Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity.
Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity.
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DOI：
10.1038/ng.337
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发表时间：
2009-03
期刊：
影响因子：
30.8
通讯作者：
Fraenkel, Ernest
中科院分区：
文献类型：
--
作者：
Yeger-Lotem, Esti;Riva, Laura;Su, Linhui Julie;Gitler, Aaron D.;Cashikar, Anil G.;King, Oliver D.;Auluck, Pavan K.;Geddie, Melissa L.;Valastyan, Julie S.;Karger, David R.;Lindquist, Susan;Fraenkel, Ernest
细胞通过各种过程的变化对刺激做出反应，包括信号通路和基因表达。识别这些反应的组成部分的努力越来越依赖于mRNA分析和遗传文库筛选，但这些测定所识别的基因的功能作用往往仍然是谜。通过比较这两种测定法在各种细胞反应中的结果，我们发现它们始终是不同的。此外，基因筛选往往会识别反应调节因子，而mRNA分析经常检测代谢反应。我们开发了一种综合方法，使用已知的分子相互作用弥合这些数据之间的差距，从而突出了主要的反应途径。我们利用这种方法来揭示与α-突触核蛋白相关的细胞通路，α-突触核蛋白是一种与包括帕金森病在内的几种神经退行性疾病有关的小脂质结合蛋白。为此，我们筛选了一个已建立的α-突触核蛋白毒性的酵母模型，以鉴定当过表达时改变细胞存活的基因。我们的算法应用于这些数据和mRNA分析数据提供了许多这些基因的功能解释，并揭示了α-突触核蛋白毒性和基本细胞通路之间的新关系。
Cells respond to stimuli by changes in various processes, including signaling pathways and gene expression. Efforts to identify components of these responses increasingly depend on mRNA profiling and genetic library screens, yet the functional roles of the genes identified by these assays often remain enigmatic. By comparing the results of these two assays across various cellular responses, we found that they are consistently distinct. Moreover, genetic screens tend to identify response regulators, while mRNA profiling frequently detects metabolic responses. We developed an integrative approach that bridges the gap between these data using known molecular interactions, thus highlighting major response pathways. We harnessed this approach to reveal cellular pathways related to alpha-synuclein, a small lipid-binding protein implicated in several neurodegenerative disorders including Parkinson disease. For this we screened an established yeast model for alpha-synuclein toxicity to identify genes that when overexpressed alter cellular survival. Application of our algorithm to these data and data from mRNA profiling provided functional explanations for many of these genes and revealed novel relations between alpha-synuclein toxicity and basic cellular pathways.
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