全血全基因组表达谱分析和网络分析提示了线粒体脑肌病伴乳酸血症和卒中样发作（MELAS）的主要调控因子。

Whole blood genome-wide expression profiling and network analysis suggest MELAS master regulators.

作者信息

Mende Susanne, Royer Loic, Herr Alexander, Schmiedel Janet, Deschauer Marcus, Klopstock Thomas, Kostic Vladimir S, Schroeder Michael, Reichmann Heinz, Storch Alexander

机构信息

Department of Neurology, Dresden University of Technology, Germany.

出版信息

Neurol Res. 2011 Jul;33(6):638-55. doi: 10.1179/1743132810Y.0000000016.

DOI:10.1179/1743132810Y.0000000016

PMID:21708074

Abstract

BACKGROUND

The heteroplasmic mitochondrial DNA (mtDNA) mutation A3243G causes the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome as one of the most frequent mitochondrial diseases. The process of reconfiguration of nuclear gene expression profile to accommodate cellular processes to the functional status of mitochondria might be a key to MELAS disease manifestation and could contribute to its diverse phenotypic presentation.

OBJECTIVE

To determine master regulatory protein networks and disease-modifying genes in MELAS syndrome.

METHODS

Analyses of whole blood transcriptomes from 10 MELAS patients using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses.

RESULTS

Hierarchical cluster analysis elucidated that the relative abundance of mutant mtDNA molecules is decisive for the nuclear gene expression response. Further analyses confirmed not only transcription factors already known to be involved in mitochondrial diseases (such as TFAM), but also detected the hypoxia-inducible factor 1 complex, nuclear factor Y and cAMP responsive element-binding protein-related transcription factors as novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation. Correlation analyses of gene alterations and clinico-genetic data detected significant correlations between A3243G-induced nuclear gene expression changes and mutant mtDNA load as well as disease characteristics. These potential disease-modifying genes influencing the expression of the MELAS phenotype are mainly related to clusters primarily unrelated to cellular energy metabolism, but important for nucleic acid and protein metabolism, and signal transduction.

DISCUSSION

Our data thus provide a framework to search for new pathogenetic concepts and potential therapeutic approaches to treat the MELAS syndrome.

摘要

背景

异质性线粒体DNA（mtDNA）突变A3243G导致线粒体脑肌病、乳酸酸中毒和卒中样发作（MELAS）综合征，这是最常见的线粒体疾病之一。核基因表达谱重新配置以适应细胞过程和线粒体功能状态的过程可能是MELAS疾病表现的关键，并可能导致其多样的表型呈现。

目的

确定MELAS综合征中的主要调控蛋白网络和疾病修饰基因。

方法

采用一种新策略，将经典的Affymetrix寡核苷酸微阵列分析与调控和蛋白质相互作用网络分析相结合，对10例MELAS患者的全血转录组进行分析。

结果

层次聚类分析表明，突变mtDNA分子的相对丰度对核基因表达反应起决定性作用。进一步分析不仅证实了已知参与线粒体疾病的转录因子（如线粒体转录因子A），还检测到缺氧诱导因子1复合物、核因子Y和cAMP反应元件结合蛋白相关转录因子是响应MELAS突变重新配置核基因表达的新型主要调控因子。基因改变与临床遗传数据的相关性分析检测到A3243G诱导的核基因表达变化与突变mtDNA负荷以及疾病特征之间存在显著相关性。这些影响MELAS表型表达的潜在疾病修饰基因主要与主要与细胞能量代谢无关，但对核酸和蛋白质代谢以及信号转导很重要的簇相关。