UCSF

The coordination of cellular processes is largely controlled at the level of transcriptional regulation. Previous work, dating back over forty years, has focused on a few details of transcriptional regulation, providing a window through which to view the basic workings of transcriptional regulation. Recent developments have allowed broader analyses, providing new views into how whole transcriptional programs mold cellular processes.

To provide the first complete example of a transcriptional circuit, we completely dissected the transcriptional regulation that underlies the specification of the three cell types in Saccharomyces cerevisiae. In addition to providing an example of a completely mapped circuit, this analysis uncovered genes not expected to be associated with specific cell types. We have extended this approach to a second fungal species, uncovering processes of molecular evolution on a whole circuit level.

We adopted a similar approach to describe the transcriptional regulatory mechanism that governs the switch between the white and opaque states in Candida albicans, the primary fungal pathogen in humans. This process modulates the virulence properties and mating competence of this species, and involves the regulation of hundreds of genes. We showed that one transcriptional regulator, Wor1 governs the mechanism underlying the switch. Our analysis revealed that Wor1 directs an extensive and complex transcriptional program to set up the opaque state.

Finally, to understand how changes in transcriptional regulation shape evolution of organisms, we explored the evolution of a large transcriptional circuit in fungi. This is an important endeavor, since phenotypic differences between evolutionarily divergent species are thought to be largely due to differences in gene expression. While several anecdotal examples of molecular evolution events exist, a broad analysis would yield insights into what types of changes figure importantly in shaping evolution on a systems level. To this end, we mapped the large combinatorial circuit controlled by Mcm1 in three fungal species; this provided an unprecedented view into the evolution of a large transcriptional circuit, and offered two examples where circuitry had been dramatically restructured. Ongoing informatics analysis is refining this view, allowing us to distill out the molecular processes that are important in the evolution of circuits.