The impact of DNA point mutations and epigenetic modifications on the nucleosome wrapping energy

Nucleosome positioning and mobility, which plays an important role in gene expression and regulation, is in turn modulated by DNA sequence and its underlying mechanical properties. The free energy, required to deform a 147 bp linear DNA fragment into a nucleosomal configuration, is a way to quantify DNA mechanical propensity for nucleosome formation. This work explores how such energy, referred to as the nucleosome wrapping energy, is altered by DNA sequence mutations and epigenetic modifications. The nucleosome wrapping energy is computed using a newly developed computational method based on minimising the <i>cgNA+</i> coarse-grain model energy with elastic constraints on phosphate positions. We find that the effect of sequence mutations and epigenetic modifications is highly dependent on the positions along the sequence of the modified bases. Most point mutations as well as cytosine methylation and hydroxymethylation, depending on their positions, can lead both to an increase and decrease in the nucleosome wrapping energy. We use the data of mutation-caused energy changes to identify sequence patterns in specific positions, leading to the smallest and highest wrapping energy values. Furthermore, we construct sequences corresponding to extremely low and high nucleosome wrapping energies, compared to energy distribution for human genome sequences. We believe that our findings are helpful for better understanding the role of DNA sequence and its epigenetic modifications in nucleosome positioning. Furthermore, our constructed minimum energy sequence could be used as a candidate for producing stable synthetic nucleosomes.