cis-trans compensation

Kuo D, Licon K, Bandyopadhyay S, Chuang R, Luo C, Catalana J, Ravasi T, Tan K & Ideker T 2010 Coevolution within a transcriptional network by compensatory trans and cis mutations. Genome Res 20:1672-1678.

  • a trans mutation has occurred very recently in a single AP-1 family member
  • despite their different DNA-binding domains, the AP-1 orthologs regulate a conserved block of genes
  • this conservation is enabled by concomitant changes in the cis-regulatory motifs upstream of each gene
  • both trans and cis mutations have perturbed the yeast AP-1 regulatory system in such a way as to compensate for one another
  • given the dramatic changes that appear to be occurring in transcriptional networks, a key question is how such systems retain essential functions over evolutionary time
  • rather than replacing specific cofactors, it is conceivable that the DNA-binding domains of the TFs that bind these cis-regulatory sequences might be altered in lock-step with changes in cis, similarly to the evolution of protein-binding partners
  • such a mechanism of evolution has yet to be observed
  • here, we present a direct example of such "coevolution," where a specific change to a DNA-binding transcription factor and its cis-regulatory site have occurred in compensatory fashion
  • we performed an amino acid sequence alignment of the DNA-binding domains of all eight AP-1-like TFs in S. cerevisiae
  • to assess the functional implications of changes in yAP-1 binding, we generated genome-wide mRNA expression profiles for each mutant in comparison to the unmutated parental strain
  • upstream DNA-binding motifs of CgAp1 targets have evolved from YRE-O to YRE-A (Fig. 3E)
  • such a switch may have also been accompanied by concordant changes in secondary cis-regulatory DNA motifs
  • and possible functional divergence
  • the most plausible explanation is that these motifs have coevolved with a Lys 12 mutation in CgAp1
  • with the result that this transcriptional system has retained regulatory control of the same set of target genes over evolutionary time
  • conservation of the AP-1 regulatory program in yeast occurs through coordinated evolution of both the sequence of the TF (trans) and in its DNA-binding motifs (cis)