Abstract
Lysine acylations on histones and their recognition by chromatin-binding reader domains and removal by histone deacylases function as an important mechanism for eukaryotic gene regulation. Histone lysine crotonylation (Kcr) is an epigenetic mark associated with active transcription, and its installation and removal are dynamically regulated by cellular epigenetic enzymes. Here, we report binding studies and enzyme assays with histone H3K9 peptides bearing simplest Kcr analogs with varying hydrocarbon chain length, bulkiness, rigidity and polarity. We demonstrate that the AF9 YEATS domain displays selectivity for binding of different acylation modifications on histone H3K9 peptides and exhibits preference for bulkier cinnamoylated lysine over crotonylated lysine and its mimics. SIRT2 shows deacylase activity against most of acylated H3K9 peptides bearing different crotonyllysine mimics, however, it displays a poor ability for the removal of cinnamoyl and trifluorocrotonyl groups. These results demonstrate different substrate selectivities of epigenetic proteins acting on crotonyllysine and pave the way for rational design and development of AF9 YEATS and SIRT2 inhibitors for treatment of human diseases, including cancer.
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