Affiliation: Center for Mechanisms of Evolution, School of Life Sciences, Arizona State University, Tempe, AZ
Keywords: Molecular Evolution
Protein misfolding is a problem across all organisms in the tree of life, but the reasons behind misfolded protein toxicity to cells are largely unknown. To better understand toxicity, I investigate if toxicity from misfolded proteins affects all cells equally or affects some cell subpopulations more than others, such as older cells. To define cell subpopulations, I optimized a cutting-edge single-cell RNA sequencing platform (scRNAseq) for yeast, which is a common model organism for investigating protein misfolding. By using scRNAseq in yeast, I study the expression variability of many genes across populations of thousands of cells. I study how the transcriptomes of single cells differ from one another in various conditions: at different stages in the growth phase and with different engineered misfolded proteins. One specific hypothesis I will investigate is whether older cells are more sensitive to misfolded proteins. To do so, I will measure whether cells with gene expression markers related to aging, when challenged by misfolded proteins, express more genes related to stress responses (i.e. chaperones) than younger cells. After identifying subpopulations with a more severe transcriptional response to misfolded proteins, I can study the cells’ physiology to gain insights about why that subpopulation is sensitive to misfolded proteins. Thus, understanding the non-uniform distribution of responses to protein misfolding can provide insight into evolutionary biology. For example, it is well known that heterogeneity within microbial populations can be beneficial to their fitness by allowing that population to thrive in diverse environments. This study adds to a growing body of literature documenting and quantifying the degree of non-genetic heterogeneity in nature. Further, it provides insights on the gene regulatory responses associated with misfolded protein toxicity by revealing which type of cells are most sensitive to this intracellular threat.