How Do Nucleosome Dynamics Regulate Protein Search on DNA?

Abstract

Nearly three-fourths of all eukaryotic DNA is occupied by nucleosomes, protein−DNA complexes comprising octameric histone core proteins and ∼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.

Why Are Nucleosome Breathing Dynamics Asymmetric?

“…They have the ability to invade the DNA target sites even in inaccessible regions, and subsequently, they create permissive states for the following regulatory processes to occur. − Therefore, the proper functioning of pioneer TFs is of critical importance because their misregulation can create defects in large-scale chromatin structures and compromise human health . Indeed, pioneer TFs are found both up- and down-regulated, mutated, or amplified in their genomic locus in many forms of cancer. , The mechanisms by which pioneer TFs can access the nucleosome-covered DNA remain not well understood, − although several theoretical ideas to explain their functioning have been already proposed. ,− …”

Role of Nucleosome Sliding in the Protein Target Search for Covered DNA Sites

“…Recent theoretical investigation 40 has attempted to evaluate the effect of nucleosome sliding in a protein target search for specific sites by analyzing a coarse-grained stochastic model in which the DNA sites that are facing outward from the histone protein are assumed to be accessible and those sites that are in close proximity to the histone proteins remain inaccessible. Using analytical calculations and computer simulations, a description of the protein target search process was obtained, clarifying some important differences between nucleosome breathing and nucleosome sliding.…”