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Functional divergence of a global regulatory complex governing fungal filamentation
Elizabeth J. Polvi, 1 Amanda O. Veri, 1 Zhongle Liu, 1 Saif Hossain, 1 Sabrina Hyde, 1 Sang Hu Kim, 1 Faiza Tebbji, 2 Adnane Sellam, 2 Robert T. Todd, 3 Jinglin L. Xie, 1 Zhen-Yuan Lin, 4 Cassandra J. Wong, 4 Rebecca S. Shapiro, 1 Malcolm Whiteway, 5 Nicole Robbins, 1 Anne-Claude Gingras, 1 Anna Selmecki, 3 Leah E. Cowen 1
1  Department of Molecular Genetics, University of Toronto, Ontario, Canada
2  Infectious Disease Research Centre, Universit√© Laval, Quebec, Canada
3  Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska, United States of America
4  Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Ontario, Canada
5  Department of Biology, Concordia University, Quebec, Canada

Published: 07 January 2019 by Public Library of Science (PLoS) in PLoS Genetics
Public Library of Science (PLoS), Volume 15; 10.1371/journal.pgen.1007901
Abstract: Morphogenetic transitions are prevalent in the fungal kingdom. For a leading human fungal pathogen, Candida albicans, the capacity to transition between yeast and filaments is key for virulence. For the model yeast Saccharomyces cerevisiae, filamentation enables nutrient acquisition. A recent functional genomic screen in S. cerevisiae identified Mfg1 as a regulator of morphogenesis that acts in complex with Flo8 and Mss11 to mediate transcriptional responses crucial for filamentation. In C. albicans, Mfg1 also interacts physically with Flo8 and Mss11 and is critical for filamentation in response to diverse cues, but the mechanisms through which it regulates morphogenesis remained elusive. Here, we explored the consequences of perturbation of Mfg1, Flo8, and Mss11 on C. albicans morphogenesis, and identified functional divergence of complex members. We observed that C. albicans Mss11 was dispensable for filamentation, and that overexpression of FLO8 caused constitutive filamentation even in the absence of Mfg1. Harnessing transcriptional profiling and chromatin immunoprecipitation coupled to microarray analysis, we identified divergence between transcriptional targets of Flo8 and Mfg1 in C. albicans. We also established that Flo8 and Mfg1 cooperatively bind to promoters of key regulators of filamentation, including TEC1, for which overexpression was sufficient to restore filamentation in the absence of Flo8 or Mfg1. To further explore the circuitry through which Mfg1 regulates morphogenesis, we employed a novel strategy to select for mutations that restore filamentation in the absence of Mfg1. Whole genome sequencing of filamentation-competent mutants revealed chromosome 6 amplification as a conserved adaptive mechanism. A key determinant of the chromosome 6 amplification is FLO8, as deletion of one allele blocked morphogenesis, and chromosome 6 was not amplified in evolved lineages for which FLO8 was re-located to a different chromosome. Thus, this work highlights rewiring of key morphogenetic regulators over evolutionary time and aneuploidy as an adaptive mechanism driving fungal morphogenesis. Fungal infections pose a severe burden to human health worldwide. Candida albicans is a leading cause of systemic fungal infections, with mortality rates approaching 40%. One of the key virulence traits of this fungus is its ability to transition between yeast and filamentous forms in response to diverse host-relevant cues. The model yeast Saccharomyces cerevisiae is also capable of filamentous growth in certain conditions, and previous work has identified a key transcriptional complex required for filamentation in both species. However, here we discover that the circuitry governed by this complex in C. albicans is largely distinct from that in the non-pathogenic S. cerevisiae. We also employ a novel selection strategy to perform experimental evolution, identifying chromosome triplication as a mechanism to restore filamentation in a non-filamentous...
Keywords: gene expression, Gene regulation, Saccharomyces cerevisiae, Candida albicans, fungal pathogens, Hyperexpression techniques, Morphogenesis, Regulator genes
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