Systematic Identification, Characterization, and Conservation of Adjacent-Gene Coregulation in the Budding Yeast Saccharomyces cerevisiae

Abstract

It is essential that cells orchestrate gene expression for the specific niche that they occupy, and this often requires coordination of the expression of large sets of genes. There are multiple regulatory systems that exist for modulation of gene expression, including the adjacent-gene coregulation of the rRNA and ribosome biogenesis and ribosomal protein families. Both gene families exhibit a nonrandom genomic distribution, often clustered directly adjacent to another member of the same family, which results in a tighter transcriptional coordination among adjacent paired genes than that of the unpaired genes within each regulon and can result in a shared promoter that coordinates expression of the pairs. This nonrandom genomic distribution has been seen in a few functionally related gene families, and many of these functional pairings are conserved across divergent fungal lineages. To date, the significance of these observations has not been extended in a systematic way to characterize how prevalent the role of adjacent-gene coregulation is in transcriptional regulation. In the present study, we systematically analyzed the transcriptional coherence of the functional pairs compared to the singletons within all gene families defined by the Gene Ontology Slim designation, using Saccharomyces cerevisiae as a model system, finding that clusters exhibit a tighter transcriptional correlation under specific contexts. We found that the longer a functional pairing is conserved the tighter its response to broad stress and nutritional responses, that roughly 25% of gene families exhibit a nonrandom genomic distribution, and that many of these clusters are conserved. This suggests that adjacent-gene coregulation is a widespread, yet underappreciated, transcriptional mechanism.IMPORTANCE The spatial positioning of genes throughout the genome arrangement can alter their expression in many eukaryotic organisms. Often this results in a genomic context-specific effect on transcription. One example of this is through the clustering of functionally related genes, which results in adjacent-gene coregulation in the budding yeast Saccharomyces cerevisiae In the present study, we set out to systematically characterize the prevalence of this phenomenon, finding the genomic organization of functionally related genes into clusters is a characteristic of myriad gene families. These arrangements are found in many evolutionarily divergent fungi and thus represent a widespread, yet underappreciated, layer of transcriptional regulation.

Keywords: Saccharomyces cerevisiae; adjacent-gene coregulation; gene expression; spatial positioning.

FIG 1

Tighter transcriptional correlation of functionally clustered genes increases with evolutionary conservation. Shown is the transcriptional correlation for every possible functional clustering arrangement that could have arisen through the use of bootstrapping with replacement. The PCC was calculated for 10,000 iterations that represent every possible combination of clustering that could have evolved (of comparable size to the actual cluster for each set), and the frequency histograms are presented for the ribosomal protein, nitrogen metabolism, carbohydrate metabolism, DNA damage response, and heat shock protein gene families (from top to bottom) in Saccharomyces cerevisiae (A), Saccharomyces paradoxus (B), Saccharomyces mikatae (C), and Saccharomyces kudriavzevii (D). The PCC for the actual clustered set of genes for each family is indicated with the arrows. For anticorrelations that have a PCC of less than −0.1, all of the values are binned at −0.1.

FIG 2

The functionally clustered genes are a combination of conserved, ancestral pairings and newly evolved species-specific pairings. The functionally clustered gene pairings from Saccharomyces cerevisiae were analyzed for conservation of the pairings that are seen in S. cerevisiae. The relationship of the species analyzed in this study is shown in panel A, and the levels of conservation are shown in divergent fungal lineages (B) and the last common ancestor before the whole-genome duplication event (C). The heat map depicts the conservation with either yellow (conservation of the pairing) or black (no conservation of the pairing).