Evolutionary Origins of Cellular Adaptation and Stress Response Prioritization Revealed by Single-Cell Transcriptomics

Cells activate transcriptional stress response programs to adapt to environmental fluctuations. While responses to single stressors like heat or osmotic shock are well studied, responses to multi-stress environments remain unpredictable. In S. cerevisiae, one model of adaptation suggests cells simplify environmental complexity into a generic representation of stress, resulting in reduced ribosome biogenesis and growth. However, genetic evidence reveals specific factors are essential for distinct stress responses. We bridge both models and reveal environmental information is hierarchically represented in transcriptional variation. We performed single-cell RNA sequencing on 10⁵ cells exposed to 20 complex environments varying in carbon, temperature, osmotic, and oxidative stress. Spectral decomposition and information theory revealed that environmental information is processed in semi-discrete channels along the principal component spectrum, suggesting a functional hierarchy and prioritization for integrating environment information. Experimental results support this hierarchy; for example, cells prioritize the response to hyperosmotic stress over heat shock. Further, directed evolution under constant osmotic stress for ~3000 generations led to a collapse in hierarchical information processing. Cells evolve a prioritization hierarchy that reflects the statistics of environmental fluctuations over its evolutionary history, linking adaptability to selection history.