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

Genome Biology

Richard R Meehan¹  Wendy A Bickmore⁴  Ian R Adams⁴  John M Greally⁵  Emma Whitelaw³  Bernard H Ramsahoye²  Heidi Mjoseng⁴  James G Prendergast⁴  Donncha S Dunican⁴  Diana Reinhardt⁴  Masako Suzuki⁵  Neil A Youngson³  Judith Reichmann⁴  Colm E Nestor¹  Sara M Perricone⁴  James P Reddington⁴ 

[1] Breakthrough Breast Cancer Research Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK;Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK;Queensland Institute of Medical Research, Herston, Queensland 4006, Australia;MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK;Departments of Genetics (Computational Genetics) and Center for Epigenomics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, USA

关键词: regulation of transcription;    PRC2;    Polycomb;    H3K27me3;    DNA methylation;   

Others  :  866876
DOI  :  10.1186/gb-2013-14-3-r25

 received in 2012-08-10, accepted in 2013-03-25,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Reddington et al.; licensee BioMed Central Ltd.

【 图 表 】

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