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Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism

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Hnisz,  Denes
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;
Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA;

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Citation

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.


Cite as: http://hdl.handle.net/21.11116/0000-0003-54E0-1
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.