The short-chain fatty acids (SCFAs) acetate, propionate, and butyrate are produced in large quantities by the gut microbiome and contribute to a wide array of physiological processes. While the underlying mechanisms are largely unknown, many effects of SCFAs have been traced to changes in epigenetic state. Here, we systematically investigate how SCFAs alter the epigenome. Using quantitative proteomics of histone modification states, we identified rapid and sustained increases in histone acetylation after addition of butyrate or propionate, but not acetate. While decades of prior observations would have suggested that hyperacetylation induced by SCFAs are attributed to inhibition of histone deacetylases (HDACs), we found that propionate and butyrate instead activate the acetyltransferase p300/CBP. Propionate and butyrate are rapidly converted to the corresponding acyl-CoAs which are then used by p300/CBP to catalyze auto-acylation of the autoinhibitory loop, activating the enzyme for histone/protein acetylation. This data challenges the long-held belief that SCFAs mainly regulate chromatin by inhibiting HDACs, and instead reveals a previously unappreciated mechanism of HAT activation that can explain how even low levels of SCFAs can alter epigenomes.
[doi:10.25345/C5HR7D]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: short-chain fatty acids, metabolomics, proteomics, p300/CBP
Principal Investigators: (in alphabetical order) |
John Denu, University of Wisconsin - Madison, United States |
Submitting User: | Sydney_Thomas |
Sydney P Thomas, John M Denu.
Short-chain fatty acids activate acetyltransferase p300.
eLife 2021;10:e72171.
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