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

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 ac...

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Autores principales: Lay, Fides D., Liu, Yaping, Kelly, Theresa K., Witt, Heather, Farnham, Peggy J., Jones, Peter A., Berman, Benjamin P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381519/
https://www.ncbi.nlm.nih.gov/pubmed/25747664
http://dx.doi.org/10.1101/gr.183368.114
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author Lay, Fides D.
Liu, Yaping
Kelly, Theresa K.
Witt, Heather
Farnham, Peggy J.
Jones, Peter A.
Berman, Benjamin P.
author_facet Lay, Fides D.
Liu, Yaping
Kelly, Theresa K.
Witt, Heather
Farnham, Peggy J.
Jones, Peter A.
Berman, Benjamin P.
author_sort Lay, Fides D.
collection PubMed
description 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.
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spelling pubmed-43815192015-04-06 The role of DNA methylation in directing the functional organization of the cancer epigenome Lay, Fides D. Liu, Yaping Kelly, Theresa K. Witt, Heather Farnham, Peggy J. Jones, Peter A. Berman, Benjamin P. Genome Res Research 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. Cold Spring Harbor Laboratory Press 2015-04 /pmc/articles/PMC4381519/ /pubmed/25747664 http://dx.doi.org/10.1101/gr.183368.114 Text en © 2015 Lay et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ 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/.
spellingShingle Research
Lay, Fides D.
Liu, Yaping
Kelly, Theresa K.
Witt, Heather
Farnham, Peggy J.
Jones, Peter A.
Berman, Benjamin P.
The role of DNA methylation in directing the functional organization of the cancer epigenome
title The role of DNA methylation in directing the functional organization of the cancer epigenome
title_full The role of DNA methylation in directing the functional organization of the cancer epigenome
title_fullStr The role of DNA methylation in directing the functional organization of the cancer epigenome
title_full_unstemmed The role of DNA methylation in directing the functional organization of the cancer epigenome
title_short The role of DNA methylation in directing the functional organization of the cancer epigenome
title_sort role of dna methylation in directing the functional organization of the cancer epigenome
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381519/
https://www.ncbi.nlm.nih.gov/pubmed/25747664
http://dx.doi.org/10.1101/gr.183368.114
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