How do cells differentiate and switch between alternate phenotypic states?
Classic views of cell development were built on the idea that pluripotent progenitor cells progress in a unidirectional manner to the differentiated state. But given the numerous observations of transdifferentiation and cellular reprogramming events, we now appreciate that perhaps all cell types—even those that are ‘terminally’ differentiated—have the capacity to access other phenotypic states. During these switches in cell phenotype, it is clear that the master regulatory transcription factors that specify a new cell lineage must be activated, but we know surprisingly little about the other half of these transitions: the fate of the master regulators that had promoted and defined the previous cell state. The ubiquitin-proteasome system (UPS) has been implicated by the few studied examples of normal differentiation pathways, but the crucial question remains: how does the UPS erase the previous phenotypic state and promote emergence of the new cellular phenotype? Without this mechanistic insight, we are currently unable to explain, intuitively predict, or exploit the mechanisms used to engender transitions between distinct cellular states, making the prospect of deliberately modulating cell phenotypes for therapeutic purposes rather unlikely.
Our long-term goal is to understand the molecular basis by which cells change their patterns of gene expression and switch between alternative phenotypic states. Our studies focus on a particularly robust and manipulatable example of a natural, UPS-dependent cell transdifferentiation event: the transition between the two haploid cell types of the yeast Saccharomyces cerevisiae, which ultimately allows the organism to access the advantageous diploid state. Using the variety of experimental tools that are available in this model system, including genetic, cell biological, biochemical, and computational methods, we are working to understand how cells adopt robust yet dynamic phenotypes.