Short-chain fatty acids activate acetyltransferase p300

  1. Sydney P Thomas
  2. John M Denu  Is a corresponding author
  1. University of Wisconsin - Madison, United States


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 the cell’s 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. Propionate and butyrate are rapidly converted to the corresponding acyl-CoAs which are then used by p300 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 unknown mechanism of HAT activation that can explain how an influx of low levels of SCFAs alters global chromatin states.

Data availability

Mass spectrometry data has been uploaded to MassIVE (MSV000087800). All other source data is included in Source Data 1 and 2.

The following data sets were generated

Article and author information

Author details

  1. Sydney P Thomas

    University of Wisconsin - Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. John M Denu

    University of Wisconsin - Madison, Madison, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9415-0365


National Institutes of Health (GM059785)

  • John M Denu

National Science Foundation (GRFP)

  • Sydney P Thomas

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Xiaobing Shi, Van Andel Institute, United States

Publication history

  1. Received: July 14, 2021
  2. Preprint posted: July 21, 2021 (view preprint)
  3. Accepted: October 19, 2021
  4. Accepted Manuscript published: October 22, 2021 (version 1)
  5. Version of Record published: November 11, 2021 (version 2)


© 2021, Thomas & Denu

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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  1. Sydney P Thomas
  2. John M Denu
Short-chain fatty acids activate acetyltransferase p300
eLife 10:e72171.
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