(66e) Regulatory Role of Tandem Repeats Containing Transcription Factor Binding Sites

Tandem repeats of DNA are widely prevalent in higher eukaryotic genomes. Because their growth and decay can occur after only a few generations, the lengths of these tracts are often hypervariable and vary between individuals. Here we explore the regulatory impact that tandem repeats of DNA that contain transcription factor (TF) binding sites can have on gene expression, using a synthetic biology approach in budding yeast. Not surprisingly, we find that the addition of arrays of repeated binding sites for a transcriptional activator competitively inhibit the normal TF-promoter interactions and reduce gene expression. More surprisingly, the repeat sites convert the linear dose-response of the promoter with respect to the TF into a more ultrasensitive response. This can be explained by a model whereby the repeat sites have 10-100 fold higher affinity to the TF compared with the promoter. We discuss the origins and implications of this difference and demonstrate how the changes in the repeat number of off-target binding sites can qualitatively affect gene regulation.