Transcriptional control of <i>C. albicans</i> white-opaque switching and modulation by environmental cues and strain background

The opportunistic fungal pathogen <i>Candida albicans</i> can undergo cellular transitions in response to environmental cues that impact its lifestyle and its interactions with the human host. This is exemplified by the white-opaque switch, which is a heritable transition between two phenotypic states that is regulated by a highly interconnected network of transcription factors (TFs). To obtain greater understanding of the transcriptional regulation of the switch, we generated a genome-wide, tetracycline-inducible TF library in the WO-1 strain background and identified those TFs whose forced expression induces white cells to switch to the opaque state. This set of opaque-inducing TFs was also evaluated for their ability to induce switching in a second strain background, that of the standard reference strain SC5314, as well as during growth on different laboratory media. These experiments identify 14 TFs that can drive white-to-opaque switching when overexpressed but that do so in a highly strain- and media-specific manner. In particular, changes in pH, amino acids, and zinc concentrations had marked effects on the ability of TFs to drive phenotypic switching. These results provide insights into the complex transcriptional regulation of switching in <i>C. albicans</i> and reveal that an interplay between genetic and environmental factors determines TF function and cell fate.IMPORTANCEThe white-opaque switch in <i>Candida albicans</i> represents a model system for understanding an epigenetic switch in a eukaryotic pathogen. Here, we generated an inducible library of the set of transcription factors (TFs) present in <i>C. albicans</i> and identify 14 TFs that can drive the white-to-opaque transition when ectopically expressed. We demonstrate that several of these TFs induce the switch in a highly strain- and media-specific manner. This highlights that both strain background and changes in experimental conditions (including different water sources) can profoundly impact the phenotypic consequences of TF overexpression. Moreover, the inducible TF library provides an invaluable tool for the further analysis of TF function in this important human pathogen.