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. Prendegast, Heidi Mjoseng, Bernard H. Ramsahoye, Emma Whitelaw, John M. Greally, Ian R. Adams, Wendy A. Bickmore, Richard R. Meehan

Research output: Contribution to journalArticle

104 Citations (Scopus)

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 (PRC2)-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 PRC2 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 PRC2 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 (US)
JournalGenome Biology
DOIs
StateAccepted/In press - Mar 25 2013

Fingerprint

DNA methylation
DNA Methylation
Polycomb Repressive Complex 2
DNA
methylation
gene
Genes
genes
epigenetics
Epigenetic Repression
Histone Code
Homeobox Genes
Chromosome Mapping
cells
Multigene Family
targeting
somatic cells
multigene family
Epigenomics
histones

ASJC Scopus subject areas

  • Genetics
  • Medicine(all)

Cite this

Reddington, J. P., Perricone, S. M., Nestor, C. E., Reichmann, J., Youngson, N. A., Suzuki, M., ... Meehan, R. R. (Accepted/In press). Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb-target genes. Genome Biology. https://doi.org/10.1186/gb-2013-14-3-r25

Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb-target genes. / Reddington, James P.; Perricone, Sara M.; Nestor, Colm E.; Reichmann, Judith; Youngson, Neil A.; Suzuki, Masako; Reinhardt, Diana; Dunican, Donncha S.; Prendegast, James G.; Mjoseng, Heidi; Ramsahoye, Bernard H.; Whitelaw, Emma; Greally, John M.; Adams, Ian R.; Bickmore, Wendy A.; Meehan, Richard R.

In: Genome Biology, 25.03.2013.

Research output: Contribution to journalArticle

Reddington, JP, Perricone, SM, Nestor, CE, Reichmann, J, Youngson, NA, Suzuki, M, Reinhardt, D, Dunican, DS, Prendegast, JG, Mjoseng, H, Ramsahoye, BH, Whitelaw, E, Greally, JM, Adams, IR, Bickmore, WA & Meehan, RR 2013, 'Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb-target genes', Genome Biology. https://doi.org/10.1186/gb-2013-14-3-r25
Reddington, James P. ; Perricone, Sara M. ; Nestor, Colm E. ; Reichmann, Judith ; Youngson, Neil A. ; Suzuki, Masako ; Reinhardt, Diana ; Dunican, Donncha S. ; Prendegast, James G. ; Mjoseng, Heidi ; Ramsahoye, Bernard H. ; Whitelaw, Emma ; Greally, John M. ; Adams, Ian R. ; Bickmore, Wendy A. ; Meehan, Richard R. / Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb-target genes. In: Genome Biology. 2013.
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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 (PRC2)-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 PRC2 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 PRC2 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.",
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AU - Youngson, Neil A.

AU - Suzuki, Masako

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