The role of DNA methylation in directing the functional organization of the cancer epigenome
- Fides D. Lay1,2,6,
- Yaping Liu2,3,6,7,
- Theresa K. Kelly1,8,
- Heather Witt1,
- Peggy J. Farnham1,
- Peter A. Jones1,4,6 and
- Benjamin P. Berman3,5,6,9
- 1Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA;
- 2Program in Genetic, Molecular and Cellular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA;
- 3USC Epigenome Center, University of Southern California, Los Angeles, California 90033, USA;
- 4Van Andel Institute, Grand Rapids, Michigan 49503, USA;
- 5Department of Preventive Medicine, University of Southern California, Los Angeles, California 90033, USA
- Corresponding authors: benjamin.berman{at}cshs.org, pjones{at}med.usc.edu
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↵6 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.183368.114.
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Freely available online through the Genome Research Open Access option.
- Received August 22, 2014.
- Accepted February 6, 2015.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
