Modulation of the DNA Accessibility in the Nucleosome -- Insights from Physics Models

Abstract

The nucleosome, a complex of 147 base-pairs of DNA with eight histone proteins, must protect its DNA, but, at the same time, allow on-demand access to it when needed by the cell. The exact mechanism of the control remain unclear. A simplified coarse-grained electrostatic model of the nucleosome reveals that at physiological conditions the complex is close to the phase boundary separating it from the “unwrapped” states where the DNA is more accessible. A small drop in the charge of the globular histone core (e.g. through acetylation of a lysine) can significantly lower the nucleosome stability, and thus increase the DNA accessibility. A follow-up multi-state atomistic model explores virtually all possible charge-altering post-translational modifications (PTMs) in the globular histone core. The model reveals a rich and nuanced picture: the effect of PTMs varies greatly depending on location, including counter-intuitive trends such as decrease of DNAaccessibility for some lysine acetylations in the core. The findings suggest that charge-altering post-translational modifications in the histone core might be utilized by the cell to modulate accessibility to its DNA at the nucleosome level. A connection to transcription regulation in-vivo is made.