Nucleosome Rewrapping Facilitates Transcription Factor Exchange

Abstract

Transcription factors (TFs) play a central role in regulating the transcriptional state of gene. However, TFs are sterically occluded from their target sequences when it is wrapped around the histone octamer into a nucleosome. The combination of nucleosomal DNA unwrapping fluctuations and the high DNA sequence specificity of TFs facilitate TF to binding within nucleosomes. TFs achieve their high DNA sequence specificity by having resident times at their recognition sites that are much longer than minutes. This dramatically limits the rate at which a gene can switch between transcriptionally active and repressed states. We investigated with single-molecule Fluorescence Resonance Energy Transfer(FRET) measurements the influence of nucleosomal DNA wrapping fluctuations on TF binding and release from its target sequence within a mononucleosome and/or a nucleosome array. As expected, we find that nucleosomes inhibit the binding rate of a TF to its target sequence within a nucleosome. In contrast,we observe that the rate of TF dissociation from a nucleosome is increase by over a 100-fold as compared to dissociation from duplex DNA. This result suggests that the nucleosome promotes TF dissociation to facilitate the exchange of TFs at their target sequences and enable rapid regulation of gene expression.