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The zinc cluster transcription factor Ahr1p directs Mcm1p regulation of Candida albicans adhesion

ABSTRACT: Biofilm development by Candida albicans requires cell adhesion for the initial establishment of the biofilm and the continued stability after hyphal development occurs; however, the regulation of the process has not been fully established. Using chromatin immunoprecipitation coupled to microarray analysis (ChIP-chip) we have characterized a regulon containing the Mcm1p factor that is required for the initial surface adhesion during biofilm formation. In the yeast Saccharomyces cerevisiae several Mcm1p regulons have been characterized in which regulatory specificity is achieved through co-factors binding a sequence adjacent to the Mcm1p-binding site. This new Mcm1p regulon in C. albicans also requires a co-factor, which we identify as the transcription factor Ahr1p. However, in contrast to the other yeast regulons, Ahr1p alone binds the target promoters, which include several key adhesion genes, and recruits Mcm1p to these sites. Through transcription profiling and qPCR analysis, we demonstrate that this Ahr1p-Mcm1p complex directly activates these adhesion genes. When the regulon was disrupted by deleting AHR1, the strain displayed reduced adherence to a polystyrene surface. We also demonstrate a role for the regulon in hyphal growth and in virulence. Our work thus establishes a new mechanism of Mcm1p-directed regulation distinct from those observed for other Mcm1p co-regulators.

ORGANISM(S): Candida albicans

PROVIDER: GSE25174 | GEO | 2010/11/10

SECONDARY ACCESSION(S): PRJNA134433

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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The zinc cluster transcription factor Ahr1p directs Mcm1p regulation of Candida albicans adhesion

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