组蛋白表观遗传学修饰在胎盘ADAM12表达中的作用

妊娠期胎盘合成大量蛋白酶ADAM12，导致妊娠期母体血ADAM12水平特征性升高，此酶通过降解IGFBP3游离IGF-1/2，从而加强IGF-1/2促胎儿/胎盘生长作用，因此研究胎盘ADAM12的表达调控对于认识胎儿发育和宫内生长受限机制具有理论和临床意义。本课题组通过滋养细胞转录组学数据交汇分析发现，ADAM12和转录因子STAT5B被合体化和EZH2抑制剂共同上调，而且ADAM12基因启动子区存在STAT5B反应元件，因此本项目提出研究由EZH2介导的组蛋白H3K27甲基化在滋养细胞合体化过程ADAM12和STAT5B表达调控中的作用，并认为ADAM12的表达增加通过降解IGFBP3使得IGF-1/2游离增加，后者激活STAT5B磷酸化导致ADAM12表达进一步增加，从而形成合体化过程中IGFBP3降解/IGF-1/2游离/STAT3磷酸化/ADAM12表达之间的自我强化机制。

The placenta synthesizes a large amount of ADAM12, a protease which degrades IGFBP3 to free IGF1/2 from its sequestration thus enhancing IGF actions on fetal growth. This unique feature of the placenta is responsible for elevated ADAM12 levels in the maternal blood, a unique signature of pregnancy. In consideration of the crucial role of ADAM12 and IGF in fetal growth, it is of clinical significance to investigate the regulation of ADAM12 expression in the placenta in order to understand the mechanism of fetal growth regulation and the etiology of intrauterine growth restriction. Our conjoining RAN seqence data derived from trophoblast syncytialization and EZH2 inhibitor-treated trophoblasts revealed that both ADAM12 and the transcriptional factor STAT5B were among the genes which were upregulated by both syncytialization and inhibition of EZH2. Further promoter analysis showed the presence of STAT5B binding sites in ADAM12 gene. Therefore, we propose that the expression of ADAM12 might be under the transcriptional regulation of STAT5B as well as EZH2-mediated H3K27 methylation during syncytializatoin. We hypothesize that increased free IGF1/2 as a result of increased IGFBP3 breakdown by ADAM12 would further enhance STAT5B phosphorylation to increase the transcriptional activity of STAT5B thereby formulating a mutual enhancing mechanism between the expression of ADAM12 and release of IGF-1/2 from IGFBP3. We will test this hypothesis by using muliple approaches in this study, including an in vitro human trophoblast syncytialziation model, analysis of placental tissue derived from intrauterine growth restriction as well as an animal model.