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

Clémence Kress (1) , Hélène Thomassin (1) , Thierry Grange (1)

1 IJM (UMR_7592) - Institut Jacques Monod

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.

Mots clés: Epigenetics; Transcription; Nuclear receptor; DNA methylation; DNA repair; Cytosine; Gene silencing

Domaines: Biochimie, Biologie Moléculaire; Génétique

Clémence Kress, Hélène Thomassin, Thierry Grange. Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks.. Proceedings of the National Academy of Sciences of the United States of America, 2006, 103(30), pp.11112-7. ⟨10.1073/pnas.0601793103⟩. ⟨hal-00093585⟩