Metagenomic mining reveals novel viral histones in dsDNA viruses

Using metagenomic mining of the IMG/VR 4 database, the group of Dr. Yue Liu (School of Medicine, Zhejiang University), Dr. Yang Liu (School of Medicine, Zhejiang University), and Dr. Haibo Wang (Institute of Translational Medicine, Zhejiang University) has now identified over 1,500 viral histones and histone-fold proteins (HFPs). While the presence of histones in dsDNA viruses beyond giant viruses remains largely unexplored, this study broadens the scope and reveals potential histone-related features across diverse dsDNA viral lineages. Notably, these newly identified viral proteins include those previously undescribed in the viral class Caudoviricetes, a class of tailed dsDNA bacteriophages primarily infecting archaea and bacteria.

Combining Alphafold3 predictions with experimental nucleosome reconstitution, viral histone triplets and singlets from Caudoviricetes and Megaviricetes were shown to assemble into nucleosome-like particles (NLPs) with the 145-bp Widom 601 DNA, potentially mimicking the DNA-packaging function of eukaryotic histones.

Further computational analysis revealed six novel types of structurally and functionally distinct viral histone-fold proteins (HFPs). Some viral HFPs structurally resemble bacterial and archaeal histones, while others exhibit unique structural features, such as containing a KOW domain. These findings suggest that viral histones and HFPs may play diverse roles beyond nucleosome formation, with potential functions in viral genome organization and virus-host interactions.

Finally, the team revealed that the presence of viral histones is positively correlated with chromatin-related proteins (CRPs), particularly those containing the SNF2 chromatin remodelling domain. This indicates a functional association between viral histones and chromatin remodelling factors. “These exciting results uncover a previously unrecognized diversity of viral histones and related chromatin-associated proteins,” says Liu. “This work lays the foundation for future structural and functional characterizations of viral histones, which could potentially refresh our understanding of virus-host interactions.”

Collectively, this work has provided new opportunities for unravelling the evolutionary trajectory of histones and opened up exciting avenues for studying viral epigenetics.

See the article:

Metagenomic mining reveals novel viral histones in dsDNA viruses

https://doi.org/10.1016/j.hlife.2025.02.005

Funders: National Key Research and Development Program of China (2023YFC2306800 to Yue Liu), the National Natural Science Foundation of China (82188102 to HaiboWang), and the European Molecular Biology Organization Scientific Exchange Grant (10347 to Yang Liu).