Metagenomic mining reveals novel viral histones in dsDNA viruses
The 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 class Caudoviricetes. Structural predictions and in vitro assays 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. HighlightsO_LIHistone triplets and singlets co-occurring in the same dsDNA viral genomes assemble into nucleosome-like particles C_LIO_LISix novel types of structurally and functionally distinct viral histone-fold proteins are identified C_LIO_LIThe presence of viral histones is significantly positively associated with proteins containing SNF2 chromatin remodeling domain found in viral genomes C_LI