Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart.
Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart.
复制标题
发育中的人类唐氏综合症的大脑和心脏中的一级和继发性转录作用。
DOI：
10.1186/gb-2005-6-13-r107
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发表时间：
2005
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
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作者：
对唐氏综合症患者胎儿小脑和心脏组织转录水平的微阵列分析显示，仅 21 号染色体基因表达受到破坏。唐氏综合症由 21 三体染色体引起，是导致智力低下的主要原因。最近的研究表明，21 三体中 21 号染色体基因表达出现剂量依赖性增加。然而，尚不清楚是否整个转录组被破坏，或者分配给 21 号染色体的那些基因的表达增加是否受到更限制。此外，人类唐氏综合症组织中差异表达基因的统计显着性尚未报道。我们使用 DNA 微阵列测量了人类胎儿小脑和心脏组织中的转录物水平，并证明了 21 三体性导致不同组织/细胞类型的转录出现剂量依赖性增加。此外，通过更大的样本量，结合来自四种不同组织和细胞类型的数据，并使用方差分析方法，我们鉴定了 21 三体性中表达显着改变的单个基因，其中一些基因以组织特异性方式表现出这种失调。我们通过对分配给 21 号染色体和其他染色体的 28 个基因进行 5,600 多次定量实时 PCR 验证了我们的微阵列数据。来自 21 号染色体（但不是来自其他染色体）的基因表达值可以从整倍体样本中准确分类 21 三体性。我们的数据还表明 21 三体性中可能受到干扰的功能群。在唐氏综合症中，21 号染色体基因表达破坏具有主要转录效应，而对其余转录组没有普遍的次级效应。失调基因和通路的识别表明，分子变化可能是唐氏综合症表型的基础。
Microarray analysis of transcript levels in fetal cerebellum and heart tissues of Down syndrome patients showed a disruption only of chromosome 21 gene expression. Down syndrome, caused by trisomic chromosome 21, is the leading genetic cause of mental retardation. Recent studies demonstrated that dosage-dependent increases in chromosome 21 gene expression occur in trisomy 21. However, it is unclear whether the entire transcriptome is disrupted, or whether there is a more restricted increase in the expression of those genes assigned to chromosome 21. Also, the statistical significance of differentially expressed genes in human Down syndrome tissues has not been reported. We measured levels of transcripts in human fetal cerebellum and heart tissues using DNA microarrays and demonstrated a dosage-dependent increase in transcription across different tissue/cell types as a result of trisomy 21. Moreover, by having a larger sample size, combining the data from four different tissue and cell types, and using an ANOVA approach, we identified individual genes with significantly altered expression in trisomy 21, some of which showed this dysregulation in a tissue-specific manner. We validated our microarray data by over 5,600 quantitative real-time PCRs on 28 genes assigned to chromosome 21 and other chromosomes. Gene expression values from chromosome 21, but not from other chromosomes, accurately classified trisomy 21 from euploid samples. Our data also indicated functional groups that might be perturbed in trisomy 21. In Down syndrome, there is a primary transcriptional effect of disruption of chromosome 21 gene expression, without a pervasive secondary effect on the remaining transcriptome. The identification of dysregulated genes and pathways suggests molecular changes that may underlie the Down syndrome phenotypes.