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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Cold Spring Harbor Laboratory Press
2015
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| Online Access: | http://hdl.handle.net/1721.1/97064 https://orcid.org/0000-0003-4165-7693 |
| _version_ | 1826205958501564416 |
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| author | Lay, Fides D. Liu, Yaping Kelly, Theresa K. Witt, Heather Farnham, Peggy J. Jones, Peter A. Berman, Benjamin P. |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory 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 | MIT |
| 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. |
| first_indexed | 2024-09-23T13:21:45Z |
| format | Article |
| id | mit-1721.1/97064 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:21:45Z |
| publishDate | 2015 |
| publisher | Cold Spring Harbor Laboratory Press |
| record_format | dspace |
| spelling | mit-1721.1/970642022-09-28T13:39:13Z 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. Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Liu, Yaping 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. Charles Heidelberger Memorial Fellowship 2015-05-22T19:05:25Z 2015-05-22T19:05:25Z 2015-04 2014-08 Article http://purl.org/eprint/type/JournalArticle 1088-9051 1549-5469 http://hdl.handle.net/1721.1/97064 Lay, Fides D., Yaping Liu, Theresa K. Kelly, Heather Witt, Peggy J. Farnham, Peter A. Jones, and Benjamin P. Berman. “The Role of DNA Methylation in Directing the Functional Organization of the Cancer Epigenome.” Genome Res. 25, no. 4 (March 6, 2015): 467–477. https://orcid.org/0000-0003-4165-7693 en_US http://dx.doi.org/10.1101/gr.183368.114 Genome Research Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Cold Spring Harbor Laboratory Press Cold Spring Harbor Laboratory Press |
| spellingShingle | 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 |
| url | http://hdl.handle.net/1721.1/97064 https://orcid.org/0000-0003-4165-7693 |
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