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

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.

Perricone, Sara MUniversity of Edinburgh, UK (author)
Nestor, Colm E,1977-University of Edinburgh, UK(Swepub:liu)colne37 (author)
Reichmann, JudithUniversity of Edinburgh, UK (author)
Youngson, Neil AQueensland Institute of Medical Research, Herston, Queensland, Australia (author)
Suzuki, MasakoAlbert Einstein College of Medicine, Bronx, NY, USA (author)
Reinhardt, DianaUniversity of Edinburgh, UK (author)
Dunican, Donncha SUniversity of Edinburgh, UK (author)
Prendergast, James GUniversity of Edinburgh, UK (author)
Mjoseng, HeidiUniversity of Edinburgh, UK (author)
Ramsahoye, Bernard HUniversity of Edinburgh, UK (author)
Whitelaw, EmmaQueensland Institute of Medical Research, Herston, Queensland, Australia (author)
Greally, John MAlbert Einstein College of Medicine, Bronx, NY, USA (author)
Adams, Ian RUniversity of Edinburgh, UK (author)
Bickmore, Wendy AUniversity of Edinburgh, UK (author)
Meehan, Richard RUniversity of Edinburgh, UK (author)
University of Edinburgh, UKQueensland Institute of Medical Research, Herston, Queensland, Australia (creator_code:org_t)

In:Genome Biology: Springer Science and Business Media LLC14:3, s. R25-1465-69061474-760X

By the author/editor: Reddington, Jame ...; Perricone, Sara ...; Nestor, Colm E, ...; Reichmann, Judit ...; Youngson, Neil A; Suzuki, Masako; show more...; Reinhardt, Diana; Dunican, Donncha ...; Prendergast, Jam ...; Mjoseng, Heidi; Ramsahoye, Berna ...; Whitelaw, Emma; Greally, John M; Adams, Ian R; Bickmore, Wendy ...; Meehan, Richard ...; show less...

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