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Transfer of genetic information starts with transcription factors (TFs) binding to specific sites on DNA. But in living cells, DNA is mostly covered by nucleosomes. There are proteins, known as pioneer TFs, that can efficiently reach the DNA sites hidden by nucleosomes, although the underlying mechanisms are not understood. Using the recently proposed idea of interaction-compensation mechanism, we develop a stochastic model for the target search on DNA with nucleosome breathing. It is found that nucleosome breathing can significantly accelerate the search by pioneer TFs in comparison to situations without breathing. We argue that this is the result of the interaction-compensation mechanism that allows proteins to enter the inner nucleosome region through the outer DNA segment. It is suggested that nature optimized pioneer TFs to take advantage of nucleosome breathing. The presented theoretical picture provides a possible microscopic explanation for the successful invasion of nucleosome-buried genes.

All major biological processes start after protein molecules known as transcription factors detect specific regulatory sequences on DNA and initiate genetic expression by associating to them. But in eukaryotic cells, much of the DNA is covered by nucleosomes and other chromatin structures, preventing transcription factors from binding to their targets. At the same time, experimental studies show that there are several classes of proteins, called "pioneer transcription factors", that are able to reach the targets on nucleosomal DNA; however, the underlying microscopic mechanisms remain not well understood. We propose a new theoretical approach that might explain how pioneer transcription factors can find their targets. It is argued that pioneer transcription factors might weaken the interactions between the DNA and nucleosome by substituting them with similar interactions between transcription factors and DNA. Using this idea, we develop a discrete-state stochastic model that allows for exact calculations of target search dynamics on nucleosomal DNA using first-passage probabilities approach. It is found that the target search on nuclesomal DNA for pioneer transcription factors might be significantly accelerated while the search is slower on naked DNA in comparison with normal transcription factors. Our theoretical predictions are supported by Monte Carlo computer simulations, and they also agree with available experimental observations.

Protein searching and binding to specific sites on DNA is a fundamentally important process that marks the beginning of all major cellular transformations. While the dynamics of protein-DNA interactions in in vitro settings is well investigated, the situation is much more complex for in vivo conditions because the DNA molecules in live cells are packed into chromosomal structures where they are undergoing strong dynamic and conformational fluctuations. In this work, we present a theoretical investigation on the role of DNA looping and DNA conformational fluctuations in the protein target search. It is based on a discrete-state stochastic analysis that allows for explicit calculations of dynamic properties, which is also supplemented by Monte Carlo computer simulations. It is found that for stronger nonspecific interactions between DNA and proteins the search occurs faster on the DNA looped conformation in comparison with the unlooped conformation, and the fastest search is observed when the loop is formed near the target site. It is also shown that DNA fluctuations between the looped and unlooped conformations influence the search dynamics, and this depends on the magnitude of conformational transition rates and on which conformation is more energetically stable. Physical-chemical arguments explaining these observations are presented. Our theoretical study suggests that the geometry and conformational changes in DNA are additional factors that might efficiently control the gene regulation processes.