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PMID: 11522830 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Reversal of methylation-mediated repression with short-chain fatty acids: evidence for an additional mechanism to histone deacetylation.

Nucleic acids research ·Vol. 29 ·No. 17 ·2001-09-01 ·Pages 3603-10

Benjamin D, Jost JP

Abstract

We have constructed a stable cell line, human embryonal kidney 293M+, containing a lacZ reporter gene controlled by an in vitro methylated hormone-responsive enhancer. Methylation of the enhancer-promoter abolishes lacZ expression controlled by ponasterone A (an analogue of ecdysone). Ponasterone A-induced expression is restored by the short-chain fatty acids valeric > butyric > propionic > acetic acid, but not by the histone deacetylase inhibitors trichostatin A and suberoylanilide hydroxamic acid (SAHA). lacZ expression is restored to levels approaching that from an unmethylated counterpart. Incubation with short-chain fatty acids alone does not promote demethylation of the lacZ promoter, however, some demethylation (30%) is observed when transcription is triggered by addition of ponasterone A. Similar levels of hyperacetylated histones H3 and H4 were observed in cells treated with short-chain fatty acids, trichostatin A or SAHA. In vivo DNase I footprinting indicates a more open chromatin structure at the promoter region for butyric acid-treated cells. A synergistic effect in reversing the methylation-mediated repression of the lacZ gene is obtained by combined treatments with the normally ineffective compounds trichostatin A and the short-chain fatty acid caproic acid. Our results suggest the existence of an alternative silencing mechanism to histone deacetylation in executing methylation-directed gene silencing.

MeSH Terms
Animals Butyric Acid/pharmacology Caproates/pharmacology Cell Line Chromatin/drug effects,genetics,metabolism DNA/genetics,metabolism DNA Footprinting DNA Methylation Drug Synergism Ecdysterone/analogs & derivatives,pharmacology Fatty Acids, Volatile/pharmacology Gene Expression Regulation/drug effects Gene Silencing Histone Deacetylases/metabolism Histones/drug effects,metabolism Humans Hydroxamic Acids/pharmacology Kinetics Lac Operon/genetics Plasmids/genetics Promoter Regions, Genetic/genetics Time Factors beta-Galactosidase/drug effects,metabolism
Chemicals
Caproates Chromatin Fatty Acids, Volatile Histones Hydroxamic Acids Butyric Acid trichostatin A Ecdysterone ponasterone A DNA beta-Galactosidase Histone Deacetylases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Benjamin D
Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Jost J P
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/29.17.3603
Published
2001-09-01
Pages
3603-10
Language
English
Region
England
NLM ID
0411011
PMCID
PMC55875
Subset
IM
External Links
PubMed source DOI: 10.1093/nar/29.17.3603 PMC Full Text View journal details
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