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Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11112-7. Epub 2006 Jul 13.

Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks.

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1
Institut Jacques Monod du Centre National de la Recherche Scientifique, Universités Paris 6-7, Tour 43, 2 Place Jussieu, 75251 Paris Cedex 05, France.

Abstract

Cytosine methylation at CpG dinucleotides contributes to the epigenetic maintenance of gene silencing. Dynamic reprogramming of DNA methylation patterns is believed to play a key role during development and differentiation in vertebrates. The mechanisms of DNA demethylation remain unclear and controversial. Here, we present a detailed characterization of the demethylation of an endogenous gene in cultured cells. This demethylation is triggered in a regulatory region by a transcriptional activator, the glucocorticoid receptor. We show that DNA demethylation is an active process, occurring independently of DNA replication, and in a distributive manner without concerted demethylation of cytosines on both strands. We demonstrate that the DNA backbone is cleaved 3' to the methyl cytidine during demethylation, and we suggest that a DNA repair pathway may therefore be involved in this demethylation.

PMID:
16840560
PMCID:
PMC1544051
DOI:
10.1073/pnas.0601793103
[Indexed for MEDLINE]
Free PMC Article
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