Impact of Histone Variant and Post-Translational Modification on Nucleosome

Abstract

Eukaryotic genome DNA is compactly packaged into a nucleus of cell in a form of protein-DNA complex. This protein-DNA complex is called as nucleosome which is composed of a histone octamer formed by two copies each of the four core histones H3, H4, H2A and H2B and about 150 bp of DNA wrapping almost twice around the octamer. Nucleosome, however, changes its form by replacing histones with their variants and post-translational modifications to function in transcription, DNA duplication and DNA repair processes. To study the impact of histone variants and post-translational modifications on the structure and stability of nucleosome, we have performed molecular dynamics simulations with enhanced sampling methods. Free energy profiles obtained by nucleosomal DNA-unwrapping simulations exhibited that H3-containing nucleosome was stable in a fully wrapped state. It cost about 10 kcal/mol for unwrapping the first 8 bp from the DNA end. The cost much decreased for further unwrapping up to 20 bp-unwrapping. In contrast, CENP-A containing nucleosome was the most stable in a state where 5 to 10 bp of DNA were unwrapped from either end of DNA. For both nucleosomes, we observed that DNA was unwrapped asymmetrically.Next we evaluated a post-translational modification, K14 acetylation of H3 histone in a nucleosome structure. Our simulations indicated that H3 histone tail was almost always located nearby DNA regardless of the acetylation, however, K14 acetylation enhanced unwrapping of DNA at entry/exit regions. This can be explained by reduction of interactions between the histone tail and DNA due to the charge neutralization and increase in α-helical content in the histone tail. As a consequence, K14 acetylation increases the chance that DNA-binding proteins access DNA. These results give a new view of how acetylation affects chromatin conformation.