Histone variants: The bricks that fit differently

Histone proteins organize nuclear DNA in eukaryotic cells and play crucial roles in regulating chromatin structure and function. Histone variants are produced by distinct histone genes and are produced independently of their canonical counterparts throughout the cell cycle. Even though histone variants may differ by only one or a few amino acids relative to their canonical counterparts, these minor variations can profoundly alter chromatin structure, accessibility, dynamics, and gene expression. Histone variants often interact with dedicated chaperones and remodelers and can have unique post-translational modifications that shape unique gene expression landscapes. Histone variants also play essential roles in DNA replication, damage repair, and histone–protamine transition during spermatogenesis. Importantly, aberrant histone variant expression and DNA mutations in histone variants are linked to various human diseases, including cancer, developmental disorders, and neurodegenerative diseases. In this review, we explore how core histone variants impact nucleosome structure and DNA accessibility, the significance of variant-specific post-translational modifications, how variant-specific chaperones and remodelers contribute to a regulatory network governing chromatin behavior, and discuss current knowledge about the association of histone variants with human diseases.