Butyrate blocks specific histone acetylation

Butyrate, a short-chain fatty acid (SCFA) produced by microbial fermentation of dietary fiber, exerts beneficial metabolic and immunomodulatory functions through inhibition of histone deacetylases (HDAC) and hyperactivation of the histone acetylase (HAT) p3004. These effects are widely believed to result in the acetylation of distinct histones that regulate specific genes. However, we show that this is not the case, as butyrate dose-dependently increases the acetylation of histones throughout the entire genome regardless of their position at transcription starting sites (TSS). Mechanistically, we found that, although butyrylated p300 has increased acetylation activity as reported, it is no longer recruited to acetylated histones through its bromodomain, and thereby likely cannot maintain the acetylation of specific histones through positive feedback. Thus, butyrate does not regulate specific genes at the epigenetic level, but increases histone acetylation globally resulting in opening of the entire chromatin structure.