Effect of genomic distance on coexpression of coregulated genes in E. coli

Abstract

In prokaryotes, genomic distance is a feature that in addition to coregulation affects coexpression. Several observations, such as genomic clustering of highly coexpressed small regulons, support the idea that coexpression behavior of coregulated genes is affected by the distance between the coregulated genes. However, the specific contribution of distance in addition to coregulation in determining the degree of coexpression has not yet been studied systematically. In this work, we exploit the rich information in RegulonDB to study how the genomic distance between coregulated genes affects their degree of coexpression, measured by pairwise similarity of expression profiles obtained under a large number of conditions. We observed that, in general, coregulated genes display higher degrees of coexpression as they are more closely located on the genome. This contribution of genomic distance in determining the degree of coexpression was relatively small compared to the degree of coexpression that was determined by the tightness of the coregulation (degree of overlap of regulatory programs) but was shown to be evolutionary constrained. In addition, the distance effect was sufficient to guarantee coexpression of coregulated genes that are located at very short distances, irrespective of their tightness of coregulation. This is partly but definitely not always because the close distance is also the cause of the coregulation. In cases where it is not, we hypothesize that the effect of the distance on coexpression could be caused by the fact that coregulated genes closely located to each other are also relatively more equidistantly located from their common TF and therefore subject to more similar levels of TF molecules. The absolute genomic distance of the coregulated genes to their common TF-coding gene tends to be less important in determining the degree of coexpression. Our results pinpoint the importance of taking into account the combined effect of distance and coregulation when studying prokaryotic coexpression and transcriptional regulation.

Fig 1. The distance between coregulated genes negatively influences their coexpression degree.

The plot shows the mean coexpression degree as a function of the maximum distance between two genes. The distance (x-axis) is measured by the number of kb (kilo base pairs, equal to 1000 base pairs) between the structural gene start positions of two genes. Coexpression degree (y-axis) is measured by the median SCR (a low median SCR implies high degree of coexpression) of genes with a distance lower or equal to the distance indicated on the x-axis. The effect of distance on coexpression is shown for all coregulated genes (dark-blue curve). Coexpression degree of coregulated genes can be compared to the negative control containing all genes not known to be coregulated (red curve). Note that breaks in the x-axis between distances <10 and <20 kb and between distances <100 and <500 correspond to scale differences. The numbers above each data point of the dark-blue curve represent the number of pairs of coregulated genes for which the median SCR was calculated.

Fig 2. The distance between coregulated genes has a larger influence on their coexpression degree if genes are less tightly coregulated.

The coexpression behavior of coregulated genes was disentangled, depending on whether the regulatory programs displayed complete versus partial overlap (blue versus orange) and depending on the number of common TFs present in the overlapping part of their regulatory program (dotted line for 1 TF versus full line for >1 TF).

Fig 3. Effect of relative distance between TF and target genes on the degree of coexpression of the target genes.

The coexpression behavior of genes that are coregulated by one TF is disentangled, depending on whether genes are equidistantly located (grey) or not equidistantly located (purple) relative to their common TF-coding gene. Y-axis displays the degree of coexpression (SCR), X-axis displays the maximum genomic distance between the coregulated genes.

Fig 4. Evolutionary conservation of distance between coregulated genes.

The x-axis represents the pairwise genomic distance between coregulated genes in E. coli, measured in intervening genes. The y-axis represents the degree to which for coregulated genes in E. coli the genomic distance is evolutionarily conserved in other gamma-proteobacteria which is expressed as the fraction of orthologous gene pairs for which the distance is equal or smaller (y-axis) than the distance between the corresponding genes in E. coli (x-axis) over the total number of analyzed orthologous genes. Orthologous genes are pairs of genes in other species that are orthologous to a pair considered in E. coli, i.e. a pair of coregulated genes in E. coli is expected to have an orthologous counterpart in other gamma-proteobacterial species if both genes in the E. coli pair have an orthologous counterpart in the considered gamma-proteobacterial species. Results are shown for respectively pairs of genes that are highly coexpressed (SCR < 100) (black curve) versus pairs of genes that are not coexpressed (SCR > 1000) (blue curve).