How Do Nucleosome Dynamics Regulate Protein Search on DNA?

Nearly three-fourths of all eukaryotic DNA is occupied by nucleosomes, protein-DNA complexes comprising octameric histone core proteins and & SIM;150 base pairs of DNA. In addition to acting as a DNA compaction vehicle, the dynamics of nucleosomes regulate the DNA site accessibility for the nonhistone proteins, thereby controlling regulatory processes involved in determining the cell identity and cell fate. Here, we propose an analytical framework to analyze the role of nucleosome dynamics on the target search process of transcription factors through a simple discrete-state stochastic description of the search process. By considering the experimentally determined kinetic rates associated with protein and nucleosome dynamics as the only inputs, we estimate the target search time of a protein via first-passage probability calculations separately during nucleosome breathing and sliding dynamics. Although both the nucleosome dynamics permit transient access to the DNA sites that are otherwise occluded by the histone proteins, our result suggests substantial differences between the protein search mechanism on a nucleosome performing breathing and sliding dynamics. Furthermore, we identify the molecular factors that influence the search efficiency and demonstrate how these factors together portray a highly dynamic landscape of gene regulation. Our analytical results are validated using extensive Monte Carlo simulations.

Automated summary

Almost 75% of eukaryotic DNA is occupied by nucleosomes, which consist of histone proteins and DNA. Nucleosome dynamics regulate the accessibility of DNA sites for nonhistone proteins, therefore controlling the processes involved in determining cell identity and fate. This study proposes an analytical framework to analyze the impact of nucleosome dynamics on the target search process of transcription factors.