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Molecular and Cellular Biology, November 2007, p. 7462-7474, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.01120-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Acetylation-Induced Transcription Is Required for Active DNA Demethylation in Methylation-Silenced Genes{triangledown}

Ana C. D'Alessio, Ian C. G. Weaver, and Moshe Szyf*

Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada

Received 23 June 2007/ Returned for modification 5 July 2007/ Accepted 9 August 2007

A hallmark of vertebrate genes is that actively transcribed genes are hypomethylated in critical regulatory sequences. However, the mechanisms that link gene transcription and DNA hypomethylation are unclear. Using a trichostatin A (TSA)-induced replication-independent demethylation assay with HEK 293 cells, we show that RNA transcription is required for DNA demethylation. Histone acetylation precedes but is not sufficient to trigger DNA demethylation. Following histone acetylation, RNA polymerase II (RNAP II) interacts with the methylated promoter. Inhibition of RNAP II transcription with actinomycin D, {alpha}-amanitin, or CDK7-specific small interfering RNA inhibits DNA demethylation. H3 trimethyl lysine 4 methylation, a marker of actively transcribed genes, was associated with the cytomegalovirus promoter only after demethylation. TSA-induced demethylation of the endogenous cancer testis gene GAGE follows a similar sequence of events and is dependent on RNA transcription as well. These data suggest that DNA demethylation follows rather than precedes early transcription and point towards a novel function for DNA demethylation as a memory of actively transcribed genes.

* Corresponding author. Mailing address: Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada. Phone: (514) 398-7107. Fax: (514) 487-1834. E-mail: moshe.szyf{at}mcgill.ca

{triangledown} Published ahead of print on 20 August 2007.

Molecular and Cellular Biology, November 2007, p. 7462-7474, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.01120-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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