Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism
Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differin...
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Elsevier
2018
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| Online Access: | http://hdl.handle.net/1721.1/117042 https://orcid.org/0000-0002-0385-6176 https://orcid.org/0000-0003-0998-9882 https://orcid.org/0000-0001-6263-2423 https://orcid.org/0000-0001-8855-8647 |
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| author | Schuijers, Jurian Day, Daniel Sindt Hnisz, Denes Lee, Tong Ihn Manteiga, John Colonnese Weintraub, Abraham Selby Zamudio Montes de Oca, Alicia Young, Richard A. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Schuijers, Jurian Day, Daniel Sindt Hnisz, Denes Lee, Tong Ihn Manteiga, John Colonnese Weintraub, Abraham Selby Zamudio Montes de Oca, Alicia Young, Richard A. |
| author_sort | Schuijers, Jurian |
| collection | MIT |
| description | Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types. |
| first_indexed | 2024-09-23T07:55:48Z |
| format | Article |
| id | mit-1721.1/117042 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T07:55:48Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1170422022-09-30T01:04:33Z Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism Schuijers, Jurian Day, Daniel Sindt Hnisz, Denes Lee, Tong Ihn Manteiga, John Colonnese Weintraub, Abraham Selby Zamudio Montes de Oca, Alicia Young, Richard A. Massachusetts Institute of Technology. Department of Biology Manteiga, John Colonnese Weintraub, Abraham Selby Zamudio Montes de Oca, Alicia Young, Richard A Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types. National Institutes of Health (U.S.) (grant HG002668) Virginia and Daniel K. Ludwig Graduate Fellowship National Science Foundation (U.S.). Graduate Research Fellowship Program 2018-07-23T16:50:12Z 2018-07-23T16:50:12Z 2018-04 2018-02 2018-07-13T16:56:18Z Article http://purl.org/eprint/type/JournalArticle 2211-1247 http://hdl.handle.net/1721.1/117042 Schuijers, Jurian, John Colonnese Manteiga, Abraham Selby Weintraub, Daniel Sindt Day, Alicia Viridiana Zamudio, Denes Hnisz, Tong Ihn Lee, and Richard Allen Young. “Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism.” Cell Reports 23, no. 2 (April 2018): 349–360. ª 2018 The Author(s). https://orcid.org/0000-0002-0385-6176 https://orcid.org/0000-0003-0998-9882 https://orcid.org/0000-0001-6263-2423 https://orcid.org/0000-0001-8855-8647 http://dx.doi.org/10.1016/j.celrep.2018.03.056 Cell Reports Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Elsevier Elsevier |
| spellingShingle | Schuijers, Jurian Day, Daniel Sindt Hnisz, Denes Lee, Tong Ihn Manteiga, John Colonnese Weintraub, Abraham Selby Zamudio Montes de Oca, Alicia Young, Richard A. Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism |
| title | Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism |
| title_full | Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism |
| title_fullStr | Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism |
| title_full_unstemmed | Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism |
| title_short | Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism |
| title_sort | transcriptional dysregulation of myc reveals common enhancer docking mechanism |
| url | http://hdl.handle.net/1721.1/117042 https://orcid.org/0000-0002-0385-6176 https://orcid.org/0000-0003-0998-9882 https://orcid.org/0000-0001-6263-2423 https://orcid.org/0000-0001-8855-8647 |
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