Venancio Thiago M, Balaji S, Geetha S, Aravind L
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
Mol Biosyst. 2010 Aug;6(8):1475-91. doi: 10.1039/c002567b. Epub 2010 Jun 2.
A vast amount of data on the natural resistance of Saccharomyces cerevisiae to a diverse array of chemicals has been generated over the past decade (chemical genetics). We endeavored to use this data to better characterize the "systems" level properties of this phenomenon. By collating data from over 30 different genome-scale studies on growth of gene deletion mutants in presence of diverse chemicals, we assembled the largest currently available gene-chemical network. We also derived a second gene-gene network that links genes with significantly overlapping chemical-genetic profiles. We analyzed properties of these networks and investigated their significance by overlaying various sources of information, such as presence of TATA boxes in their promoters (which typically correlate with transcriptional noise), association with TFIID or SAGA, and propensity to function as phenotypic capacitors. We further combined these networks with ubiquitin and protein kinase-substrate networks to understand chemical tolerance in the context of major post-translational regulatory processes. Hubs in the gene-chemical network (multidrug resistance genes) are notably enriched for phenotypic capacitors (buffers against phenotypic variation), suggesting the generality of these players in buffering mechanistically unrelated deleterious forces impinging on the cell. More strikingly, analysis of the gene-gene network derived from the gene-chemical network uncovered another set of genes that appear to function in providing chemical tolerance in a cooperative manner. These appear to be enriched in lineage-specific and rapidly diverging members that also show a corresponding tendency for SAGA-dependent regulation, evolutionary divergence and noisy expression patterns. This set represents a previously underappreciated component of the chemical response that enables cells to explore alternative survival strategies. Thus, systems robustness and evolvability are simultaneously active as general forces in tolerating environmental variation. We also recover the actual genes involved in the above-discussed network properties and predict the biochemistry of their products. Certain key components of the ubiquitin system (e.g. Rcy1, Wss1 and Ubp16), peroxisome recycling (e.g. Irs4) and phosphorylation cascades (e.g. NPR1, MCK1 and HOG) are major participants and regulators of chemical resistance. We also show that a major sub-network boosting mitochondrial protein synthesis is important for exploration of alternative survival strategies under chemical stress. Further, we find evidence that cellular exploration of survival strategies under chemical stress and secondary metabolism draw from a common pool of biochemical players (e.g. acetyltransferases and a novel NTN hydrolase).
在过去十年中，已经产生了大量关于酿酒酵母对多种化学物质的天然抗性的数据（化学遗传学）。我们试图利用这些数据更好地描述这一现象的“系统”层面特性。通过整理来自30多项不同的全基因组规模研究的数据，这些研究涉及基因缺失突变体在多种化学物质存在下的生长情况，我们构建了目前最大的基因-化学物质网络。我们还推导了第二个基因-基因网络，该网络将具有显著重叠化学遗传图谱的基因联系起来。我们分析了这些网络的特性，并通过叠加各种信息来源来研究它们的重要性，比如它们启动子中TATA框的存在情况（这通常与转录噪声相关）、与TFIID或SAGA的关联以及作为表型电容器发挥作用的倾向。我们进一步将这些网络与泛素和蛋白激酶-底物网络相结合，以便在主要的翻译后调控过程的背景下理解化学耐受性。基因-化学物质网络中的枢纽（多药耐药基因）显著富集了表型电容器（针对表型变异的缓冲器），这表明这些参与者在缓冲作用于细胞的机制上不相关的有害力量方面具有普遍性。更引人注目的是，对从基因-化学物质网络推导而来的基因-基因网络的分析揭示了另一组似乎以协同方式发挥作用以提供化学耐受性的基因。这些基因似乎在谱系特异性和快速分化的成员中富集，它们还表现出相应的依赖SAGA调控、进化分化和噪声表达模式的倾向。这一组基因代表了化学应答中一个以前未被充分认识的组成部分，它使细胞能够探索替代的生存策略。因此，系统稳健性和可进化性作为耐受环境变异的普遍力量同时发挥作用。我们还找出了涉及上述网络特性的实际基因，并预测了它们产物的生物化学性质。泛素系统的某些关键成分（如Rcy1、Wss1和Ubp16）、过氧化物酶体循环（如Irs4）和磷酸化级联反应（如NPR1、MCK1和HOG）是化学抗性的主要参与者和调节因子。我们还表明，促进线粒体蛋白质合成的一个主要子网络对于在化学应激下探索替代生存策略很重要。此外，我们发现有证据表明，细胞在化学应激下对生存策略的探索和次级代谢利用了一组共同的生化参与者（如乙酰转移酶和一种新型NTN水解酶）。
