Department of Electrical Engineering, Yale University, 10 Hillhouse Avenue, New Haven, CT 06520, USA.
Systems Biology Institute, Yale University, 850 West Campus Drive, West Haven, CT 06516, USA.
Sci Adv. 2018 Apr 18;4(4):e1701775. doi: 10.1126/sciadv.1701775. eCollection 2018 Apr.
Cells often respond to environmental stimuli by activating specific transcription factors. Upon exposure to glucose limitation stress, it is known that yeast cells dephosphorylate the general stress response factor Msn2, leading to its nuclear localization, which in turn activates the expression of many genes. However, the precise dynamics of Msn2 nucleocytoplasmic translocations and whether they are inherited over multiple generations in a stress-dependent manner are not well understood. Tracking Msn2 localization events in yeast lineages grown on a microfluidic chip, here we report how cells modulate the amplitude, duration, frequency, and dynamic pattern of the localization events in response to glucose limitation stress. Single yeast cells were found to modulate the amplitude and frequency of Msn2 nuclear localization, but not its duration. Moreover, the Msn2 localization frequency was epigenetically inherited in descendants of mother cells, leading to a decrease in cell-to-cell variation in localization frequency. An analysis of the time dynamic patterns of nuclear localizations between genealogically related cell pairs using an information theory approach found that the magnitude of pattern similarity increased with stress intensity and was strongly inherited by the descendant cells at the highest stress level. By dissecting how general stress response dynamics is contributed by different modulation schemes over long time scales, our work provides insight into which scheme evolution might have acted on to optimize fitness in stressful environments.
细胞通常通过激活特定的转录因子来响应环境刺激。当酵母细胞暴露在葡萄糖限制应激下时，已知细胞会去磷酸化一般应激反应因子 Msn2，导致其核定位，进而激活许多基因的表达。然而，Msn2 核质转运的精确动态，以及它们是否以应激依赖的方式在多个世代中遗传，尚不清楚。在微流控芯片上培养的酵母谱系中跟踪 Msn2 定位事件，我们报告了细胞如何响应葡萄糖限制应激来调节定位事件的幅度、持续时间、频率和动态模式。我们发现，单个酵母细胞可以调节 Msn2 核定位的幅度和频率，但不能调节其持续时间。此外，Msn2 定位频率在母细胞的后代中表现出表观遗传遗传，导致定位频率的细胞间变异性降低。使用信息论方法对具有亲缘关系的细胞对之间的核定位时间动态模式进行分析发现，模式相似性的幅度随着应激强度的增加而增加，并且在最高应激水平下，后代细胞强烈遗传。通过剖析一般应激反应动力学是如何通过不同的调制方案在长时间尺度上贡献的，我们的工作深入了解了哪种方案的进化可能在优化应激环境中的适应性方面发挥了作用。
