Butyrate Selectively Targets Super-Enhancers and Transcriptional Networks Associated with Human Mast Cell Function

Mast cells are key drivers of allergic inflammation. We have previously shown that butyrate, a short-chain fatty acid derived from dietary fibers, inhibits human mast cell activation and degranulation. Here, we characterized the mechanisms underlying butyrate-mediated control of mast cell activity. To this end, we assessed the genome-wide impact of butyrate, a histone deacetylase (HDAC) inhibitor, on the epigenomic control of mast cell gene expression by integrating transcriptome and histone acetylation (H3K27Ac) profiles obtained from butyrate-treated primary human mast cells. Butyrate affected a selective set of genes and gene regulatory elements in mast cells. Most prominent was the hypoacetylation of promoter regions of highly expressed genes and super-enhancers controlling key mast cell identity genes. Perturbation of super-enhancer activity via pharmacological bromodomain inhibition suppressed degranulation of primary human mast cells, evoking repression of key mast cell identity genes that resembled the inhibitory effects of butyrate. Our data indicate that butyrate inhibits human mast cell activity via surprisingly selective targeting of super-enhancers to regulate the core mast cell transcriptional program.