Butyrate causes loss of specific acetylation by the histone acetyltransferase p300

Butyrate, a short-chain fatty acid produced by microbial fermentation of dietary fiber, exerts beneficial metabolic and immunomodulatory functions through butyrylation of the histone acetyltransferase p300. This is thought to result in histone hyperacetylation at transcription starting sites and enhancers that regulate specific genes. However, we show that butyrate-induced hyperacetylation is not specific but occurs at histones throughout the entire genome. Mechanistically, our data show that butyrylation of p300 prevents its recruitment to acetylated histones through its bromodomain, and thereby p300 cannot maintain the acetylation of specific histones through positive feedback. Thus, the epigenetic regulation of specific genes by butyrate is limited, but butyrate instead increases histone acetylation globally along the entire chromatin structure.