TET2调控滋养细胞功能及其机制研究

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, where dysregulation of DNA methylation is always found. However, the underlying mechanism still remains elusive up to now. Our previous results showed that the level of genomic DNA methylation is increased in preeclampsia placenta in comparison to normal placenta. While the transcription and protein level of TET2 significantly reduces in preeclampsia placenta. Moreover, knockdown of TET2 obviously inhibited the migration and invasion of trophoblast cells. These results implied that TET2 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 TET2 biological functions in placenta trophoblast cell and its critical roles in the progression of preeclampsia, identify the downstream key functional genes by microarray, CHIP-seq, etc, reveal the effect of TET2 on placental structure and pregnancy outcome through the mouse model, thereby providing new strategies and evidences for target therapy of preeclampsia.

滋养细胞是胎盘的基础性功能细胞，对妊娠的建立和维持具有重要作用，其功能障碍会导致多种妊娠疾病，如子痫前期等。研究表明子痫前期中存在DNA甲基化的异常调控，目前对其调控的生物学机制尚不明确。本课题组前期研究表明：与正常孕晚期胎盘相比，子痫前期胎盘中基因组DNA甲基化升高，DNA去甲基化酶TET2的转录及蛋白水平降低；在体外敲降TET2后，滋养细胞的迁移侵袭能力显著下降。这些结果提示TET2可能通过调控基因组DNA甲基化参与滋养细胞生物学功能，其异常表达可能会导致子痫前期的发生。本课题将进一步确定TET2与子痫前期的相关性；明确其参与滋养细胞的生物学功能调控；通过功能分类基因芯片、染色质免疫共沉淀等技术寻找TET2靶向调控的下游基因，明确TET2对滋养细胞生物学功能调控的作用机制；并通过小鼠模型揭示TET2对胎盘结构功能及妊娠结局的影响，为子痫前期的靶向性治疗提供新的线索和理论依据。

滋养细胞是胎盘的基础性功能细胞，对妊娠的建立和维持具有重要作用，其功能障碍会导致多种妊娠疾病，如子痫前期等。研究表明子痫前期中存在DNA甲基化的异常调控，目前对其调控的生物学机制尚不明确。该项目以DNA去甲基化酶TET2为对象，深入研究其在滋养细胞中的生物学功能，进而揭示TET2异常表达在子痫前期发生中的作用机制。首先，我们发现与正常孕晚期胎盘相比，子痫前期胎盘中TET2的蛋白表达显著降低；免疫组织化学分析显示与对照胎盘中TET2定位在滋养细胞，且子痫前期胎盘中TET2在滋养细胞阳性染色的比例明显下降；敲降TET2后，滋养细胞的增殖、迁移和侵袭能力明显下降。这提示我们TET2参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。该项研究揭示了异常表达的TET2在子痫前期发生中的重要作用，为子痫前期的靶向治疗提供了新思路。