DNA甲基转移酶3A在子痫前期发生中的作用及机制研究

滋养细胞是胎盘的基础性功能细胞，它对妊娠的建立和维持具有重要作用。研究表明妊娠过程中滋养细胞的功能障碍会导致子痫前期、自然流产等多种妊娠疾病，而其中往往存在DNA甲基化的异常调控。但目前对其调控的生物学机制尚不清楚。本课题组发现DNA甲基转移酶3A(DNMT3A)在其中可能起着关键的作用。我们前期研究结果表明：与正常孕晚期胎盘相比，重度子痫前期胎盘中DNMT3A的蛋白表达显著降低。敲降DNMT3A后，滋养细胞的迁移侵袭能力明显下降。这些结果提示DNMT3A参与胎盘滋养细胞的生物学调控，而其异常表达可能是引发病理性妊娠的重要原因。本课题将通过多方面研究明确DNMT3A在滋养细胞中的生物学功能，确定其在子痫前期发生中的关键作用，并通过RNAseq、DNA甲基化测序、染色质免疫共沉淀-测序等技术寻找下游关键靶基因，揭示DNMT3A作用的分子机制，从而为子痫前期的靶向性治疗提供新的线索和理论依据。

Trophoblast cells, playing important roles in the establishment and maintenance of pregnancy, are basically functional to placenta. It has been reported that dysfunction of trophoblast cell can cause gestational diseases such as preeclampsia and spontaneous abortion, where dysregulation of DNA methylation is always found. However, the underlying mechanism still remains elusive up to now. We found that DNA methyltransferase 3A (DNMT3A) may play significant roles in this diseases. Our previous results showed that DNMT3A protein level significantly reduces in preeclampsia placenta in comparison to normal placenta. Moreover, knockdown of DNMT3A obviously inhibited the migration and invasion of trophoblast cells. These results implied that DNMT3A regulates placenta trophoblast cell and its aberrant expression is probably one important reason for giving rise to preeclampsia. Thus, on the basis of the comprehensive study, this project is helpful to understand DNMT3A biological functions in placenta trophoblast cell and its critical roles in the progression of preeclampsia, identify the downstream key functional genes and reveal the molecular mechanisms by RNAseq, Bisulfite sequencing, CHIP-seq, etc, thereby providing new strategies and evidences for target therapy of preeclampsia.