多梳家族蛋白（PcG）是一类对保持细胞记忆和可塑性至关重要的染色质调控因子。前期研究发现Fbxl10募集PcG结合于CpG岛，并建立相应组蛋白修饰，但是该特征在胚胎着床期才逐步建立，Fbxl10长异构体（Fbxl10-LF）具备H3K36me2去甲基化酶活性，在着床期特异性高表达，因此我们提出假说：着床期Fbxl10-LF在CpG岛营造H3K36me2缺失的局部染色质环境，使PcG功能得以建立，调控着床后胚胎发育。本项目拟探索着床期Fbxl10-LF转录激活的分子机制；建立Fbxl10-LF酶活性突变的胚胎干细胞及小鼠模型，通过细胞培养体系及早期胚胎发育追踪，观察对胚胎干细胞退出原始态多能性以及胚胎发育的影响，检测CpG岛H3K36me2滞留对PcG蛋白结合及相应组蛋白修饰水平的影响，以明确Fbxl10作为PcG募集者及CpG岛环境改造者的双重作用，揭示胚胎发育早期细胞命运转变的调控网络。

Polycomb group (PcG) proteins play essential roles in maintaining cellular memory and plasticity. We previously demonstrated Fbxl10 recruits PcG to bind to CpG islands and promotes histone H2AK119 monoubiquitylation. However this establishment of PcG functions starts from the peri-implantation period. Interestingly the long isoform of Fbxl10 (Fbxl10-LF), a form with histone demethylase activity against H3K36me2, is specifically expressed during implantation. Therefore we hypothesize that Fbxl10-LF creates an H3K36me2-depleted nucleation site at CpG islands to allow the establishment of PcG functions for the control of embryo development after implantation. Here we will briefly explore the molecular mechanisms for the transcriptional activation of Fbxl10-LF during implantation. To confirm the importance of the demethylase activity of Fbxl10-LF, we will generate the catalytically inactive mutation of Fbxl10-LF in mouse embryonic stem cells (mESCs) and embryos. By the dynamic in vitro culture systems and embryo development tracking, we will observe how the mutation affects the exit of naive pluripotency of mESCs and the early embryonic development. Meanwhile, we will examine how the retention of H3K36me2 at CpG islands affect the binding of PcG and the accordingly histone modifications (H3K27me3 and H2AK119ub1) in mESCs as well as in embryos before and after implantation (E3.5 and E6.5). This study will hopefully link the dual roles of Fbxl10 in PcG recruitment and CpG island construction to early embryonic development.