Featuring the nucleosome surface as a therapeutic target

•Chromatin dynamics depend on competition by NBPs and the histone H4 tail to bind to the nucleosome's acidic patch.•eNBMs and distinct NBPs lead to specific chromatin and cellular states.•The nucleosome surface is a therapeutic target.•Peptide-like molecules are the most promising eNBMs.

Chromatin is the major regulator of gene expression and genome maintenance. Proteins that bind the nucleosome, the repetitive unit of chromatin, and the histone H4 tail are critical to establishing chromatin architecture and phenotypic outcomes. Intriguingly, nucleosome-binding proteins (NBPs) and the H4 tail peptide compete for the same binding site at an acidic region on the nucleosome surface. Although the essential facts about the nucleosome were revealed 17 years ago, new insights into its atomic structure and molecular mechanisms are still emerging. Several complex nucleosome:NBP structures were recently revealed, characterizing the NBP-binding sites on the nucleosome surface. Here we discuss the potential of the nucleosome surface as a therapeutic target and the impact and development of exogenous nucleosome-binding molecules (eNBMs).