Abstract
Histone modifications critically regulate chromatin architecture, gene transcription, and epigenetic inheritance. These modifications are dynamically regulated by writers and erasers. In addition, readers recognize site-specific histone marks to mediate downstream cellular activities. Therefore, precise identification and functional investigation of these regulatory enzymes and proteins are essential for elucidating the biological roles of histone modifications. Chemical probes, due to their target-specificity, serve as indispensable tools for investigating readers and erasers in chemical biology. This perspective summarizes the previous and cutting-edge development of histone probes. We first discuss affinity-based probes, which exploit binding interactions to proteins of interest (POIs) but suffer from limited efficacy for enrichment of low-abundance proteins and proteins with transient interactions. Covalent crosslinking probes could overcome these limitations. We thus next introduce photoreactive probes that crosslink POIs from highly reactive intermediates generated under UV irradiation. In addition, we summarize activity-based probes that selectively bind and crosslink readers and erasers inside pockets due to the unique warheads. At the end, we discuss our perspective on the field in the future, touching on key challenges and emerging directions.