Lynch Kathryn S, Keener James P
Mathematics, University of Utah, 155 1400 E, Salt Lake City, 84112, UT, USA.
Bull Math Biol. 2025 Aug 9;87(9):125. doi: 10.1007/s11538-025-01505-2.
Switch-like behavior and bistability are important features in gene regulatory networks, allowing cells to distinguish between changing environments and express certain genes only under the appropriate conditions. Vibrio vulnificus, an opportunistic Gram-negative marine pathogen, has iron as a limiting growth factor. When inside a human host, this bacteria utilizes heme as a source of iron, necessitating the ability to turn this heme acquisition system off and on in response to environmental pressures. As establishment of infection depends on V. vulnificus's ability to change from a marine to human environment, the ability to switch on the heme-intake system is an important part of establishment of initial infection. In particular, the protein HupA is a key part of the bacteria's heme importation complex, and is regulated primarily by a divergently transcribed protein, HupR. The dynamics of this regulation result in a genetic switch, allowing the bacteria to differentiate between high iron or high heme environments, determining which source of iron should be used. Bifurcation analysis of this network uncovers a saddle-node bifurcation, which encodes this switch-like behavior into the regulation of the heme transport system and allows different levels of expression for HupA depending on external concentrations of heme and iron. The influences of other parameters in this system are also investigated; in particular, promoter leakage is found to be required to enable this bistability, indicating the importance of imperfect regulation in a cell's ability to respond to the environment.
开关式行为和双稳态是基因调控网络的重要特征，使细胞能够区分不断变化的环境，并仅在适当条件下表达某些基因。创伤弧菌是一种机会性革兰氏阴性海洋病原体，铁是其生长的限制因素。当在人类宿主内时，这种细菌利用血红素作为铁的来源，因此需要具备根据环境压力开启和关闭这种血红素获取系统的能力。由于感染的建立取决于创伤弧菌从海洋环境转变为人类环境的能力，开启血红素摄取系统的能力是初始感染建立的重要组成部分。特别是，蛋白质HupA是细菌血红素导入复合体的关键部分，主要受一个反向转录的蛋白质HupR调控。这种调控的动力学导致了一个基因开关，使细菌能够区分高铁或高血红素环境，从而决定应使用哪种铁源。对该网络的分岔分析揭示了一个鞍结分岔，它将这种开关式行为编码到血红素运输系统的调控中，并根据血红素和铁的外部浓度使HupA具有不同的表达水平。还研究了该系统中其他参数的影响；特别是，发现启动子泄漏是实现这种双稳态所必需的，这表明不完美调控在细胞对环境作出反应的能力中具有重要意义。
