A lattice model for transcription factor access to nucleosomal DNA

Nucleosomes, the basic repeating unit of chromatin, consist of 147 basepairs of DNA that are wrapped in almost two turns around a histone protein octamer core. Because ∼3/4 of the human genomic DNA is found within nucleosomes, their position and DNA interaction is an essential determinant for the DNA access of gene-specific transcription factors and other proteins. Here, a DNA lattice model was developed for describing ligand binding in the presence of a nucleosome. The model takes into account intermediate states, in which DNA is partially unwrapped from the histone octamer. This facilitates access of transcription factors to up to 60 DNA basepairs located in the outer turn of nucleosomal DNA, while the inner DNA turn was found to be more resistant to competitive ligand binding. As deduced from quantitative comparisons with recently published experimental data, our model provides a better description than the previously used all-or-none lattice-binding model. Importantly, nucleosome-occupancy maps predicted by the nucleosome-unwrapping model also differed significantly when partial unwrapping of nucleosomal DNA was considered. In addition, large effects on the cooperative binding of transcription factors to multiple binding sites occluded by the nucleosome were apparent. These findings indicate that partial unwrapping of DNA from the histone octamer needs to be taken into account in quantitative models of gene regulation in chromatin.