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

Association of protein transcription factors (TFs) to specific DNA sites in promoter regions is the fundamental event that initiates gene regulation. However eukaryotic DNA is mostly covered by nucleosomes, creating obstacles for TFs to access their targets. Nature solved this problem by utilizing a special class of protein molecules, known as pioneer TFs, that are capable to enter chromatin structures and reach DNA sites hidden by nucleosomes. However, the microscopic origin of the underlying processes remains not well understood. In this chapter, we present a brief review of the current understanding of the molecular mechanisms of the target search by pioneer TFs. It is argued that it is not enough for TFs to explore only nucleosome breathing, and they might also need to directly displace the nucleosome native contacts, substituting them with equivalent contacts between nucleosomal DNA and pioneer TFs. Using this idea, a comprehensive discrete-state stochastic framework is developed to evaluate the protein target search phenomena on nucleosome-embedded DNA.