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

James P Reddington, Sara M Perricone, Colm E Nestor, Judith Reichmann, Neil A Youngson, Masako Suzuki, Diana Reinhardt, Donncha S Dunican, James G Prendergast, Heidi Mjoseng, Bernard H Ramsahoye, Emma Whitelaw, John M Greally, Ian R Adams, Wendy A Bickmore, Richard Meehan

Research output: Contribution to journalArticlepeer-review

Abstract


Background

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.

Results

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.

Conclusions

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.
Original languageEnglish
Article numberR25
Number of pages17
JournalGenome Biology
Volume14
Issue number3
DOIs
Publication statusPublished - 30 Mar 2013

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