Abstract 1826 Single-cell analysis of H3K9me-mediated adaptive pathways in response to heterochromatin misregulation in fission yeast

Histones undergo post-translational modifications that dynamically regulate gene expression. These modifications enable transcriptome reprogramming in response to intracellular, environmental, or metabolic changes. The mechanisms that dictate the selection of specific genes as targets for adaptive silencing, and how these processes contribute to fitness and survival, remain unknown. Understanding how cells leverage epigenetic mechanisms to adapt under acute stress has significant implications for how microbes develop antifungal resistance or cancers become unresponsive to chemotherapy. Specifically, histone H3 lysine 9 methylation (H3K9me), a modification associated with gene silencing, has been identified as a core component in how fission yeast cells mount an adaptive response. We developed an inducible, on-demand system to monitor how cells adapt when faced with heterochromatin misregulated stress. We identified populations of stressed cells undergoing dynamic changes in transcriptional patterns that eventually lead to successful adaptation. To determine how individual cells make adaptive choices, we leveraged single-cell transcriptomics to map and distinguish between stress-induced stochastic gene expression and optimal bet-hedging expression patterns. Our methodology unmasks intercellular transcript variation and provides insight into potential suboptimal transcriptional choices. By unraveling single-cell transcript compositions, our research illuminates how dynamic H3K9me alterations within individual genomes can influence how cells perpetually monitor, adapt, and refine their fitness. This work was supported by the National Science Foundation (NSF) (grant no. EF-2316281 to K.R.).