Comparative Gene Expression Analysis by a Differential Clustering Approach: Application to the Candida albicans Transcription Program

Abstract

Differences in gene expression underlie many of the phenotypic variations between related organisms, yet approaches to characterize such differences on a genome-wide scale are not well developed. Here, we introduce the “differential clustering algorithm” for revealing conserved and diverged co-expression patterns. Our approach is applied at different levels of organization, ranging from pair-wise correlations within specific groups of functionally linked genes, to higher-order correlations between such groups. Using the differential clustering algorithm, we systematically compared the transcription program of the fungal pathogen Candida albicans with that of the model organism Saccharomyces cerevisiae. Many of the identified differences are related to the differential requirement for mitochondrial function in the two yeasts. Distinct regulation patterns of cell cycle genes and of amino acid metabolic genes were also revealed and, in some cases, could be linked to the differential appearance of cis-regulatory elements in the gene promoter regions. Our study provides a comprehensive framework for comparative gene expression analysis and a rich source of hypotheses for uncharacterized open reading frames and putative cis-regulatory elements in C. albicans.

Rearrangements of the transcriptional regulatory networks of metabolic pathways in fungi

“…This S. cerevisiae AA starvation response governed by Gcn4 appears globally conserved throughout the ascomycetes phylogeny [44 ,45]. However, transcriptional profiling of the amino-acid starvation response in Neurospora crassa suggested that in these cells AA biosynthesis genes and tRNA-aminoacyl-transferases are highly co-regulated [44 ] and a meta-analysis of expression co-regulation between S. cerevisiae and C. albicans identified distinctions in the mode of tRNA-aminoacyl-transferases co-regulation between the two species [4]. Consistently, phylogenetic analyses of the Gcn4 element (TGASTCA) enrichment showed that it is conserved in the amino-acid biosynthesis regulon in most ascomycetes and that it is found upstream of genes encoding tRNA-aminoacyltransferases in many species but excluded from the S. cerevisiae branch (Figure 1c) [16,44] ( Figure 1).…”

“…Early evidence for changes in gene regulation among fungi came from transcriptional profiling studies comparing S. cerevisiae, S. pombe and C. albicans [13][14][15]. Furthermore, predictions of cis-regulatory sequences, and meta-analyses of gene co-expression revealed that transcription networks have a great deal of flexibility [4,[16][17][18]. A well characterized example of comparative genomics applied to gene expression evolution is mating type identity that is controlled by distinct circuits with identical logic in S. cerevisiae and C. albicans [19 ].…”

Gene duplication and the evolution of ribosomal protein gene regulation in yeast

“…Genes encoding RPs are tightly coexpressed in organisms from bacteria to humans (3,4), consistent with a selective pressure to conserve coordinated transcript levels to maintain a stoichoimetric balance in ribosome assembly. The transcription factors controlling RP gene expression have changed several times since the last common ancestor of the Ascomycota fungi, which span Saccharomyces cerevisiae and Schizosaccharomyces pombe (4-6).…”

Differential biclustering for gene expression analysis

“…To copy otherwise, to republish, to post on servers or to redistribute to lists, requires prior specific permission and/or a fee. of some genes can cause phenotypic diversity among different conditions [9]. Moreover, the activities of genes are not independent of each other.…”