A Biophysical Model Of Interactions Between Transcription Factors And Chromatin

Abstract

Binding of transcription factors (TFs) to DNA is critical for triggering a cascade of events that lead to gene expression. The role of chromatin in this process is not considered by traditional biochemical models of protein-DNA interaction, or is limited to the passive DNA sequestration by the nucleosomes. Taking into account dynamic structure of chromatin is important for understanding transcription regulation in eukaryotes.Here we present a biophysical model of interactions between TFs and chromatinized DNA. The model takes into account dynamics of nucleosomes as well as other important features of eukaryotic regulatory regions such as the clustering TF binding sites, nucleosome-positioning DNA signals etc. Our model demonstrates that a wide range of biological phenomena can be explained by interactions between TFs and chromatin, and provides a quantitative description of the following processes:•cooperative binding and synergistic action of non-interacting TFs;•access of TFs to chromatinized DNA;•displacement of nucleosomes from regulatory regions;•rapid evolutionary changes in arrangement and membership of TF-binding sites in eukaryotic regulatory regions.Strikingly, we found that cooperative binding of TFs to chromatinized DNA is identical to the Monod-Wyman-Changeux model of allosteric cooperativity in hemoglobin, pointing at a general mechanism of cooperativity employed in a range of biological systems. This parallel allowed us to use classical results in biochemistry to gain deep insights into the mechanisms of gene regulation.