Genomewide protein-DNA binding dynamics suggest a clutch for transcription factor function

Dynamic access to genetic information is central to organismal development and environmental response. Consequently, genomic processes must be regulated by mechanisms that alter genome function relatively rapidly(1-4). Conventional chromatin immunoprecipitation (ChIP) experiments measure transcription factor (TF) occupancy(5), but are blind to kinetics and are poor predictors of TF function at a given locus. To measure TF binding dynamics genome-wide, we performed competition ChIP(6,7) with a sequence-specific S. cerevisiae transcription factor, Rap1(8). Rap1 binding dynamics and Rap1 occupancy were only weakly correlated (R(2) = 0.14), but binding dynamics were more strongly linked to function than occupancy. Long Rap1 residence was coupled to transcriptional activation, while fast binding turnover, which we term “treadmilling”, was linked to low transcriptional output. Thus, DNA-binding events that appear identical by conventional ChIP may have starkly different underlying modes of interaction that lead to opposing functional outcomes. We propose that TF binding turnover is a major point of regulation in determining the functional consequences of transcription factor binding, and is mediated in large part by control of competition between TFs and nucleosomes. Our model (Supplementary Fig. 1) predicts a clutch-like mechanism that rapidly engages a treadmilling transcription factor into a stable binding state, or vice-versa, to modulate TF function.