1. Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism
- Author
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Richard A. Young, John C. Manteiga, Jurian Schuijers, Tong Ihn Lee, Daniel S. Day, Alicia V. Zamudio, Denes Hnisz, Abraham S. Weintraub, Massachusetts Institute of Technology. Department of Biology, Manteiga, John Colonnese, Weintraub, Abraham Selby, Zamudio Montes de Oca, Alicia, and Young, Richard A
- Subjects
0301 basic medicine ,CCCTC-Binding Factor ,Cell type ,Amino Acid Motifs ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Cell Line, Tumor ,Gene expression ,Humans ,Epigenetics ,Promoter Regions, Genetic ,Enhancer ,lcsh:QH301-705.5 ,Gene ,Cell Proliferation ,Gene Editing ,Regulation of gene expression ,Binding Sites ,Oncogene ,DNA Methylation ,Cell biology ,Gene Expression Regulation, Neoplastic ,Enhancer Elements, Genetic ,030104 developmental biology ,lcsh:Biology (General) ,DNA methylation ,CRISPR-Cas Systems ,Protein Binding - 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., National Institutes of Health (U.S.) (grant HG002668), Virginia and Daniel K. Ludwig Graduate Fellowship, National Science Foundation (U.S.). Graduate Research Fellowship Program
- Published
- 2018