1. European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
2. SPARTE, UMR CNRS, 6026, Université de Rennes I, Bâtiment 13, 35042 Cedex, Rennes, France
3. These authors equally contributed to this work.
4. Present addresses: Phenex Pharmaceuticals AG, J542N Werksgelände BASF, 67056 Ludwigshafen, Germany (B.S.); Science Foundation Ireland, Wilton Park House, Wilton Place, Dublin 2, Ireland (F.G.).

Correspondence to: George Reid¹ Correspondence and requests for materials should be addressed to G.R. (Email: george.reid@embl.de).

Methylation of CpG dinucleotides is generally associated with epigenetic silencing of transcription and is maintained through cellular division^{1, 2, 3}. Multiple CpG sequences are rare in mammalian genomes, but frequently occur at the transcriptional start site of active genes, with most clusters of CpGs being hypomethylated⁴. We reported previously that the proximal region of the trefoil factor 1 (TFF1, also known as pS2) and oestrogen receptor (ER) promoters could be partially methylated by treatment with deacetylase inhibitors⁵, suggesting the possibility of dynamic changes in DNA methylation. Here we show that cyclical methylation and demethylation of CpG dinucleotides, with a periodicity of around 100 min, is characteristic for five selected promoters, including the oestrogen (E2)-responsive pS2 gene, in human cells. When the pS2 gene is actively transcribed, DNA methylation occurs after the cyclical occupancy of ER and RNA polymerase II (polII). Moreover, we report conditions that provoke methylation cycling of the pS2 promoter in cell lines in which pS2 expression is quiescent and the proximal promoter is methylated. This coincides with a low-level re-expression of ER and of pS2 transcripts.

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