Gene Network and Proteomic Analyses of Cardiac Responses to Pathological and Physiological Stress
Gene Network and Proteomic Analyses of Cardiac Responses to Pathological and Physiological Stress
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DOI：
10.1161/circgenetics.113.000063
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发表时间：
2013-12-01
影响因子：
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通讯作者：
Shah, Ajay M.
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作者：
Drozdov, Ignat;Didangelos, Athanasios;Shah, Ajay M.
背景生理性和病理性左心室肥厚（LVH）的相似性和差异性的分子机制一直是研究的热点。大多数以前的工作涉及有针对性的分析个别信号通路或转录组学谱的筛选。我们开发了一个网络生物学的方法，利用基因组和蛋白质组数据来研究区分病理和生理LVH.Methods和结果的分子模式，采用图论方法进行了基于网络的分析127全基因组表达阵列在体内小鼠LVH。这揭示了表型特异性的病理和生理基因共表达网络。尽管两个网络中有>1650个共同基因，但网络结构显著不同。这在很大程度上是因为在2个网络中差异共表达的基因的重新连接;这种差异连接的新概念得到了实验的进一步验证。重新连接的网络的功能分析揭示了几个不同的细胞通路和基因集。通过对病理性LVH中线粒体、肌丝和细胞外亚蛋白质组的靶向蛋白质组学分析进行了更深入的探索。一个值得注意的发现是，mRNA-蛋白质的相关性是更大的细胞通路水平比单个locus.Conclusions这第一个相结合的基因网络和蛋白质组学分析LVH揭示了新的见解，区分病理与生理表型的综合病理机制。特别是，我们确定差异基因布线作为这些表型的主要区别特征。这种方法为研究LVH中潜在的新途径提供了一个平台，并为其他心血管疾病的类似分析提供了一个免费访问的协议（http：//sites.google.com/site/cardionetworks）。
Background The molecular mechanisms underlying similarities and differences between physiological and pathological left ventricular hypertrophy (LVH) are of intense interest. Most previous work involved targeted analysis of individual signaling pathways or screening of transcriptomic profiles. We developed a network biology approach using genomic and proteomic data to study the molecular patterns that distinguish pathological and physiological LVH.Methods and Results A network-based analysis using graph theory methods was undertaken on 127 genome-wide expression arrays of in vivo murine LVH. This revealed phenotype-specific pathological and physiological gene coexpression networks. Despite >1650 common genes in the 2 networks, network structure is significantly different. This is largely because of rewiring of genes that are differentially coexpressed in the 2 networks; this novel concept of differential wiring was further validated experimentally. Functional analysis of the rewired network revealed several distinct cellular pathways and gene sets. Deeper exploration was undertaken by targeted proteomic analysis of mitochondrial, myofilament, and extracellular subproteomes in pathological LVH. A notable finding was that mRNA-protein correlation was greater at the cellular pathway level than for individual loci.Conclusions This first combined gene network and proteomic analysis of LVH reveals novel insights into the integrated pathomechanisms that distinguish pathological versus physiological phenotypes. In particular, we identify differential gene wiring as a major distinguishing feature of these phenotypes. This approach provides a platform for the investigation of potentially novel pathways in LVH and offers a freely accessible protocol (http://sites.google.com/site/cardionetworks) for similar analyses in other cardiovascular diseases.