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  Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism

Schuijers, J., Manteiga, J. C., Weintraub, A. S., Day, D. S., Zamudio, A. V., Hnisz, D., et al. (2018). Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism. Cell Reports, 23(2), 349-360. doi:10.1016/j.celrep.2018.03.056.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-54E0-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-54E1-0
Genre: Journal Article

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© 2018 The Author(s). Published by Elsevier Inc.

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 Creators:
Schuijers, Jurian , Author
Manteiga, John Colonnese , Author
Weintraub, Abraham Selby , Author
Day, Daniel Sindt , Author
Zamudio, Alicia Viridiana , Author
Hnisz, Denes1, 2, Author              
Lee, Tong Ihn , Author
Young, Richard Allen , Author
Affiliations:
1Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014188              
2Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA, ou_persistent22              

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Free keywords: chromosome structure; enhancer docking; gene regulation; super-enhancers
 Abstract: 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.

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Language(s): eng - English
 Dates: 2018-04-10
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.celrep.2018.03.056
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Title: Cell Reports
Source Genre: Journal
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Publ. Info: Maryland Heights, MO : Cell Press
Pages: 12 Volume / Issue: 23 (2) Sequence Number: - Start / End Page: 349 - 360 Identifier: ISSN: 2211-1247
CoNE: https://pure.mpg.de/cone/journals/resource/2211-1247