Candida albicans is a common commensal yeast and the most clinically relevant opportunistic pathogen among the Candida paraphyletic group. Notably, infection by C. albicans during cardiac surgery leading to endocarditis is a major risk factor due to the high mortality rates compared to those of bacterial or viral infections. Fundamental to the success of C. albicans as a pathogen is its ability to thrive in a diverse set of host niches, potentially due to expansion of species-specific gene families that enhance phenotypic plasticity in response to various host and environmental pressures. The most dramatic gene expansion in C. albicans occurred within the telomere-associated (TLO) gene family, which expanded from a single copy in other Candida species to 14 copies in C. albicans. These genes typically reside within the highly dynamic chromosome subtelomeres, where they encode interchangeable Med2 subunits of the major transcriptional regulatory complex, Mediator. We hypothesize that expansion of the TLO gene family allows the formation of a panel of alternative Mediator types that incorporate different Tlo proteins and produce phenotypically diverse C. albicans cellular populations that can adapt to the diverse niches of its human host. Here, we aim to resolve the breadth of TLO genetic diversity in C. albicans and determine the organization of molecular and biological functions among individual paralogs. The complement of TLO genes in a collection of 21 clinical isolates will be identified by sequencing to define the selective pressures acting on the gene family during expansion (Aim 1). To determine the individual or overlapping functions among individual TLO paralogs, we will reintegrate single TLO genes into a recently constructed TLO-null strain. RNA sequencing (RNA-Seq) and chromatin-immunoprecipitation and sequencing (ChIP-Seq) will be performed in TLO reintegrant strains to determine the global and direct regulatory targets of each paralog. These integrants will also be assayed across a panel of phenotypes to connect the molecular targets of Tlo proteins with altered phenotypic outputs important for virulence across diverse conditions (Aim 2). These results will guide our understanding of TLO gene family expansion to C. albicans virulence and aid in development of drug targets which inhibit Tlo function and adaptability.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|