Evolutionary Reconfiguration of Regulatory Circuitry

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All living creatures depend critically on being able to sense their environment and mount the appropriate responses in order to survive. As a consequence, all cells have intricate systems to do this. Such systems include proteins that sense environmental change and then signal this change to other proteins, RNA, or DNA targets that they interact with. Through such interaction networks, cells can orchestrate complex morphological and cellular responses that are required to exploit new environments, acquire nutrients, and survive exposure to diverse environmental stresses such as changes in temperature or even exposure to toxins, pollutants, and chemical pesticides. Changes in these regulatory circuits over evolutionary time are fundamental to generating the remarkable diversity of form and function observed in current species. Evolution of regulatory circuits can involve changes in the proteins that control cellular signaling, or alterations in the sequence or context of their targets. Understanding the mechanisms that drive the reconfiguration of regulatory circuitry is one of the central challenges in biology, and one that we can now address with unprecedented power by exploiting advances in sequencing and functional genomics. The central goal of this research program is to dissect mechanisms underpinning the reconfiguration of regulatory circuitry that controls two traits crucial for survival, morphogenesis in response to environmental cues and resistance to environmental stress. We work with two of the most experimentally tractable organisms that are closely related to humans, the model yeast Saccharomyces cerivisiae and the most prevalent human commensal yeast and opportunistic fungal pathogen, Candida albicans. First, we will focus on circuitry governing a morphological transition from single-celled yeast to multicellular filaments, which enables foraging for nutrients, invasion of surfaces and tissues, formation of biofilms, and evasion of the immune system. We performed the first global scale analysis of genes required for filamentous growth in S. cerevisiae, and identified many novel regulators, including a previously uncharacterized gene, MFG1. Mfg1 binds to two other regulators of gene expression (transcription factors), Flo8 and Mss11, and controls morphogenesis in both S. cerevisiae and C. albicans. Strikingly, the targets of these three regulators are almost entirely distinct between the species. Second, we will focus on circuitry required for resistance to diverse stresses such as exposure to antifungal agents widely deployed in medicine and agriculture. We established that the global regulators of gene expression (lysine deacetylases, or KDACs) Hda1 and Rpd3 govern the evolution of resistance to drug-induced cellular stress in S. cerevisiae. Despite conserved effects of using drugs to inhibit KDACs between the species, we found altered circuitry such that Hda1 and Rpd3 are not sufficient to control key stress responses in C. albicans. We will exploit cutting edge genetic and genomic analyses to dissect how these regulatory circuitries have been rewired over evolutionary time. This research will establish mechanisms controlling circuitry required to access nutrients and environmental niches, cause infectious disease, form biofilms, and adapt to environmental stresses such as exposure to antifungal agents, salts, and heavy metals. Ultimately, this work will reveal the ways in which these mechanisms can be harnessed to prevent microbial infection and contamination, block the evolution of resistance to antimicrobials crucial for medicine and agriculture, and evolve microbes with enhanced capacity to tolerate stress and remediate contaminated environments, thereby improving the lives of Canadians.