Transcriptional autoregulatory loops are highly conserved in vertebrate evolution

Abstract

Background: Feedback loops are the simplest building blocks of transcriptional regulatory networks and therefore their behavior in the course of evolution is of prime interest.

Methodology: We address the question of enrichment of the number of autoregulatory feedback loops in higher organisms. First, based on predicted autoregulatory binding sites we count the number of autoregulatory loops. We compare it to estimates obtained either by assuming that each (conserved) gene has the same chance to be a target of a given factor or by assuming that each conserved sequence position has an equal chance to be a binding site of the factor.

Conclusions: We demonstrate that the numbers of putative autoregulatory loops conserved between human and fugu, danio or chicken are significantly higher than expected. Moreover we show, that conserved autoregulatory binding sites cluster close to the factors' starts of transcription. We conclude, that transcriptional autoregulatory feedback loops constitute a core transcriptional network motif and their conservation has been maintained in higher vertebrate organism evolution.

Figure 1. Comparison of fractions of genes and factors targeted by a transcription factor.

Each point corresponds to a transcription factor f∈G_F. Horizontal axes provide the fraction of factors predicted to have a conserved binding site of f. Vertical axes give the fraction of regulated genes . Three cases are shown: no conservation, conservation to danio and to fugu.

Figure 2. Relation between GC-contents of transcription factor's regulatory regions and corresponding PSCMs.

Left: human sequences were used for regulatory region GC-content calculation. Right: fragments of human sequence conserved in fugu.

Figure 3. Positional distribution of autoregulatory binding sites.

Amounts of conserved sequence and numbers of autoregulatory binding sites observed in bins located at different distances with respect to factors starts of transcription. Left axes present amount of contributing autoregulatory binding sites within a bin; right axes show fraction of conserved nucleotides in all factors within a bin. Top chart corresponds to the human sequence; below, for conserved sequence fragments to fugu and danio.