Gerhardt Jeannine
Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx 10461, USA.
Brain Res. 2017 Feb 1;1656:55-62. doi: 10.1016/j.brainres.2015.10.004. Epub 2015 Oct 20.
Patients with fragile X syndrome (FXS) exhibit moderate to severe intellectual disabilities. In addition, one-third of FXS patients show characteristics of autism spectrum disorder. FXS is caused by a trinucleotide repeat expansion, which leads to silencing of the fragile X mental retardation (FMR1) gene. The absence of the FMR1 gene product, FMRP, is the reason for the disease symptoms. It has been suggested that repeat instability and transcription of the FMR1 gene occur during early embryonic development, while after cell differentiation repeats become stable and the FMR1 gene is silent. Epigenetic marks, such as DNA methylation, are associated with gene silencing and repeat stability at the FMR1 locus. However, the mechanisms leading to gene silencing and repeat expansion are still ambiguous, because studies at the human genomic locus were limited until now. The FXS pluripotent stem cells, recently derived from FXS adult cells and FXS blastocysts, are new useful tools to examine these mechanisms at the human endogenous FMR1 locus. This review summarizes the epigenetic features and experimental studies of FXS human embryonic and FXS induced pluripotent stem cells, generated so far. This article is part of a Special Issue entitled SI: Exploiting human neurons.
脆性X综合征（FXS）患者表现出中度至重度智力残疾。此外，三分之一的FXS患者表现出自闭症谱系障碍的特征。FXS由三核苷酸重复序列扩增引起，这导致脆性X智力低下（FMR1）基因沉默。缺乏FMR1基因产物FMRP是出现疾病症状的原因。有人提出，FMR1基因的重复序列不稳定性和转录发生在胚胎发育早期，而细胞分化后重复序列变得稳定，FMR1基因沉默。表观遗传标记，如DNA甲基化，与FMR1基因座处的基因沉默和重复序列稳定性有关。然而，导致基因沉默和重复序列扩增的机制仍不明确，因为迄今为止对人类基因组位点的研究有限。最近从FXS成年细胞和FXS囊胚中获得的FXS多能干细胞，是在人类内源性FMR1基因座研究这些机制的新型有用工具。本综述总结了迄今为止所产生的FXS人类胚胎干细胞和FXS诱导多能干细胞的表观遗传特征及实验研究。本文是名为“SI：利用人类神经元”的特刊的一部分。
