Establishment of FXS-A9 panel with a single human X chromosome from fragile X syndrome-associated individual
Establishment of FXS-A9 panel with a single human X chromosome from fragile X syndrome-associated individual
复制标题
使用来自脆性 X 综合征相关个体的单个人类 X 染色体建立 FXS-A9 组合
DOI：
10.1016/j.yexcr.2020.112419
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发表时间：
2021
影响因子：
3.7
通讯作者：
Kugoh Hiroyuki
中科院分区：
文献类型：
--
作者：
Nakayama Yuji;Adachi Kaori;Shioda Nofirifumi;Maeta Shoya;Nanba Eiji;Kugoh Hiroyuki
脆性X综合征（Fragile X syndrome，FXS）是最常见的遗传性智力障碍，FMR 1基因位于人类染色体Xq 27. 3，其5′端非翻译区含有一段CGG三核苷酸重复序列。FXS是由CGG重复序列扩增超过200引起的，通过启动子超甲基化导致FMR 1沉默。CGG重复序列扩增（FXS的根本原因）背后的分子机制仍然知之甚少，部分原因是缺乏实验系统。累积的证据表明，CGG重复侧翼的大染色体区域对重复动力学至关重要。在本研究中，我们从健康的FXS前突变携带者或携带疾病相关CGG重复长度的FXS患者中分离并引入完整的人类X染色体，通过微细胞介导的染色体转移进入小鼠A9细胞。这些单染色体杂交细胞中CGG重复序列长度相关的甲基化状态和humanFMR 1表达与人类相似。因此，这组含有来自三个不同来源的CGG重复序列的A9细胞（FXS-A9组）可能为研究FXS发病过程中的一系列遗传和表观遗传CGG重复序列动力学提供有价值的资源。
Fragile X syndrome (FXS) is the most common inheritable form of intellectual disability.FMR1, the gene responsible for FXS, is located on human chromosome Xq27.3 and contains a stretch of CGG trinucleotide repeats in its 5′ untranslated region. FXS is caused by CGG repeats that expand beyond 200, resulting inFMR1silencing via promoter hypermethylation. The molecular mechanism underlying CGG repeat expansion, a fundamental cause of FXS, remains poorly understood, partly due to a lack of experimental systems. Accumulated evidence indicates that the large chromosomal region flanking a CGG repeat is critical for repeat dynamics. In the present study, we isolated and introduced whole human X chromosomes from healthy, FXS premutation carriers, or FXS patients who carried disease condition-associated CGG repeat lengths, into mouse A9 cells via microcell-mediated chromosome transfer. The CGG repeat length-associated methylation status and humanFMR1expression in these monochromosomal hybrid cells mimicked those in humans. Thus, this set of A9 cells containing CGG repeats from three different origins (FXS-A9 panel) may provide a valuable resource for investigating a series of genetic and epigenetic CGG repeat dynamics during FXS pathogenesis.