Dynamics in Eukaryotic Dormancy: Gene Expression and Aging

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PROJECT SUMMARY Dormancy is a state in which virtually all intracellular activities, such as gene expression, are thought to have (nearly) stopped. Many organisms and cells become dormant when they face dire conditions such as lack of nutrients. Despite its ubiquity, the state of dormancy remains poorly understood and underexplored. A major open question is which intracellular processes might still occur in dormancy, to what extent, and whether and how they are important for surviving dormancy. This question is relevant to dormancy of microbial spores, cancer cells, plant seeds, worms, cells in human body, and others. Microbial spores are particularly important because many microbes in nature often exist as dormant spores rather than as vegetative cells. Many fungal spores are of interest because they are infectious and are difficult to kill with existing drugs for unknown reasons. My laboratory's goal is to answer the critical question posed above for understanding dormancy. We use the dormant yeast (Saccharomyces cerevisiae) spores as a model system for studying eukaryotic dormancy. With dormant yeast spores, we focus on two fundamental aspects of life: (1) Dynamics and regulation of gene expression in dormancy (2) Dynamics and determinants of aging in dormancy My lab makes quantitative measurements at single-cell and genome-wide levels and combines them with mathematical models of gene regulations. We recently discovered that yeast spores express some genes while dormant (i.e., in water without any nutrients) and that, surprisingly, some of the expression levels can be as high as in vegetative yeasts. To extend this discovery, we adapted an RNA-Seq-based technique to detect all freshly made RNAs in dormant yeast spores. We discovered that dormant yeast spores transcribe ~65% of their genes, with ribosomal proteins being one of the most highly transcribed. With microscope-based techniques that detect mRNA and protein productions in the same single spore and mathematical models that screen various forms of gene regulation, we are now uncovering signs of globally (genome-wide) coordinated transcription and translation whose mechanisms we aim to elucidate in the next five years. Our ongoing work is also uncovering dormant yeast spores secreting molecules that help each other survive, extend lifespans, and regulate gene expression. We will elucidate the mechanisms of this "collective dormancy" and signs of aging in dormant yeast spores. A comprehensive library of gene-deleted yeast strains will help us determine how each gene accelerates or decelerates aging in dormant spores and its role in collective dormancy. Our work will advance the still- primitive understanding of eukaryotic, microbial dormancy by establishing foundational knowledge on gene regulation and aging in dormancy with quantitative approaches that have rarely been applied to these topics. More broadly, we expect that our work will provide conceptual insights into quiescent cells in general.