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Nucleic Acids Research, 2001, Vol. 29, No. 17 3603-3610
© 2001 Oxford University Press

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

Don Benjamin and Jean-Pierre Jost*

Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058 Basel, Switzerland

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.

* To whom correspondence should be addressed. Tel: +41 61 697 6688; Fax: +41 61 721 4091; Email: jost{at}fmi.ch


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