正反馈和噪声激活分枝杆菌中的严格反应调节因子Rel
Positive feedback and noise activate the stringent response regulator Rel in mycobacteria
摘要：
同基因微生物种群中的表型异质性使种群的一个子集能够在压力下持续存在。在分枝杆菌中，营养和氧气剥夺等应激激活了涉及双组分系统MprAB和sigma因子SigE的应激反应途径。SigE反过来激活严格响应调节因子rel的表达。多磷酸激酶1（PPK1）通过合成激活MprB所需的多磷酸盐来调节这一途径。只有一个亚群的细菌细胞发展持久性的精确方式仍然未知。Rel是分枝杆菌持久性所必需的。在这里，我们表明，在一个不断增长的人口分枝杆菌的rel表达水平的分布是双峰与两个不同的峰对应的低（L）和高（H）的表达状态，并进一步建立了一个正反馈回路涉及mprAB操纵子以及随机基因表达负责表型异质性。通过流式细胞术结合单细胞分析与理论建模，我们观察到，在生长期间，噪声驱动的转变使细胞亚群在稳定期之前的“机会窗口”内从L状态转变为H状态。我们发现的证据滞后的表达响应于变化浓度的PPK1的rel。我们的研究结果首次提供了证据表明，双稳态和随机基因表达可能是重要的“异质性与优势”的分枝杆菌的发展。
英文摘要：
Phenotypic heterogeneity in an isogenic, microbial population enables a subset of the population to persist under stress. In mycobacteria, stresses like nutrient and oxygen deprivation activate the stress response pathway involving the two-component system MprAB and the sigma factor, SigE. SigE in turn activates the expression of the stringent response regulator, rel. The enzyme polyphosphate kinase 1 (PPK1) regulates this pathway by synthesizing polyphosphate required for the activation of MprB. The precise manner in which only a subpopulation of bacterial cells develops persistence, remains unknown. Rel is required for mycobacterial persistence. Here we show that the distribution of rel expression levels in a growing population of mycobacteria is bimodal with two distinct peaks corresponding to low (L) and high (H) expression states, and further establish that a positive feedback loop involving the mprAB operon along with stochastic gene expression are responsible for the phenotypic heterogeneity. Combining single cell analysis by flow cytometry with theoretical modeling, we observe that during growth, noise-driven transitions take a subpopulation of cells from the L to the H state within a "window of opportunity" in time preceding the stationary phase. We find evidence of hysteresis in the expression of rel in response to changing concentrations of PPK1. Our results provide, for the first time, evidence that bistability and stochastic gene expression could be important for the development of "heterogeneity with an advantage" in mycobacteria.
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