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• W3203318329 abstract "Eukaryotic transcriptional networks are often large and contain several levels of feedback regulation. Many of these networks exhibit bistability, the ability to generate and stably maintain two distinct transcriptional states and to switch between them. In certain instances, switching between cell states is stochastic, occurring in a small subset of cells of an isogenic population in a seemingly homogenous environment. Given the scarcity and unpredictability of switching in these cases, investigating the determining molecular events is challenging. White-opaque switching in the fungal species Candida albicans is a complex bistable eukaryotic system and can serve as an experimentally accessible model system to study characteristics important for bistability and stochastic cell fate switching. In standard lab media, switching is rare, and genetically identical cells maintain their cellular identity (either “white” or “opaque”) through thousands of cell divisions. By isolating populations of white or opaque cells and measuring switching frequencies, previous studies have elucidated the many differences between the two cell states and identified a set of transcriptional regulators needed for cell type switching. Yet little is known about the molecular events that determine the rare, stochastic switching events that occur in single cells. We use microfluidics combined with fluorescent reporters to directly observe rare switching events between the white and opaque states. We investigate the stochastic nature of switching by beginning with white cells and monitoring the activation of Wor1, a master regulator and marker for the opaque state, in single cells and throughout cell pedigrees. Our results indicate that switching requires two stochastic steps; first an event occurs that predisposes a lineage of cells to switch. In the second step, some but not all, of those predisposed cells rapidly express high levels of Wor1 and commit to the opaque state. To further understand the rapid rise in Wor1, we used a synthetic inducible system in Saccharomyces cerevisiae into which a controllable C. albicans Wor1 and a reporter for its transcriptional control region have been introduced. We document that Wor1 positive autoregulation is highly cooperative (Hill coefficient > 3), leading to rapid activation and producing an “all or none” rather than a graded response. Taken together, our results suggest that reaching a threshold level of a master regulator is sufficient to drive cell type switching in single cells and that an earlier molecular event increases the probability of reaching that threshold in certain small lineages of cells. Quantitative molecular analysis of bistability in the white-opaque circuit can serve as a model for the general understanding of complex circuits." @default.
• W3203318329 created "2021-10-11" @default.
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• W3203318329 date "2021-09-24" @default.
• W3203318329 modified "2023-10-14" @default.
• W3203318329 title "Multiple molecular events determine stochastic cell fate switching in a eukaryotic bistable system" @default.
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• W3203318329 doi "https://doi.org/10.1101/2021.09.23.461488" @default.
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