Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression

Abstract The short-chain fatty acids (SCFAs) propionate and butyrate have beneficial health effects, are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. To better understand the function of these modifications, we used chromatin immunoprecipitation followed by sequencing to map the genome-wide location of four short-chain acyl histone marks, H3K18pr, H3K18bu, H4K12pr and H4K12bu, in treated and untreated colorectal cancer (CRC) and normal cells as well as in mouse intestines in vivo. We correlate these marks with open chromatin regions and gene expression to access the function of the target regions. Our data demonstrate that propionate and butyrate bind and act as promoters of genes involved in growth, differentiation and ion transport. We propose a mechanism involving direct modification of specific genomic regions by SCFAs resulting in increased chromatin accessibility and, in the case of butyrate, opposing effects on the proliferation of normal versus CRC cells.