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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
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Short-chain fatty acids activate acetyltransferase p300
Sydney P Thomas1,2, John M Denu1,2,3
1Wisconsin Institute for Discovery, Madison, United States.
Elife
|October 22, 2021
Summary
Short-chain fatty acids (SCFAs) like propionate and butyrate boost histone acetylation by activating the p300 enzyme, not by inhibiting HDACs. This reveals a new mechanism for how gut microbes influence epigenetics.
Area of Science:
- Microbiology
- Epigenetics
- Biochemistry
Background:
- Gut microbiota produce short-chain fatty acids (SCFAs) influencing physiological processes.
- SCFA effects are linked to epigenetic modifications, but mechanisms remain unclear.
- Histone deacetylase (HDAC) inhibition was the presumed SCFA mechanism.
Purpose of the Study:
- To systematically investigate how SCFAs alter the epigenome.
- To elucidate the molecular mechanisms by which SCFAs impact histone modifications.
Main Methods:
- Quantitative proteomics to analyze histone modification states.
- In vitro experiments to test SCFA effects on histone acetylation and enzyme activity.
Main Results:
- Butyrate and propionate, but not acetate, rapidly increased histone acetylation.
- Propionate and butyrate activate the acetyltransferase p300.
- SCFAs are converted to acyl-CoAs, activating p300 via auto-acylation.
Conclusions:
- SCFAs activate histone acetyltransferases (HATs), specifically p300, challenging the HDAC inhibition hypothesis.
- This HAT activation mechanism explains how SCFAs alter global chromatin states.
- Discovered a novel pathway for SCFA-mediated epigenetic regulation by gut microbes.
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