Abstract Histone post-translational modifications epigenetically regulate gene expression by modulating nucleosome structure and DNA accessibility. This review outlines how unique patterns of modifications on canonical and variant histones generate a combinatorial histone code. Interplay between multiple modifications increases the complexity as distinct histone proteoforms and nucleoforms can drive context-dependent outcomes. The histone code is highly dynamic, and we examine how histone modifications fluctuate with environmental cues, metabolic state, and cell-cycle progression. Finally, we discuss how dysregulation of histone modifications contributes to disease, and how emerging technologies to decipher the histone code are yielding new biological insights and opportunities for therapeutic development.
Malone et al. (2026) studied this question.