Post-translational modification of histone proteins, including lysine methylation and acylation, regulate gene expression through recruitment of reader proteins to the nucleosome. Dysregulation of these events is prevalent in a wide range of diseases, such that there is much interest in characterizing these modifications and their binding partners.  We have used both supramolecular chemistry and protein engineering approaches to study the protein-protein interactions that are mediated by these post-translational modifications and to develop new tools to sense them. Examples of these approaches will be discussed.