Gene expression profiling in the adult Down syndrome brain
Gene expression profiling in the adult Down syndrome brain
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DOI：
10.1016/j.ygeno.2007.08.005
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发表时间：
2007-12-01
期刊：
影响因子：
4.4
通讯作者：
Bahn, S.
中科院分区：
文献类型：
--
作者：
Lockstone, H. E.;Harris, L. W.;Bahn, S.
21三体导致特征性唐氏综合征（DS）表型的机制尚不清楚。我们首次使用全基因组微阵列来表征来自7名DS受试者和8名对照者的成人脑组织（背外侧前额叶皮层）的转录组。将这些数据与来自胎儿DS组织的公开数据集进行共分析，并进行功能分析，以确定DS的核心生物过程以及可能与迟发性病理学（特别是阿尔茨海默病神经病理学）相关的生物过程。在严格的显著性阈值（调整的p值（q）< 0.005）下，总共685个探针组在成人DS和对照脑之间差异表达，其中70%在DS中上调。21号染色体上超过25%的基因差异表达，而所有染色体的中位数为4.4%。染色体21上上调的独特特征与主要剂量效应一致，伴随着广泛的转录破坏。阿尔茨海默病的关键基因APP位于21号染色体上，通过微阵列或QPCR分析未发现在成人脑中上调。然而，许多与APP加工功能相关的其他基因失调。在胎儿和成人数据集中失调的基因的功能分析确定了包括发育（特别是Notch信号传导和Dlx家族基因）、脂质转运和细胞增殖的类别。在成人大脑中，这些过程伴随着细胞骨架调节和囊泡运输类别，以及增加的免疫反应和氧化应激反应，这可能与DS个体中阿尔茨海默病病理学的发展有关。(c)2007年爱思唯尔公司All rights reserved.
The mechanisms by which trisomy 21 leads to the characteristic Down syndrome (DS) phenotype are unclear. We used whole genome microarrays to characterize for the first time the transcriptome Of human adult brain tissue (dorsolateral prefrontal cortex) from seven DS subjects and eight controls. These data were coanalyzed with a publicly available dataset from fetal DS tissue and functional profiling was performed to identify the biological processes central to DS and those that may be related to late onset pathologies, particularly Alzheimer disease neuropathology. A total of 685 probe sets were differentially expressed between adult DS and control brains at a stringent significance threshold (adjusted p Value (q) < 0.005), 70% of these being up-regulated in DS. Over 25% of genes on chromosome 21 were differentially expressed in comparison to a median of 4.4% for all chromosomes. The unique profile Of Up-regulation on chromosome 2 1, consistent with primary dosage effects, was accompanied by widespread transcriptional disruption. The critical Alzheimer disease gene, APP, located on chromosome 21, was not found to be up-regulated in adult brain by microarray or QPCR analysis. However, numerous other genes functionally linked to APP processing were dysregulated. Functional profiling of genes dysregulated in both fetal and adult datasets identified categories including development (notably Notch signaling and Dlx family genes), lipid transport, and cellular proliferation. In the adult brain these processes were concomitant with cytoskeletal regulation and vesicle trafficking categories, and increased immune response and oxidative stress response, which are likely linked to the development of Alzheimer pathology in individuals with DS. (c) 2007 Elsevier Inc. All rights reserved.