Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos
Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos
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DOI：
10.1016/j.stem.2007.09.001
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发表时间：
2007-11-01
期刊：
影响因子：
23.9
通讯作者：
Ben-Yosef, Dalit
中科院分区：
文献类型：
--
作者：
Eiges, Rachel;Urbach, Achia;Ben-Yosef, Dalit
我们报道了从植入前脆弱的x影响胚胎中建立人类胚胎干细胞（HESC）系，并证明了其作为研究这种疾病发病机制中涉及的发育调节事件的适当模型的价值。脆性X综合征是由于FMR1基因5'UTR区域的CGG扩增导致该基因失活。由于缺乏适当的动物或细胞模型，FMR1沉默的早期事件尚未完全表征。在这里，我们表明，尽管存在完全突变，受影响的未分化HESCs表达FMR1并且DNA未甲基化。然而，DNA甲基化和组蛋白修饰导致的表观遗传沉默发生在分化过程中。我们独特的细胞系统允许对获得这些表观遗传变化的序列进行解剖，并说明HESCs在揭示与人类遗传疾病相关的发育调节机制中的重要性。
We report on the establishment of a human embryonic stem cell (HESC) line from a preimplantation fragile X-affected embryo and demonstrate its value as an appropriate model to study developmentally regulated events that are involved in the pathogenesis of this disorder. Fragile X syndrome results from FMR1 gene inactivation due to a CGG expansion at the 5'UTR region of the gene. Early events in FMR1 silencing have not been fully characterized due to the lack of appropriate animal or cellular models. Here we show that, despite the presence of a full mutation, affected undifferentiated HESCs express FMR1 and are DNA unmethylated. However, epigenetic silencing by DNA methylation and histone modification occurs upon differentiation. Our unique cell system allows the dissection of the sequence by which these epigenetic changes are acquired and illustrates the importance of HESCs in unraveling developmentally regulated mechanisms associated with human genetic disorders.