Thermodynamic modeling of genome-wide nucleosome depleted regions in yeast

Nucleosome positioning in the genome is essential for the regulation of many nuclear processes. We currently have limited capability to predict nucleosome positioning in vivo, especially the locations and sizes of nucleosome depleted regions (NDRs). Here, we present a thermodynamic model that incorporates the intrinsic affinity of histones, competitive binding of sequence-specific factors, and nucleosome remodeling to predict nucleosome positioning in budding yeast. The model shows that the intrinsic affinity of histones, at near-saturating histone concentration, is not sufficient in generating NDRs in the genome. However, the binding of a few factors, especially RSC towards GC-rich and poly(A/T) sequences, allows us to predict similar to 66% of genome-wide NDRs. The model also shows that nucleosome remodeling activity is required to predict the correct NDR sizes. The validity of the model was further supported by the agreement between the predicted and the measured nucleosome positioning upon factor deletion or on exogenous sequences introduced into yeast. Overall, our model quantitatively evaluated the impact of different genetic components on NDR formation and illustrated the vital roles of sequence-specific factors and nucleosome remodeling in this process. Author summary Nucleosome is the basic unit of chromatin, containing 147 base-pairs of DNA wrapped around a histone core. The positioning of nucleosomes, i.e., which parts of DNA are inside nucleosome and which parts are nucleosome-free, is highly regulated. In particular, regulatory sequences tend to be exposed in nucleosome-depleted regions (NDRs), and such exposure is crucial for a variety of processes including DNA replication, repair, and gene expression. Here, we used a thermodynamics model to predict nucleosome positioning on the yeast genome. The model shows that the intrinsic sequence preference of histones is not sufficient in generating NDRs. In contrast, binding of a few transcription factors, especially RSC, is largely responsible for NDR formation. Nucleosome remodeling activity is also required in the model to recapitulate the NDR sizes. This model contributes to our understanding of the mechanisms that regulate nucleosome positioning. It can also be used to predict nucleosome positioning in mutant yeast or on novel DNA sequences.