CpG island reconfiguration for the establishment and synchronization of polycomb functions upon exit from naive pluripotency
CpG island reconfiguration for the establishment and synchronization of polycomb functions upon exit from naive pluripotency
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DOI：
10.1016/j.molcel.2022.01.027
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发表时间：
2022-03-17
期刊：
影响因子：
16
通讯作者：
Wu, Xudong
中科院分区：
文献类型：
--
作者：
Huo, Dawei;Yu, Zhaowei;Wu, Xudong
多梳族（Polycomb group，PcG）蛋白通过在发育调节基因的启动子（主要是CpG岛（CGIs））上沉积抑制性组蛋白修饰而对着床后发育至关重要。然而，启动子PcG标记在受精后被擦除，并在植入期胚胎中从头建立，与从幼稚到引发的多能性的转变相一致。然而，这种建立的分子基础仍然未知。在这项研究中，我们表明，长KDM 2B亚型（KDM 2BLF），其中包含脱甲基酶结构域的表达，是专门诱导围植入期和它的H3 K36 me 2脱甲基酶活性所需的PcG富集CGIs。此外，KDM 2BLF与BRG 1/BRM相关因子（BAF）相互作用，并稳定BAF在CGI上的占有率，以便随后获得PcG富集之前的可及性。一致地，KDM 2BLF失活导致显著延迟的植入后发育。总之，我们的数据揭示了退出幼稚多能性过程中CGIs的动态染色质构型，并为PcG功能的时空建立提供了概念框架。
Polycomb group (PcG) proteins are essential for post-implantation development by depositing repressive histone modifications at promoters, mainly CpG islands (CGIs), of developmental regulator genes. However, promoter PcG marks are erased after fertilization and de novo established in peri-implantation embryos, coinciding with the transition from naive to primed pluripotency. Nevertheless, the molecular basis for this establishment remains unknown. In this study, we show that the expression of the long KDM2B isoform (KDM2BLF), which contains the demethylase domain, is specifically induced at peri-implantation and that its H3K36me2 demethylase activity is required for PcG enrichment at CGIs. Moreover, KDM2BLF interacts with BRG1/BRM-associated factor (BAF) and stabilizes BAF occupancy at CGIs for subsequent gain of accessibility, which precedes PcG enrichment. Consistently, KDM2BLF inactivation results in significantly delayed post-implantation development. In summary, our data unveil dynamic chromatin configuration of CGIs during exit from naive pluripotency and provide a conceptual framework for the spatiotemporal establishment of PcG functions.