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Genome Res. 2015 Apr;25(4):467-77. doi: 10.1101/gr.183368.114. Epub 2015 Mar 6.

The role of DNA methylation in directing the functional organization of the cancer epigenome.

Author information

1
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA; Program in Genetic, Molecular and Cellular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA;
2
Program in Genetic, Molecular and Cellular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA; USC Epigenome Center, University of Southern California, Los Angeles, California 90033, USA;
3
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA;
4
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA; Van Andel Institute, Grand Rapids, Michigan 49503, USA; benjamin.berman@cshs.org pjones@med.usc.edu.
5
USC Epigenome Center, University of Southern California, Los Angeles, California 90033, USA; Department of Preventive Medicine, University of Southern California, Los Angeles, California 90033, USA benjamin.berman@cshs.org pjones@med.usc.edu.

Abstract

The holistic role of DNA methylation in the organization of the cancer epigenome is not well understood. Here we perform a comprehensive, high-resolution analysis of chromatin structure to compare the landscapes of HCT116 colon cancer cells and a DNA methylation-deficient derivative. The NOMe-seq accessibility assay unexpectedly revealed symmetrical and transcription-independent nucleosomal phasing across active, poised, and inactive genomic elements. DNA methylation abolished this phasing primarily at enhancers and CpG island (CGI) promoters, with little effect on insulators and non-CGI promoters. Abolishment of DNA methylation led to the context-specific reestablishment of the poised and active states of normal colon cells, which were marked in methylation-deficient cells by distinct H3K27 modifications and the presence of either well-phased nucleosomes or nucleosome-depleted regions, respectively. At higher-order genomic scales, we found that long, H3K9me3-marked domains had lower accessibility, consistent with a more compact chromatin structure. Taken together, our results demonstrate the nuanced and context-dependent role of DNA methylation in the functional, multiscale organization of cancer epigenomes.

PMID:
25747664
PMCID:
PMC4381519
DOI:
10.1101/gr.183368.114
[Indexed for MEDLINE]
Free PMC Article

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