Transient cyclical methylation of promoter DNA

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Abstract
Two papers in this issue report cycles of DNA methylation and demethylation of CpG dinucleotides at gene promoters. The findings contrast sharply with the prevailing view of DNA methylation as a stable epigenetic 'mark' capable of transmitting a specific pattern of gene expression through mitosis and into the daughter cells. Métivier et al. observed DNA methylation/demethylation cycles at the pS2 gene promoter during its activation by oestrogen, accompanied by cycling of DNA methyltransferases and other factors. And Kangaspeska et al. report cyclical DNA methylation at five active promoters including pS2 and the oestrogen receptor α. One of two papers this issue reporting cycles of DNA methylation and demethylation of CpG dinucleotides at gene promoters. Here, cyclical DNA methylation is reported at five active promoters; this contrasts with the accepted view of DNA methylation as a stable epigenetic mark. Methylation of CpG dinucleotides is generally associated with epigenetic silencing of transcription and is maintained through cellular division1,2,3. 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 α (ERα) 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 ERα 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 ERα and of pS2 transcripts.