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Transcriptional Profiling of Biofilm Regulators Identified by an Overexpression Screen in S. cerevisiae

ABSTRACT: Biofilm formation by microorganisms is a major cause of recurring infections and removal of biofilms has proven to be extremely difficult given their inherent drug resistance. Understanding the biological processes that underlie biofilm formation is thus extremely important and could lead to the development of more effective drug therapies, resulting in better infection outcomes. Using the yeast S. cerevisiae as a biofilm model, overexpression screens identified DIG1, SFL1, HEK2, TOS8, SAN1 and ROF1/YHR177W as regulators of biofilm formation. Subsequent RNA-seq analysis of biofilm and non-biofilm forming strains revealed that all of the overexpression strains, other than DIG1 and TOS8, were adopting a single differential expression profile, although induced to varying degrees. TOS8 adopted a separate profile, while the expression profile of DIG1 reflected the common pattern seen in most of the strains, plus substantial DIG1-specific expression changes. We interpret the existence of the common transcriptional pattern seen across multiple, unrelated overexpression strains as reflecting a real transcriptional state, that the yeast cell can access through regulatory signaling mechanisms, allowing an adaptive morphological change between biofilm-forming and non-biofilm states.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE98079 | GEO | 2017/04/25

SECONDARY ACCESSION(S): PRJNA383899

REPOSITORIES: GEO

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Project description:Candida albicans is an opportunistic fungal pathogen that can infect oral mucosal surfaces despite being under continuous flow from saliva. Previous studies have shown that under specific conditions C. albicans will form microcolonies that more closely resemble the biofilms formed in vivo than standard in vitro biofilm models. However, very little is known about these microcolonies, particularly genomic differences between these specialized biofilm structures and the traditional in vitro biofilms. In this study, we used a novel flow system, in which C. albicans spontaneously forms microcolonies, to further characterize the architecture of fungal microcolonies and their genomics compared to non-microcolony conditions. Fungal microcolonies arise from radially branching filamentous hyphae that increasingly intertwine with one another to form extremely dense biofilms, and closely resemble the architecture of in vivo oropharyngeal candidiasis. We identified 20 core microcolony genes that were differentially regulated in flow-induced microcolonies using RNA-seq. These genes included HWP1, ECE1, IHD1, PLB1, HYR1, PGA10, and SAP5. To better understand the regulatory elements for microcolonies, we utilized a predictive algorithm to discover ten transcriptional regulators potentially involved in microcolony formation. Of these transcription factors, we found that six played a key role in microcolony formation and development (Rob1, Ndt80, Efg1, Sfl1, Sfl2, and Nrg1). We also found that Hwp1, Sap5, Pga10, and all the microcolony regulators promoted adhesion and invasion of the microcolonies to oral epithelium. Furthermore, epithelial cells infected with deletion mutants of ROB1, NDT80, SFL2, EFG1, and MCM1 had reduced immune response, evidenced by reduced phosphorylation of MKP1 and c-Fos, key signal transducers in the hyphal invasion response. This profile of microcolony transcriptional regulators more closely reflects Sfl1 and Sfl2 hyphal regulatory networks than biofilm regulatory networks, suggesting that hyphal morphogenesis plays a more central role in the development of flow-induced microcolonies.

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Transcriptional Profiling of Biofilm Regulators Identified by an Overexpression Screen in S. cerevisiae

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