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Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes

James P Reddington1, Sara M Perricone1, Colm E Nestor12, Judith Reichmann1, Neil A Youngson3, Masako Suzuki4, Diana Reinhardt1, Donncha S Dunican1, James G Prendergast1, Heidi Mjoseng1, Bernard H Ramsahoye5, Emma Whitelaw3, John M Greally4, Ian R Adams1, Wendy A Bickmore1 and Richard R Meehan12*

Author Affiliations

1 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK

2 Breakthrough Breast Cancer Research Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK

3 Queensland Institute of Medical Research, Herston, Queensland 4006, Australia

4 Departments of Genetics (Computational Genetics) and Center for Epigenomics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, USA

5 Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK

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Genome Biology 2013, 14:R25  doi:10.1186/gb-2013-14-3-r25

Published: 25 March 2013



DNA methylation and the Polycomb repression system are epigenetic mechanisms that play important roles in maintaining transcriptional repression. Recent evidence suggests that DNA methylation can attenuate the binding of Polycomb protein components to chromatin and thus plays a role in determining their genomic targeting. However, whether this role of DNA methylation is important in the context of transcriptional regulation is unclear.


By genome-wide mapping of the Polycomb Repressive Complex 2-signature histone mark, H3K27me3, in severely DNA hypomethylated mouse somatic cells, we show that hypomethylation leads to widespread H3K27me3 redistribution, in a manner that reflects the local DNA methylation status in wild-type cells. Unexpectedly, we observe striking loss of H3K27me3 and Polycomb Repressive Complex 2 from Polycomb target gene promoters in DNA hypomethylated cells, including Hox gene clusters. Importantly, we show that many of these genes become ectopically expressed in DNA hypomethylated cells, consistent with loss of Polycomb-mediated repression.


An intact DNA methylome is required for appropriate Polycomb-mediated gene repression by constraining Polycomb Repressive Complex 2 targeting. These observations identify a previously unappreciated role for DNA methylation in gene regulation and therefore influence our understanding of how this epigenetic mechanism contributes to normal development and disease.

DNA methylation; H3K27me3; Polycomb; PRC2; regulation of transcription