A Statistical Thermodynamic Approach for Predicting the Sequence-Dependent Nucleosome Positioning Along Genomes

Nucleosomes are the fundamental repeating unit of chromatin and constitute the structural building blocks of the eukaryotic genome. The distribution of nucleosomes along the genome is a significant aspect of chromatin structure and influences gene regulation through modulation of DNA accessibility. For this reason, an increasing interest is arising in models capable of predicting the nucleosome positioning along genomes. Toward this goal, we propose a theoretical model for predicting nucleosome thermodynamic stability in terms of DNA sequence. The model, based on a statistical mechanical approach allows the calculation of the canonical ensemble free energy involved in nucleosome formation. The theoretical free energies were evaluated for about one hundred nucleosome DNA tracts and successfully compared with those obtained in different laboratories with nucleosome competitive reconstitution (correlation coefficient equal to 0.92). We extended these results to the nucleosome positioning along genomes. To test our model, the theoretical nucleosome distribution was compared with that of yeast genome experimentally determined. The results are comparable with those obtained by different authors adopting models based on identifying some recurrent sequence features obtained from the statistical analysis of a very large pool of nucleosomal DNA sequences provided by the positioning maps of genomes