Kurafeiski J.D., Pinto P., Bornberg-Bauer E.
Evolutionary potential of cis-regulatory mutations to cause rapid changes in transcription factor binding
GBE, 2018

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Transcriptional regulation is crucial for all biological processes and well investigated at the molecular level for
a wide range of organisms. However, it is quite unclear how innovations, such as the activity of a novel regulatory element evolve. In the case of transcription factor (TF) binding, both a novel TF and a novel binding site would need to evolve in a coordinated fashion. Promiscuous functions have recently been identified as important intermediate steps in creating novel specific function in many areas such as enzyme evolution and protein-protein interactions.
In this work, we investigate binding behaviour of several hundred transcription factors from different species at unprecedented breadth. Specifically, we ask which role promiscuous binding of TFs to trancription factor binding sites (TFBS) plays for robustness and evolvability of this tightly regulated system.
Our results show that binding specificity correlates with binding strength. Strong binding interactions between TFs and their binding TFBSs are often less numerous and consequently more specific than weak bonds. We observed different levels of binding specificity depending on the utilized binding domain, with homeobox domain TFs exhibiting the highest level of unspecific binding behaviour.
Furthermore, we identified a subset of binding motifs, the majority having an A/T-content of seven out of eight nucleotides. Motifs in this subset had many functionally neutral neighbours for a TF their interacted with, and were bound by multiple different binding domains.
In this study we identify binding motifs exhibiting behaviour indicating high evolutionary potential for innovations in transcriptional regulation.