Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer
Background: One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter r...
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| Format: | Article |
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Biomed Central Ltd
2018
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| Online Access: | http://hdl.handle.net/1721.1/116983 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1811076382578442240 |
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| author | Heyn, Holger Vidal, Enrique Ferreira, Humberto J. Vizoso, Miguel Sayols, Sergi Gomez, Antonio Moran, Sebastian Boque-Sastre, Raquel Guil, Sonia Martinez-Cardus, Anna Royo, Romina Sanchez-Mut, Jose V. Martinez, Ramon Gut, Marta Torrents, David Orozco, Modesto Gut, Ivo Esteller, Manel Lin, Charles Y. Young, Richard A. |
| author2 | Massachusetts Institute of Technology. Computational and Systems Biology Program |
| author_facet | Massachusetts Institute of Technology. Computational and Systems Biology Program Heyn, Holger Vidal, Enrique Ferreira, Humberto J. Vizoso, Miguel Sayols, Sergi Gomez, Antonio Moran, Sebastian Boque-Sastre, Raquel Guil, Sonia Martinez-Cardus, Anna Royo, Romina Sanchez-Mut, Jose V. Martinez, Ramon Gut, Marta Torrents, David Orozco, Modesto Gut, Ivo Esteller, Manel Lin, Charles Y. Young, Richard A. |
| author_sort | Heyn, Holger |
| collection | MIT |
| description | Background: One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized. Results: Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis. Conclusions: We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes. |
| first_indexed | 2024-09-23T10:20:34Z |
| format | Article |
| id | mit-1721.1/116983 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T10:20:34Z |
| publishDate | 2018 |
| publisher | Biomed Central Ltd |
| record_format | dspace |
| spelling | mit-1721.1/1169832022-09-26T17:22:21Z Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer Heyn, Holger Vidal, Enrique Ferreira, Humberto J. Vizoso, Miguel Sayols, Sergi Gomez, Antonio Moran, Sebastian Boque-Sastre, Raquel Guil, Sonia Martinez-Cardus, Anna Royo, Romina Sanchez-Mut, Jose V. Martinez, Ramon Gut, Marta Torrents, David Orozco, Modesto Gut, Ivo Esteller, Manel Lin, Charles Y. Young, Richard A. Massachusetts Institute of Technology. Computational and Systems Biology Program Massachusetts Institute of Technology. Department of Biology Lin, Charles Young, Richard A Background: One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized. Results: Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis. Conclusions: We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes. 2018-07-13T17:50:18Z 2018-07-13T17:50:18Z 2016-01 2018-07-13T17:35:24Z Article http://purl.org/eprint/type/JournalArticle 1474-760X http://hdl.handle.net/1721.1/116983 Heyn, Holger et al. “Epigenomic Analysis Detects Aberrant Super-Enhancer DNA Methylation in Human Cancer.” Genome Biology 17, 1 (January 2016): 11 © 2016 Heyn et al https://orcid.org/0000-0001-8855-8647 http://dx.doi.org/10.1186/S13059-016-0879-2 Genome Biology Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Biomed Central Ltd BioMedCentral |
| spellingShingle | Heyn, Holger Vidal, Enrique Ferreira, Humberto J. Vizoso, Miguel Sayols, Sergi Gomez, Antonio Moran, Sebastian Boque-Sastre, Raquel Guil, Sonia Martinez-Cardus, Anna Royo, Romina Sanchez-Mut, Jose V. Martinez, Ramon Gut, Marta Torrents, David Orozco, Modesto Gut, Ivo Esteller, Manel Lin, Charles Y. Young, Richard A. Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer |
| title | Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer |
| title_full | Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer |
| title_fullStr | Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer |
| title_full_unstemmed | Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer |
| title_short | Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer |
| title_sort | epigenomic analysis detects aberrant super enhancer dna methylation in human cancer |
| url | http://hdl.handle.net/1721.1/116983 https://orcid.org/0000-0001-8855-8647 |
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