Conservation and Evolution of Cis-Regulatory Systems in Ascomycete Fungi

Abstract

Relatively little is known about the mechanisms through which gene expression regulation evolves. To investigate this, we systematically explored the conservation of regulatory networks in fungi by examining the cis-regulatory elements that govern the expression of coregulated genes. We first identified groups of coregulated Saccharomyces cerevisiae genes enriched for genes with known upstream or downstream cis-regulatory sequences. Reasoning that many of these gene groups are coregulated in related species as well, we performed similar analyses on orthologs of coregulated S. cerevisiae genes in 13 other ascomycete species. We find that many species-specific gene groups are enriched for the same flanking regulatory sequences as those found in the orthologous gene groups from S. cerevisiae, indicating that those regulatory systems have been conserved in multiple ascomycete species. In addition to these clear cases of regulatory conservation, we find examples of cis-element evolution that suggest multiple modes of regulatory diversification, including alterations in transcription factor-binding specificity, incorporation of new gene targets into an existing regulatory system, and cooption of regulatory systems to control a different set of genes. We investigated one example in greater detail by measuring the in vitro activity of the S. cerevisiae transcription factor Rpn4p and its orthologs from Candida albicans and Neurospora crassa. Our results suggest that the DNA binding specificity of these proteins has coevolved with the sequences found upstream of the Rpn4p target genes and suggest that Rpn4p has a different function in N. crassa.

Rearrangements of the transcriptional regulatory networks of metabolic pathways in fungi

“…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). …”

“…It is thus becoming apparent that the level of plasticity of these networks during evolution is very high. In addition to these spectacular rearrangements of metabolic regulators, other studies provide support for massive rearrangements of the proteasome regulatory network and subtler rewirings of cell cycle regulatory circuits [16,55]. Surprisingly, large-scale modifications in transcriptional regulatory network connections occur in the control of pathways and complexes essential for cellular growth like the ribosomal and glycolytic regulons, while other apparently less constrained pathways are conserved [55].…”

“…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 ].…”

Cis- and trans-regulatory divergence between progenitor species determines gene-expression novelty in Arabidopsis allopolyploids

“…start sites, is correlated with the chromatin structure 34 . In the human genome, synonymous substitution rate at non-CpG sites is the highest in regions of the open chromatin 35 , linking cis effects with chromatin structure. On the other hand, trans expression variability is largely affected by chromatin factors, which have more important roles in creating regulatory variation than transcription factors 36 .…”

Ccr4 Promotes Resolution of the Endoplasmic Reticulum Stress Response during Host Temperature Adaptation in Cryptococcus neoformans

“…For example, in Drosophila, the Pumilio protein binds proteins involved in embryo patterning, whereas the S. cerevisiae homologue, Puf3, binds nuclear-encoded mitochondrial transcripts (22). When cis elements were compared among ascomycete fungi, PUF elements were found to be conserved, but the functional classes of genes in which they were found diverged substantially (9). The enrichment of nuclear-encoded mitochondrial transcripts containing Puf3 elements in fungi is lost along with fermentative capacity, suggesting that the function of the Puf3 cis-trans module has evolved while the structure remains unaltered (14).…”