Domains of genome-wide gene expression dysregulation in Down's syndrome
Domains of genome-wide gene expression dysregulation in Down's syndrome
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DOI：
10.1038/nature13200
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发表时间：
2014-04-17
期刊：
影响因子：
64.8
通讯作者：
Antonarakis, Stylianos E.
中科院分区：
文献类型：
--
作者：
Letourneau, Audrey;Santoni, Federico A.;Antonarakis, Stylianos E.
21三体是导致认知障碍的最常见的遗传原因。为了评估21三体基因表达的扰动，并消除基因组变异的噪声，我们研究了一对与21三体不一致的同卵双胞胎胎儿成纤维细胞的转录组。在这里，我们表明，双胞胎之间的差异表达是在所有上调或下调的染色体上组织的区域。这些基因表达失调结构域(GEDD)可以由其基因含量的表达水平来定义，并且在双胞胎成纤维细胞来源的诱导多能干细胞中非常保守。Ts65Dn唐氏综合征模型小鼠和正常产仔小鼠成纤维细胞的转录组比较也显示出沿着小鼠染色体的GEDD，而人类的GEDD是共线的。GEDD与哺乳动物细胞的膜相关结构域(LAD)和复制结构域相关。LADS在三体细胞中的总位置没有改变，但三体成纤维细胞的H3K4me3图谱被修改，并准确地遵循GEDD模式。这些结果表明，三体细胞的核室经历了染色质环境的改变，从而影响了整个转录组，因此GEDD可能有助于一些21三体的表型。
Trisomy 21 is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in trisomy 21, and to eliminate the noise of genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy 21. Here we show that the differential expression between the twins is organized in domains along all chromosomes that are either upregulated or downregulated. These gene expression dysregulation domains (GEDDs)can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins' fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of Down's syndrome and normal littermate mouse fibroblasts also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlate with the lamina- associated (LADs)and replication domains of mammalian cells. The overall position of LADs was not altered in trisomic cells; however, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. These results indicate that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome, and that GEDDs may therefore contribute to some trisomy 21 phenotypes.