Department of Biology, Duke University, Durham, NC 27708, USA and Center for Systems Biology, Institute for Genome Science and Policy, Duke University, Durham, NC 27708, USA.
Nucleic Acids Res. 2013 Oct;41(18):8546-58. doi: 10.1093/nar/gkt659. Epub 2013 Jul 26.
Organisms across all three domains of life use gene regulatory networks (GRNs) to integrate varied stimuli into coherent transcriptional responses to environmental pressures. However, inferring GRN topology and regulatory causality remains a central challenge in systems biology. Previous work characterized TrmB as a global metabolic transcription factor in archaeal extremophiles. However, it remains unclear how TrmB dynamically regulates its ∼100 metabolic enzyme-coding gene targets. Using a dynamic perturbation approach, we elucidate the topology of the TrmB metabolic GRN in the model archaeon Halobacterium salinarum. Clustering of dynamic gene expression patterns reveals that TrmB functions alone to regulate central metabolic enzyme-coding genes but cooperates with various regulators to control peripheral metabolic pathways. Using a dynamical model, we predict gene expression patterns for some TrmB-dependent promoters and infer secondary regulators for others. Our data suggest feed-forward gene regulatory topology for cobalamin biosynthesis. In contrast, purine biosynthesis appears to require TrmB-independent regulators. We conclude that TrmB is an important component for mediating metabolic modularity, integrating nutrient status and regulating gene expression dynamics alone and in concert with secondary regulators.
在所有三个生命领域的生物中，都使用基因调控网络（GRN）将各种刺激整合到对环境压力的一致转录反应中。然而，推断 GRN 的拓扑结构和调控因果关系仍然是系统生物学的一个核心挑战。先前的工作将 TrmB 描述为古菌极端微生物中的全局代谢转录因子。然而，TrmB 如何动态调节其约 100 个代谢酶编码基因靶标仍不清楚。使用动态扰动方法，我们阐明了模型古菌盐沼盐杆菌中 TrmB 代谢 GRN 的拓扑结构。动态基因表达模式的聚类表明，TrmB 单独起作用来调节中心代谢酶编码基因，但与各种调节剂合作来控制外围代谢途径。使用动力模型，我们预测了一些 TrmB 依赖性启动子的基因表达模式，并推断了其他启动子的次要调节剂。我们的数据表明，钴胺素生物合成存在前馈基因调控拓扑。相比之下，嘌呤生物合成似乎需要 TrmB 独立的调节剂。我们的结论是，TrmB 是介导代谢模块化的重要组成部分，它可以单独整合营养状态并调节基因表达动力学，也可以与次级调节剂协同作用。
