Optimal Substrate-Trapping Mutants to Discover Substrates of HDAC1

Histone deacetylase 1 (HDAC1) regulates transcription by deacetylating histones. In addition to histones, several non-histone proteins are HDAC1 substrates, which suggests a role for HDAC1 beyond epigenetics. Unfortunately, the identification of non-histone substrates has been largely serendipitous, which makes full characterization of HDAC1 functions difficult. To overcome this challenge, inactive trapping mutants were recently developed to identify HDAC1 substrates. To optimize substrate trapping, the relative trapping abilities of 17 inactive HDAC1 mutants was assessed. HDAC1 H141A, F150A, and C151A showed strong binding to substrates LSD1 and p53. Interestingly, each mutant preferentially trapped a different substrate. By combining several inactive mutants, the trapping strategy will facilitate the discovery of new HDAC1 substrates and shed light on the variety of HDAC1-related functions in cell biology.