Histone variant H2A.Z modulates nucleosome dynamics to promote DNA accessibility

Abstract

Nucleosomes containing the histone variant H2A.Z are important for gene transcription initiation and termination, chromosome segregation and DNA double-strand break repair, among other functions. However, the underlying mechanism of how H2A.Z influences nucleosome stability, dynamics and DNA accessibility remains elusive as experimental and computational evidence are inconclusive. Our modeling efforts of nucleosome stability and dynamics, along with comparisons with experimental data show that the incorporation of H2A.Z results in a substantial decrease of the energy barrier for DNA unwrapping. This leads to spontaneous DNA unwrapping of about forty base pairs in total, enhanced DNA accessibility, nucleosome gapping and histone plasticity, which otherwise is not observed for canonical nucleosomes. We demonstrate that both N- and C-terminal tails of H2A.Z play major roles in these events, whereas H3.3 variant exerts a negligible impact in modulating the DNA end unwrapping. In summary, our results indicate that H2A.Z deposition makes nucleosomes more mobile and DNA more accessible to transcriptional machinery and other chromatin components.