Selenalysine as a Chemical Tool for Probing Histone Post-Translational Modifications

Post-translational modifications (PTMs) on histones play a crucial role in determining the structure and function of chromatin, thereby regulating the eukaryotic gene expression. Histone lysine methylation and acetylation are among the most widespread and biomedically important PTMs, with new chemical tools for their examination in high demand. Here, we report the first use of γ-selenalysine as an efficient lysine mimic for enzymatic methylation, acetylation, and deacetylation reactions catalyzed by histone lysine methyltransferases, acetyltransferases, and a deacetylase. We also show that easily accessible selenocysteine and cysteine residues can undergo chemo- and site-selective alkylation reactions to generate both unmodified and modified γ-selenalysine and related γ-thialysine residues in histone peptides. This dual-modification strategy enables the site-specific incorporation of two distinct functionalities into peptides, mimicking lysine post-translational modifications commonly found on histones. Our research presents a novel approach in which selenocysteine serves as a unique handle for the chemoselective introduction of selenalysine, along with its methylated and acetylated analogues. These tools are designed to facilitate the study of epigenetic proteins that are important for human health and disease.