Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases

The recently discovered histone post-translational modification crotonylation connects cellularmetabolism to gene regulation. Its regulation and tissue-specific functions are poorlyunderstood. We characterize histone crotonylation in intestinal epithelia and find that histoneH3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestinecrypt and colon, and is linked to gene regulation. We show that this modification is highlydynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1,HDAC2, and HDAC3, as major executors of histone decrotonylation. We show that knownHDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation.Consistent with this, we find that depletion of the gut microbiota leads to a globalchange in histone crotonylation in the colon. Our results suggest that histone crotonylationconnects chromatin to the gut microbiota, at least in part, via short-chain fatty acids andHDACs.