Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism
Name
1-s2.0-S2211124718304017-main.pdf
Size
2.33 MB
Format
Adobe PDF
Checksum (MD5)
7d5d786879e5ec48caf0138e114cfb59
Author(s)
Schuijers, Jurian
Day, Daniel Sindt
Hnisz, Denes
Lee, Tong Ihn
Manteiga, John Colonnese
Weintraub, Abraham Selby
Zamudio Montes de Oca, Alicia
Young, Richard A.
Date Issued
April 2018
Journal
Cell Reports
Publisher
Elsevier
Citation
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).
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.celrep.2018.03.056
