Domains of genomewide gene expression dysregulation in Down syndrome [Dnase HS mapping]. Homo sapiens

Trisomy 21 (T21) is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in T21, and to eliminate the noise of the genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for T21. Here we show that the differential expression between the twins is organized in domains along all chromosomes that are either up- 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 DS and wild-type, 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 LADs position was not altered in trisomic cells. However, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. These results suggest 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 T21 phenotypes. Overall design: DNaseI HS mapping in monozygotic twins discordant for trisomy 21 (2 replicates of each).

21-三体综合征（Trisomy 21, T21）是引发认知障碍的最常见遗传病因。为评估21-三体综合征中的基因表达扰动，并消除基因组变异带来的实验噪声，我们对一对21-三体状态不一致的同卵双胞胎的胎儿成纤维细胞转录组开展了研究。本研究发现，双胞胎间的差异表达沿所有染色体形成具有上调或下调特征的调控区域。此类基因表达失调区域（Gene Expression Dysregulation Domains, GEDDs）可通过其包含基因的表达水平进行界定，且在由双胞胎成纤维细胞诱导得到的诱导多能干细胞（induced pluripotent stem cells, iPSCs）中具有高度保守性。对唐氏综合征（Down Syndrome, DS）模型小鼠Ts65Dn与野生型小鼠的转录组进行比较分析，同样发现小鼠染色体上存在与人类同源的GEDDs。GEDDs与哺乳动物细胞的核纤层关联结构域（Lamina-Associated Domains, LADs）及复制区域存在相关性。三体细胞中LADs的整体位置并未发生改变，但三体成纤维细胞的H3K4me3修饰谱发生了改变，且其分布模式与GEDDs高度吻合。上述结果表明，三体细胞的核区室发生了染色质环境的改变，进而影响整体转录组；因此GEDDs可能参与了部分21-三体综合征的表型形成。整体实验设计：针对21-三体状态不一致的同卵双胞胎，开展DNase I超敏位点作图分析（每组设置2次生物学重复）。