Department of Bioengineering, University of California San Diego, San Diego, California, USA.
Department of Biological Sciences, University of California San Diego, San Diego, California, USA.
mSystems. 2022 Dec 20;7(6):e0048022. doi: 10.1128/msystems.00480-22. Epub 2022 Nov 2.
The complex cross talk between metabolism and gene regulatory networks makes it difficult to untangle individual constituents and study their precise roles and interactions. To address this issue, we modularized the transcriptional regulatory network (TRN) of the Staphylococcus aureus USA300 strain by applying independent component analysis (ICA) to 385 RNA sequencing samples. We then combined the modular TRN model with a metabolic model to study the regulation of carbon and amino acid metabolism. Our analysis showed that regulation of central carbon metabolism by CcpA and amino acid biosynthesis by CodY are closely coordinated. In general, S. aureus increases the expression of CodY-regulated genes in the presence of preferred carbon sources such as glucose. This transcriptional coordination was corroborated by metabolic model simulations that also showed increased amino acid biosynthesis in the presence of glucose. Further, we found that CodY and CcpA cooperatively regulate the expression of ribosome hibernation-promoting factor, thus linking metabolic cues with translation. In line with this hypothesis, expression of CodY-regulated genes is tightly correlated with expression of genes encoding ribosomal proteins. Together, we propose a coarse-grained model where expression of S. aureus genes encoding enzymes that control carbon flux and nitrogen flux through the system is coregulated with expression of translation machinery to modularly control protein synthesis. While this work focuses on three key regulators, the full TRN model we present contains 76 total independently modulated sets of genes, each with the potential to uncover other complex regulatory structures and interactions. Staphylococcus aureus is a versatile pathogen with an expanding antibiotic resistance profile. The biology underlying its clinical success emerges from an interplay of many systems such as metabolism and gene regulatory networks. This work brings together models for these two systems to establish fundamental principles governing the regulation of S. aureus central metabolism and protein synthesis. Studies of these fundamental biological principles are often confined to model organisms such as Escherichia coli. However, expanding these models to pathogens can provide a framework from which complex and clinically important phenotypes such as virulence and antibiotic resistance can be better understood. Additionally, the expanded gene regulatory network model presented here can deconvolute the biology underlying other important phenotypes in this pathogen.
代谢和基因调控网络的复杂串扰使得难以理清各个组成部分，并研究它们的确切作用和相互作用。为了解决这个问题，我们通过对 385 个 RNA 测序样本应用独立成分分析 (ICA)，将金黄色葡萄球菌 USA300 菌株的转录调控网络 (TRN) 模块化。然后，我们将模块化的 TRN 模型与代谢模型结合起来，研究碳和氨基酸代谢的调控。我们的分析表明，CcpA 对中心碳代谢的调控和 CodY 对氨基酸生物合成的调控是紧密协调的。一般来说，金黄色葡萄球菌在存在葡萄糖等首选碳源的情况下，会增加 CodY 调控基因的表达。代谢模型模拟也表明，在存在葡萄糖的情况下，氨基酸生物合成增加，这证实了这种转录协调。此外，我们发现 CodY 和 CcpA 合作调控核糖体休眠促进因子的表达，从而将代谢线索与翻译联系起来。根据这一假设，CodY 调控基因的表达与核糖体蛋白编码基因的表达密切相关。总之，我们提出了一个粗粒化模型，其中控制系统中碳通量和氮通量的金黄色葡萄球菌基因编码酶的表达与翻译机制的表达是模块化调控蛋白质合成的共调控。虽然这项工作集中在三个关键调节剂上，但我们提出的完整 TRN 模型包含 76 个总独立调节的基因集，每个基因集都有可能揭示其他复杂的调节结构和相互作用。金黄色葡萄球菌是一种多功能病原体，其抗生素耐药性不断扩大。其临床成功的生物学基础来自于许多系统的相互作用，如代谢和基因调控网络。这项工作将这两个系统的模型结合起来，建立了金黄色葡萄球菌中心代谢和蛋白质合成调节的基本原理。这些基本生物学原理的研究通常局限于大肠杆菌等模式生物。然而，将这些模型扩展到病原体可以提供一个框架，从中可以更好地理解复杂的和临床上重要的表型，如毒力和抗生素耐药性。此外，这里提出的扩展基因调控网络模型可以剖析这种病原体中其他重要表型的生物学基础。
