Structural and Functional Analysis of Gene and Protein Sequence Families

National Library Of Medicine

Investigators

Linked publications & trials

Abstract

Histones are basic nuclear proteins that help to pack DNA into nucleosomes and chromatosomes. Nucleosome comprises 147 bp of DNA wrapped around a histone octamer and is a central point in coordinating various signaling pathways involved in epigenetic regulation. The molecular recognition of nucleosomes by chromatin factors frequently occurs through the interactions with the nucleosomal and linker DNA, histone tails, histone globular domains, and by recognizing their specific covalent modifications. Elucidating the physicochemical properties of these interactions is essential for our understanding of the principles of chromatin organization and regulation. In our recent work, we performed a comprehensive mapping of human histone interaction networks by using data from structural, chemical cross-linking, and various high-throughput studies, including 5308 proteins and 10,330 interactions. We further explored histone interactions at different levels of granularity: protein, domain and residue-levels and detected two types of histone binding modes including interfaces conserved in most histone variants and variant-specific interfaces. Our analysis points to the abundance and high specificity of histone interactions in a large variety of cellular processes. In current project, we further investigate the modulation of histone interactions by mutations and post-translational modifications using the interaction network data and bioinformatics approaches. In another project, we investigated the mechanisms of how histone tails modulate the nucleosomal and linker DNA solvent accessibility and recognition of nucleosomes by other macromolecules. Histone tails are intrinsically disordered and thus it is difficult to characterize their physicochemical properties in experiments. Here, we performed 65 microseconds of molecular dynamics simulations and generated extensive atomic level conformational ensembles of histone tails in the context of the full human nucleosome. We explored the histone tail binding modes with the nucleosomal and linker DNA and observed rapid conformational transitions between bound and unbound states. Our results show that different histone types exhibit distinct, although conformationally heterogeneous, binding modes and each histone type occludes specific DNA regions from the solvent. Furthermore, we utilized experimental data on nucleosome structural complexes to explore how tail dynamics may mediate the interactions of nucleosomes with their binding partners. We find that the majority of the studied nucleosome-binding proteins and histone tails target mutually exclusive regions on nucleosomal or linker DNA around the super-helical locations =/-1, =/-2, and =/-7. This finding is explained within the generalized competitive binding and tail displacement models of protein partner recruitment to nucleosomes.