Global screening of potential Candida albicans biofilm-related transcription factors via network comparison

Abstract

Background: Candida albicans is a commonly encountered fungal pathogen in humans. The formation of biofilm is a major virulence factor in C. albicans pathogenesis and is related to antidrug resistance of this organism. Although many factors affecting biofilm have been analyzed, molecular mechanisms that regulate biofilm formation still await to be elucidated.

Results: In this study, from the gene regulatory network perspective, we developed an efficient computational framework, which integrates different kinds of data from genome-scale analysis, for global screening of potential transcription factors (TFs) controlling C. albicans biofilm formation. S. cerevisiae information and ortholog data were used to infer the possible TF-gene regulatory associations in C. albicans. Based on TF-gene regulatory associations and gene expression profiles, a stochastic dynamic model was employed to reconstruct the gene regulatory networks of C. albicans biofilm and planktonic cells. The two networks were then compared and a score of relevance value (RV) was proposed to determine and assign the quantity of correlation of each potential TF with biofilm formation. A total of twenty-three TFs are identified to be related to the biofilm formation; ten of them are previously reported by literature evidences.

Conclusions: The results indicate that the proposed screening method can successfully identify most known biofilm-related TFs and also identify many others that have not been previously reported. Together, this method can be employed as a pre-experiment screening approach that reveals new target genes for further characterization to understand the regulatory mechanisms in biofilm formation, which can serve as the starting point for therapeutic intervention of C. albicans infections.

Figure 1

The flowchart of the proposed method for screening potential biofilm-related TFs in C. albicans.

Figure 2

An example for illustration of C. albicans TF-gene regulatory association inference.

Figure 3

Schematic diagrams for illustration of gene regulatory network comparison. (a) The biofilm gene regulatory network and the planktonic gene regulatory network. The regulatory abilities for TF-gene interactions are omitted for simplicity. (b) The gain-of-function and loss-of-function subnetworks after network structure comparison. a_ij,gain and a_ij,loss indicate the regulatory abilities of the j-th TF to the i-th target gene for gain-of-function and loss-of-function, respectively, in which a positive sign indicates activation and a negative sign indicates repression.

Figure 4

Distribution of relevance values (RVs) of random network.