How motif environment influences transcription factor search dynamics: Finding a needle in a haystack

Transcription factors (TFs) have to find their binding sites, which are distributed throughout the genome. Facilitated diffusion is currently the most widely accepted model for this search process. Based on this model the TF alternates between one‐dimensional sliding along the DNA, and three‐dimensional bulk diffusion. In this view, the non‐specific associations between the proteins and the DNA play a major role in the search dynamics. However, little is known about how the DNA properties around the motif contribute to the search. Accumulating evidence showing that TF binding sites are embedded within a unique environment, specific to each TF, leads to the hypothesis that the search process is facilitated by favorable DNA features that help to improve the search efficiency. Here, we review the field and present the hypothesis that TF‐DNA recognition is dictated not only by the motif, but is also influenced by the environment in which the motif resides.