Nature2014-06-18 7:03 PM

唐氏综合征的遗传病理 Domains of genome-wide gene expression dysregulation in Down’s syndrome

论文摘要 
 
唐氏综合征被认为是由基因表达紊乱造成的,所以要了解这种表现型背后的分子机制,就需要了解携带21号染色体的全部或部分“三体”(这种疾病的典型特征)的细胞和组织中的转录组差异。对在21号染色体的“三体”性上有所不同的单卵双胞胎的胎儿细胞的转录组所作的这项研究表明,该双胞胎之间的差异化表达沿所有染色体都是按不同区域组织的。这些基因表达失调区域在关于唐氏综合征的小鼠模型中保留了下来,与“薄层相关域”(LAD)和“复制域”相关联。虽然基因组整体拓扑在“三体”细胞中没有被改变,但本文作者报告说影响整个转录组的染色质环境被改变了,同时提出,他们所识别出的失调区域因此可能会对唐氏综合征的一些表现型有贡献。

Abstract 

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.

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