Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers
- Josh Lewis Stern1,2,
- Dan Theodorescu3,4,5,
- Bert Vogelstein6,7,
- Nickolas Papadopoulos6,7 and
- Thomas R. Cech1,2,3
- 1Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, USA;
- 2Howard Hughes Medical Institute, University of Colorado BioFrontiers Institute, Boulder, Colorado 80309, USA;
- 3University of Colorado Comprehensive Cancer Center, Aurora, Colorado 80045, USA;
- 4Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA;
- 5Department of Surgery (Urology), University of Colorado, Aurora, Colorado 80045, USA;
- 6Ludwig Center, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA;
- 7Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21231, USA
- Corresponding author: thomas.cech{at}colorado.edu
Abstract
Somatic mutations in the promoter of the gene for telomerase reverse transcriptase (TERT) are the most common noncoding mutations in cancer. They are thought to activate telomerase, contributing to proliferative immortality, but the molecular events driving TERT activation are largely unknown. We observed in multiple cancer cell lines that mutant TERT promoters exhibit the H3K4me2/3 mark of active chromatin and recruit the GABPA/B1 transcription factor, while the wild-type allele retains the H3K27me3 mark of epigenetic silencing; only the mutant promoters are transcriptionally active. These results suggest how a single-base-pair mutation can cause a dramatic epigenetic switch and monoallelic expression.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.269498.115.
- Received July 30, 2015.
- Accepted October 1, 2015.
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