X染色体失活解析.pptVIP

HnRNP-U (heterogeneous nuclear ribonucleoprotein U) HnRNP-U, also known as Scaffold attachment factor A (SAF-A), has been long known to localize on Xi like YYI, hnRNP-U binds Xist close to Repeat C Depletion of hnRNP-U results in loss of Xist foci and gene silencing in ES cells HnRNP-U binds S/MARs(Scaffold associated region/Matrix attached region) perspetives Xist transcription is strictly regulated by pluripotency factors and ncRNAs that are in turn developmentally regulated. the cis-specific localization and action of Xist is subject to regulation by a plethora of protein factors However, Much remains unknown, and new knowledge raises new questions exact roles of various ncRNAs and protein factors in XCI regulation, the mechanism of Xist spreading across Xi, details for the action of Xist on gene silencing at the individual gene level ……… * * * * * * * * * * * * 启动与扩展 启动与扩展 启动之前, X is t 表达处于较低水平呈非稳定状态 启动后，X i st R N A 首先聚集并覆盖在即将失活的X染色体上。 同时反义基因T s ix 结合造成活性X 染色体上Xist 基因失活。 Xist RNA开始招募启动沉默相关因子, 这些相关因子随后又被其他的外源沉默信号所替代和增强,如组蛋白的甲基化、去乙酞化、异常组蛋白变体聚集、CpG岛甲基化等,从而形成稳定的失活状态。 这一失活状态可以在有丝分裂中得以传递和维持 X染色体失活状态的维持 失活X染色体的结构与正常染色体不同,包括: 组蛋白低乙酞化、CpG岛甲基、组蛋白macroH2A1.2的富集、S期复制滞后及Xist的覆盖等。 其中，Xist的表达与失活X 染色体的紧密连接。 DNA甲基化对维持失活的很重要,缺失CpG岛甲基化,X染色体失活是不稳定的。 组蛋白H3、H4低乙酞化是失活X染色体的另一个重要特征 DNA甲基化与组蛋白乙酞化之间存在协同关系 重要概念 X Inactivation Is Developmentally Regulated，X染色体失活受发育的调控 Chromosome Silencing Involves Multiple Levels of Epigenetic Modification，X染色体的失活包括多层次的表观遗传修饰 Some Genes Escape X Inactivation，有些基因可以逃避X染色体失活 X Inactivation Is Regulated by a Master Switch Locus, the X-Inactivation Center，X染色体失活的重要调控开关：X失活中心 卵母细胞 桑葚胚 滋养外胚层 原始内胚层 ICM和外胚层 原肠胚形成 胚胎 X Inactivation Is Developmentally RegulatedX染色体失活受发育的调控 Both X chromosomes are active in the early zygote, and inactivation then proceeds with cellular differentiation Normally,there is an equal probability that cells will inactivate their maternally or paternally derived X chromosome (Xm and Xp, respectively) An exception to this is imprinted X