Chromosomal profiles of gene expression in Huntington's disease
Chromosomal profiles of gene expression in Huntington's disease
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DOI：
10.1093/brain/awm312
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发表时间：
2008-02-01
期刊：
影响因子：
14.5
通讯作者：
Turkheimer, Federico E.
中科院分区：
文献类型：
--
作者：
Anderson, Alexander N.;Roncaroli, Federico;Turkheimer, Federico E.
最近的研究表明，亨廷顿舞蹈病是由于突变的亨廷顿蛋白、转录因子和转录共激活因子之间的异常相互作用导致广泛的转录失调。突变的亨廷顿蛋白也与组蛋白乙酰转移酶相互作用，从而干扰组蛋白的乙酰化和去乙酰化状态。由于组蛋白修饰和染色质结构协调基因簇的表达，我们应用了一种新的数学方法，Chromowave，来分析脑组织和全血的微阵列数据集，以了解突变的亨廷顿蛋白对染色质结构的影响如何改变基因组区域。结果表明，在亨廷顿氏病患者的尾状血和全血样本中，转录确实在大的基因组区域以协调的方式解除调控，这些区域的转录与疾病进展有关，并且两种组织中改变的染色体簇非常相似。这些发现支持了亨廷顿舞蹈病患者大脑和外周RNA转录破坏的共同全基因组机制的概念。
Recent studies suggested that Huntington's disease is due to aberrant interactions between mutant huntingtin protein, transcription factors and transcriptional co-activators resulting in widespread transcriptional dysregulation. Mutant huntingtin also interacts with histone acetyltransferases, consequently interfering with the acetylation and deacetylation states of histones. Because histone modifications and chromatin structure coordinate the expression of gene clusters, we have applied a novel mathematical approach, Chromowave, to analyse microarray datasets of brain tissue and whole blood to understand how genomic regions are altered by the effects of mutated huntingtin on chromatin structure. Results show that, in samples of caudate and whole blood from Huntington's disease patients, transcription is indeed deregulated in large genomic regions in coordinated fashion, that transcription in these regions is associated with disease progression and that altered chromosomal clusters in the two tissues are remarkably similar. These findings support the notion of a common genome-wide mechanism of disruption of RNA transcription in the brain and periphery of Huntington's disease patients.