Structural Mechanisms of Nucleosome Recognition by Linker Histones

Linker histones bind to the nucleosome and regulate the structure of chromatin and gene expression. Despite more than three decades of effort, the structural basis of nucleosome recognition by linker histones remains elusive. Here, we report the crystal structure of the globular domain of chicken linker histone H5 in complex with the nucleosome at 3.5 Å resolution, which is validated using nuclear magnetic resonance spectroscopy. The globular domain sits on the dyad of the nucleosome and interacts with both DNA linkers. Our structure integrates results from mutation analyses and previous cross-linking and fluorescence recovery after photobleach experiments, and it helps resolve the long debate on structural mechanisms of nucleosome recognition by linker histones. The on-dyad binding mode of the H5 globular domain is different from the recently reported off-dyad binding mode of Drosophila linker histone H1. We demonstrate that linker histones with different binding modes could fold chromatin to form distinct higher-order structures. [Display omitted] •Structure of the globular domain of linker histone H5 bound to the nucleosome•The globular domain interacts with the nucleosome dyad and both linker DNAs•Linker histones can recognize the nucleosome by on- or off-dyad binding mode•Different binding modes lead to distinct higher-order structures of chromatin Zhou et al. determined the crystal structure of the globular domain of linker histone H5 bound to the nucleosome. The globular domain binds to the nucleosome dyad and interacts with both linker DNAs. They further showed linker histones with different binding modes could lead to distinct higher-order structures of chromatin.