Large numbers of eukaryotic transcription factors (TFs) are modified by SUMO post-translational modifications. Whereas the effect of TF sumoylation on the expression of target genes is largely context-dependent, it is not known whether the modification has a common function in regulating TFs throughout eukaryotic species. Here, I highlight four studies that used genome-wide chromatin-immunoprecipitation analysis (ChIP-seq) to examine whether sumoylation affects the selection of sites on the genome that are bound by human and yeast TFs. The studies found that impairing sumoylation led to deregulated binding-site selection for all four of the examined TFs. Predominantly, compared to wild-type forms, the sumoylation-deficient forms of the TFs bound to numerous additional non-specific sites, pointing to a common role for the modification in restricting TF binding to appropriate sites. Evidence from these studies suggests that TF sumoylation influences binding-site selection by modulating protein-protein interactions with other DNA-binding TFs, or by promoting conformational changes in the TFs that alter their DNA-binding specificity or affinity. I propose a model in which, prior to their sumoylation, TFs initially bind to chromatin with reduced specificity, which leads to spurious binding but also ensures that all functional sites become bound. Once the TFs are bound to DNA, sumoylation then acts to increase specificity and promotes release of the TFs from non-specific sites. The similar observations from these four genome-wide studies across divergent species suggest that binding-site selection is a general and conserved function for TF sumoylation.
