X-chromosome inactivation in rett syndrome human induced pluripotent stem cells.
X-chromosome inactivation in rett syndrome human induced pluripotent stem cells.
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DOI：
10.3389/fpsyt.2012.00024
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发表时间：
2012
影响因子：
4.7
通讯作者：
Ellis J
中科院分区：
文献类型：
--
作者：
Cheung AY;Horvath LM;Carrel L;Ellis J
Rett综合征(RTT)是一种神经发育障碍，主要由于编码甲基CpG结合蛋白2(MECP2)的X连锁基因的杂合突变而影响女孩。随机X染色体失活(XCI)导致细胞嵌合体，其中一些细胞表达野生型(WT)MECP2，而另一些细胞表达突变型MECP2。患者特异性人类诱导多能干细胞(HiPSCs)的产生有助于在体外产生RTT-hiPSC来源的神经元，以研究疾病机制和寻找新的药物治疗。许多实验室已经报道了RTT-hiPSCs的产生，然而，RTT-hiPSCs的XCI状态一直不一致。一些报告RTT-hiPSCs保留了创建者体细胞的不活跃的X染色体(后XCI)，允许从同一患者中分离出仅表达WT或突变的MECP2等位基因的等基因RTT-hiPSCs。XCI后RTT-hiPSCs来源的神经元保留了WT或突变的MECP2的这种等位基因特异性表达模式。相反，其他人报告了RTT-hiPSCs，在RTT-hiPSCs中，创建者体细胞的不活跃的X染色体在重新编程为RTT-hiPSCs时重新激活(Pre-XCI)。XCI前RTT-hiPSC来源的神经元表现出随机的XCI，导致细胞关于WT和突变的MECP2表达的嵌合体。在这里，我们回顾并试图解释迄今为止产生的RTT-hiPSCs与其他体外和体内多能系统以及用于分析XCI的方法在XCI状态上的不一致。最后，我们讨论了XCI后和XCI前的HiPSCs在RTT和其他X连锁和常染色体转化医学疾病中的相对优势和劣势。
Rett syndrome (RTT) is a neurodevelopmental disorder that affects girls due primarily to heterozygous mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). Random X-chromosome inactivation (XCI) results in cellular mosaicism in which some cells express wild-type (WT) MECP2 while other cells express mutant MECP2. The generation of patient-specific human induced pluripotent stem cells (hiPSCs) facilitates the production of RTT-hiPSC-derived neurons in vitro to investigate disease mechanisms and identify novel drug treatments. The generation of RTT-hiPSCs has been reported by many laboratories, however, the XCI status of RTT-hiPSCs has been inconsistent. Some report RTT-hiPSCs retain the inactive X-chromosome (post-XCI) of the founder somatic cell allowing isogenic RTT-hiPSCs that express only the WT or mutant MECP2 allele to be isolated from the same patient. Post-XCI RTT-hiPSCs-derived neurons retain this allele-specific expression pattern of WT or mutant MECP2. Conversely, others report RTT-hiPSCs in which the inactive X-chromosome of the founder somatic cell reactivates (pre-XCI) upon reprogramming into RTT-hiPSCs. Pre-XCI RTT-hiPSC-derived neurons exhibit random XCI resulting in cellular mosaicism with respect to WT and mutant MECP2 expression. Here we review and attempt to interpret the inconsistencies in XCI status of RTT-hiPSCs generated to date by comparison to other pluripotent systems in vitro and in vivo and the methods used to analyze XCI. Finally, we discuss the relative strengths and weaknesses of post- and pre-XCI hiPSCs in the context of RTT, and other X-linked and autosomal disorders for translational medicine.