Metagenomic mining reveals novel viral histones in dsDNA viruses

ABSTRACTThe compaction of genomic DNA into nucleosomes with the help of histones had long been considered as a fundamental feature exclusive to eukaryotic cells. However, it was recently shown that archaea and bacteria also encode histones. A complex picture has emerged with more recent discoveries of eukaryotic-like histones within one phylum of double-stranded DNA (dsDNA) viruses. Nevertheless, the extent to which other dsDNA viruses encode histones remains largely unexplored. Here we conducted a metagenomic survey of viral histones that were further clustered based on sequence and predicted structural similarities. We identified over 1,500 viral histones and histone-fold proteins, including previously undescribed proteins found in the viral classCaudoviricetes. Structural predictions andin vitroassays demonstrated that histone triplets (where three histone folds are fused) and singlets co-occurring in the same viral genome are capable of forming nucleosome-like particles. Beyond nucleosomal histone functions, our analysis revealed six types of structurally and functionally diverse viral histone-fold proteins, some of which do not have known structural or functional homologs. Altogether, our findings reveal a previously unrecognized diversity of viral histones in dsDNA viruses, expanding the known repertoire, structural diversity, and functional versatility of viral histones beyond nucleocytoplasmic large DNA viruses.HighlightsHistone triplets and singlets co-occurring in the same dsDNA viral genomes assemble into nucleosome-like particlesSix novel types of structurally and functionally distinct viral histone-fold proteins are identifiedThe presence of viral histones is significantly positively associated with proteins containing SNF2 chromatin remodeling domain found in viral genomes