How to Find Targets That Are Always Hidden: The Story of Nucleosome-Covered DNA and Pioneer Transcription Factors

All major biological processes start after transcription factors detect specific regulatory sequences on DNA and initiate genetic expression by associating with them. However, in eukaryotic cells, much of the DNA is covered by nucleosomes, preventing the transcription factors from binding to their targets. At the same time, experiments show that several classes of proteins, called “pioneer transcription factors”, can penetrate chromatin structures. However, the underlying microscopic mechanisms remain not well understood. We propose a new theoretical approach that might explain these observations. It is argued that due to structural similarity with linker histones, pioneer transcription factors might weaken the interactions between the DNA and the nucleosome by substituting them with similar interactions between pioneer transcription factors and DNA. Using this idea, we develop a discrete-state stochastic framework that allows for explicit calculations of target search dynamics on nucleosomal DNA. It is found that finding specific sequences on nucleosomal DNA for pioneer transcription factors might be significantly accelerated while the search is slower on naked DNA segments in comparison with normal transcription factors. In addition, it is shown that nucleosome breathing makes the target search by pioneer transcription factors even faster, and theoretical arguments to explain these observations are presented. Monte Carlo computer simulations support our theoretical predictions, and they also agree with available experimental observations, providing new microscopic insights into the complex nature of protein-DNA interactions.