Abstract
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 hypo-acetylation 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 a 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 a
surprisingly selective targeting of super-enhancers to
regulate the core mast cell transcriptional program.