Determining the control circuitry of redox metabolism at the genome-scale.
Determining the control circuitry of redox metabolism at the genome-scale.
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DOI：
10.1371/journal.pgen.1004264
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发表时间：
2014-04
期刊：
影响因子：
4.5
通讯作者：
Palsson B
中科院分区：
文献类型：
--
作者：
Federowicz S;Kim D;Ebrahim A;Lerman J;Nagarajan H;Cho BK;Zengler K;Palsson B
确定兼性厌氧生物如何感知和指导细胞对电子受体可用性的反应一直是一个激烈研究的主题。然而，即使在模式生物大肠杆菌中，已建立的机制也只能解释电子受体转移过程中调控的数百个基因中的一小部分。在这里，我们提出了一个定性模型，通过详细描述大肠杆菌的两个全局转录因子（TFs）， ArcA和Fnr，如何感知关键的代谢氧化还原比率，并在全基因组的基础上调节合成代谢、分解代谢和能量产生途径，来解释受调节基因的全部广度。我们首先通过进行ChIP-chip和基因表达实验来确定463个调控事件，填补了我们对这个转录调控网络的知识空白。然后，我们将这个重建的调节网络与一个高度精心设计的基因组尺度代谢模型相结合，结果表明，在发酵和硝酸盐呼吸条件下，ArcA和Fnr调节了80%的总代谢通量和96%的差异基因表达。鉴于ArcA广泛抑制分解代谢基因和Fnr广泛激活化学渗透基因，我们提出了一种前馈反馈调节方案。我们进一步证实了这一调节方案，发现代谢通量变化与发酵和硝酸盐呼吸条件下调节活性变化之间的相关性为0.71 r2 （p<1e-6）。最后，我们能够通过将现有的转录调控网络背景化，将所提出的模型与之前生成的大量数据联系起来。所有异养生物都必须在生长和产生能量之间平衡消耗的碳化合物的部署。这两个相互竞争的目标已经被证明，无论是计算还是实验，作为代谢网络功能的主要维度存在。这些维度中的每一个也可以被认为是分解代谢、合成代谢和能量产生等熟悉的代谢功能。在这里，我们详细介绍了两个全局转录因子（TFs），即感知氧化还原比率的大肠杆菌的ArcA和Fnr，如何在全基因组的基础上通过转录控制酶和转运蛋白水平在变化的环境中协调调节这些全局代谢功能。该研究的一个模型显示了全局转录因子如何调节代谢的全局维度，并形成了一个反映代谢网络结构层次的调控层次。
Determining how facultative anaerobic organisms sense and direct cellular responses to electron acceptor availability has been a subject of intense study. However, even in the model organism Escherichia coli, established mechanisms only explain a small fraction of the hundreds of genes that are regulated during electron acceptor shifts. Here we propose a qualitative model that accounts for the full breadth of regulated genes by detailing how two global transcription factors (TFs), ArcA and Fnr of E. coli, sense key metabolic redox ratios and act on a genome-wide basis to regulate anabolic, catabolic, and energy generation pathways. We first fill gaps in our knowledge of this transcriptional regulatory network by carrying out ChIP-chip and gene expression experiments to identify 463 regulatory events. We then interfaced this reconstructed regulatory network with a highly curated genome-scale metabolic model to show that ArcA and Fnr regulate >80% of total metabolic flux and 96% of differential gene expression across fermentative and nitrate respiratory conditions. Based on the data, we propose a feedforward with feedback trim regulatory scheme, given the extensive repression of catabolic genes by ArcA and extensive activation of chemiosmotic genes by Fnr. We further corroborated this regulatory scheme by showing a 0.71 r2 (p<1e-6) correlation between changes in metabolic flux and changes in regulatory activity across fermentative and nitrate respiratory conditions. Finally, we are able to relate the proposed model to a wealth of previously generated data by contextualizing the existing transcriptional regulatory network. All heterotrophic organisms must balance the deployment of consumed carbon compounds between growth and the generation of energy. These two competing objectives have been shown, both computationally and experimentally, to exist as the principal dimensions of the function of metabolic networks. Each of these dimensions can also be thought of as the familiar metabolic functions of catabolism, anabolism, and generation of energy. Here we detail how two global transcription factors (TFs), ArcA and Fnr of Escherichia coli that sense redox ratios, act on a genome-wide basis to coordinately regulate these global metabolic functions through transcriptional control of enzyme and transporter levels in changing environments. A model results from the study that shows how global transcription factors regulate global dimensions of metabolism and form a regulatory hierarchy that reflects the structural hierarchy of the metabolic network.
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影响因子：
16.6
作者：
通讯作者：
--
DOI：
10.1073/pnas.0807227105
发表时间：
2008-12-09
影响因子：
11.1
作者：
Cho, Byung-Kwan;Barrett, Christian L.;Palsson, Bernhard O.
通讯作者：
Palsson, Bernhard O.
影响因子：
14.9
作者：
Keseler IM;Collado-Vides J;Santos-Zavaleta A;Peralta-Gil M;Gama-Castro S;Muñiz-Rascado L;Bonavides-Martinez C;Paley S;Krummenacker M;Altman T;Kaipa P;Spaulding A;Pacheco J;Latendresse M;Fulcher C;Sarker M;Shearer AG;Mackie A;Paulsen I;Gunsalus RP;Karp PD
通讯作者：
Karp PD
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS
影响因子：
3.8
作者：
Carlson, R;Srienc, F
通讯作者：
Srienc, F