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

Fides D. Lay, Yaping Liu, Theresa K. Kelly, Heather Witt, Peggy J. Farnham, Peter A. Jones, Benjamin P. Berman

Research output: Contribution to journalArticle

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)467-477
Number of pages11
JournalGenome Research
Volume25
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'The role of DNA methylation in directing the functional organization of the cancer epigenome'. Together they form a unique fingerprint.

  • Cite this

    Lay, F. D., Liu, Y., Kelly, T. K., Witt, H., Farnham, P. J., Jones, P. A., & Berman, B. P. (2015). The role of DNA methylation in directing the functional organization of the cancer epigenome. Genome Research, 25(4), 467-477. https://doi.org/10.1101/gr.183368.114