNA methylation, but also provide theoretical basis for clinical prevention and treatment for preeclampsia.