Journal
CELL REPORTS
Volume 23, Issue 2, Pages 349-360Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.03.056
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Funding
- NIH [HG002668]
- Rubicon fellowship by NWO
- Ludwig Graduate Fellowship funds
- American Cancer Society [PF-16-146-01-DMC]
- Margaret and Herman Sokol Postdoctoral Award
- National Science Foundation GRFP funds
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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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