MLL1介导的H3K4甲基化修饰在双酚A影响胚胎着床中的机制研究

Embryo implantation, a crucial early pregnancy event determining the success of term pregnancy, is effected by endometrial dsruptors like BPA. However, it remained largely unknown regarding the transcriptional regulatory mechanism., we preliminary found that BPA produced implantation defect in association with a defective uterine morphology during the implantation period. Alterations in the expression of MLL1、HOXA10 were showed, but the specific mechanism has not yet been elucidated. we hypothesized that MLL1, the methyltransferases for histone H3K4, are likely to be potential vital players during early pregnancy. To address how these histone methylation events participate in regulating the process of BPA induced implantation failure , kinds of mouse models and cell lines will be used to study the the spatiotemporal expression pattern of MLL1 in the periimplantation uterus,studying the physiological role of H3K4 methylation during embryo implantation. It is hoped that a better understanding on epigenetic regulatory aspects of embryo implantation failure inducesd by EDCs will help us to reveal the pathological change of early pregnancy

胚胎着床是决定妊娠成功与否的关键环节，环境内分泌干扰物如双酚A是影响胚胎着床的重要因素之一。目前双酚A影响胚胎着床的具体调控机制尚未阐明。研究提示组蛋白修饰在胚胎发育关键过程中发挥重要作用。前期研究证实双酚A可干扰小鼠胚胎着床期子宫内膜上组蛋白甲基化转移酶MLL1及其介导的H3K4组蛋白分子的蛋白表达，最终导致胚胎着床失败。基于以上，我们假设MLL1及其介导的H3K4甲基化修饰在双酚A影响胚胎着床中起重要的转录调控作用。围绕这一科学问题，我们拟通过在体动物实验、细胞实验及临床病例分析，研究MLL1在围植入期子宫中的动态表达模式，分析其在胚胎着床和子宫蜕膜发育中的调节机制，证实MLL1在双酚A影响胚胎着床中的关键作用，深入阐明环境内分泌干扰物对胚胎着床过程中子宫微环境的干扰机制。

子宫内膜容受性建立涉及一系列复杂的分子调控机制，有研究报道组蛋白修饰在其中发挥关键调控作用，但环境内分泌干扰物BPA是否通过组蛋白修饰影响子宫内膜容受性尚不明确。本课题我们首先探讨组蛋白甲基化转移酶MLL1如何参与调控子宫内膜容受性，然后研究不同程度的BPA暴露是否通过组蛋白修饰影响内膜容受性的建立和胚胎着床。通过多个体内外模型和临床标本数据，我们发现MLL1在子宫内膜间质细胞蜕膜化过程中，受孕激素受体（PGR）调控，而MLL1介导的H3K4me3修饰又参与孕激素信号通路的传导，并通过靶向调控多个与蜕膜化相关基因和信号通路影响内膜容受性和胚胎着床，参与反复移植失败和内异症患者不孕的发生机制。环境内分泌干扰物BPA暴露可通过下调MLL1介导的H3K4me3修饰，上调EZH2介导的H3K27me3修饰，抑制蜕膜化相关基因的表达，影响内膜容受性和胚胎着床。此外，BPA还能够通过WDR5介导的组蛋白修饰和TET2介导的DNA去甲基化修饰联合作用，促进子宫内膜中ER基因表达和子宫内膜的增殖，参与内异症的发生发展。本课题研究结果深入挖掘组蛋白甲基化修饰在子宫内膜容受性建立中的关键作用，并证实BPA通过调节组蛋白甲基化修饰影响子宫蜕膜化转变的分子机制，为改善内膜容受性的治疗提供新思路。