Inferring condition-specific modulation of transcription factor activity in yeast through regulon-based analysis of genomewide expression.
Inferring condition-specific modulation of transcription factor activity in yeast through regulon-based analysis of genomewide expression.
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DOI：
10.1371/journal.pone.0003112
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发表时间：
2008-09-03
期刊：
影响因子：
3.7
通讯作者：
Bussemaker, Harmen J.
中科院分区：
文献类型：
--
作者：
Boorsma, Andre;Lu, Xiang-Jun;Zakrzewska, Anna;Klis, Frans M.;Bussemaker, Harmen J.
系统生物学的一个关键目标是了解全基因组mRNA表达水平是如何由转录因子（TF）以条件特异性方式控制的。TF活性通常通过配体结合、共价修饰或亚细胞定位的变化在翻译后水平上进行调节。在本文中，我们演示了如何利用有关调控网络连接的先验信息来推断条件特异性TF活性作为一个隐藏的变量，从全基因组的mRNA表达模式在酵母酿酒酵母。我们首先通过实验验证，通过在由TF的推定靶组成的基因集或“调节子”水平上对差异表达进行评分，我们可以准确地预测在翻译后水平上TF活性的调节。接下来，我们创建了一个交互式数据库的推断活动的大量TF在大量的实验条件下，在S。啤酒。这使我们能够对酵母调控网络进行以TF为中心的分析。我们分析了每个TF的mRNA表达水平预测其调节活性的程度。我们还组织TF到“共调制网络”的基础上，他们推断的活动配置文件跨条件，并发现这揭示了功能和机制的关系。最后，我们提出的证据表明，PAC和rRPE基序拮抗TBP依赖的调节，并作为核心启动子元件的转录调节NC 2的功能。基于调节子的TF活性调节监测是分析调节网络功能的有力工具，应该适用于其他生物。工具和结果可在http://bussemakerlab.org/RegulonProfiler/在线获得。
A key goal of systems biology is to understand how genomewide mRNA expression levels are controlled by transcription factors (TFs) in a condition-specific fashion. TF activity is frequently modulated at the post-translational level through ligand binding, covalent modification, or changes in sub-cellular localization. In this paper, we demonstrate how prior information about regulatory network connectivity can be exploited to infer condition-specific TF activity as a hidden variable from the genomewide mRNA expression pattern in the yeast Saccharomyces cerevisiae. We first validate experimentally that by scoring differential expression at the level of gene sets or “regulons” comprised of the putative targets of a TF, we can accurately predict modulation of TF activity at the post-translational level. Next, we create an interactive database of inferred activities for a large number of TFs across a large number of experimental conditions in S. cerevisiae. This allows us to perform TF-centric analysis of the yeast regulatory network. We analyze the degree to which the mRNA expression level of each TF is predictive of its regulatory activity. We also organize TFs into “co-modulation networks” based on their inferred activity profile across conditions, and find that this reveals functional and mechanistic relationships. Finally, we present evidence that the PAC and rRPE motifs antagonize TBP-dependent regulation, and function as core promoter elements governed by the transcription regulator NC2. Regulon-based monitoring of TF activity modulation is a powerful tool for analyzing regulatory network function that should be applicable in other organisms. Tools and results are available online at http://bussemakerlab.org/RegulonProfiler/.
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影响因子：
3
作者：
Bussemaker HJ;Ward LD;Boorsma A
通讯作者：
Boorsma A
影响因子：
46.9
作者：
Berger, Michael F.;Philippakis, Anthony A.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.
影响因子：
5.3
作者：
Lee, TI;Wyrick, JJ;Young, RA
通讯作者：
Young, RA
影响因子：
64.5
作者：
Basehoar, AD;Zanton, SJ;Pugh, BF
通讯作者：
Pugh, BF
DOI：
10.1073/pnas.2136632100
发表时间：
2003-12-23
影响因子：
11.1
作者：
Liao, JC;Boscolo, R;Roychowdhury, VP
通讯作者：
Roychowdhury, VP