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Published on: May 5, 2022
Butyrate mediates decrease of histone acetylation centered on transcription start sites and down-regulation of
Alvaro Rada-Iglesias1, Stefan Enroth, Adam Ameur
1Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, SE-751 05 Sweden. alvaro.rada@genpat.uu.se
Genome Research
|June 15, 2007
Summary
Butyrate, a histone deacetylase inhibitor (HDACi), paradoxically deacetylates gene promoters, leading to gene repression. This challenges the current understanding of HDACi anti-cancer mechanisms and histone acetylation roles.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Pharmacology
Background:
- Histone deacetylase inhibitors (HDACi) like butyrate are explored for anti-cancer effects by theoretically reactivating silenced genes via histone acetylation.
- However, observed gene repression during HDACi treatment necessitates a deeper understanding of their molecular mechanisms.
Purpose of the Study:
- To investigate the precise effects of butyrate on histone acetylation patterns at gene promoters.
- To elucidate the relationship between butyrate-induced histone modifications and gene expression changes in cancer cells.
Main Methods:
- ChIP-chip assays were performed on HepG2 cells treated with butyrate to analyze histone H3 and H4 acetylation.
- Validation studies involved butyrate and trichostatin A treatment in HepG2 and HT-29 cells, assessing histone acetylation, nucleosome occupancy, and H3K4me3.
- RNA polymerase II (POLR2A) activity was examined to understand transcriptional regulation.
Main Results:
- Butyrate induced localized histone deacetylation at gene promoter regions, contrasting with global histone acetylation increases.
- This deacetylation occurred without significant changes in nucleosome loss or H3K4me3.
- Genes with deacetylated promoters were transcriptionally downregulated by butyrate, mediated by effects on POLR2A initiation/elongation.
- Global histone acetylation increases were localized to the nuclear periphery, suggesting a non-euchromatic association.
Conclusions:
- Butyrate's anti-neoplastic action may involve promoter-specific histone deacetylation and subsequent gene repression, challenging existing models.
- The findings suggest that HDACi's therapeutic effects might be more complex than previously thought, requiring revised mechanistic models.
- Localized histone deacetylation at promoters provides a molecular explanation for gene repression observed during HDACi therapy.
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