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Cell Rep. 2017 Dec 26;21(13):3700-3707. doi: 10.1016/j.celrep.2017.12.001.

Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes.

Author information

1
BioFrontiers Institute, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
2
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
3
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
4
Department of Pharmacology and University of Colorado Comprehensive Cancer Center, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
5
BioFrontiers Institute, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80303, USA. Electronic address: thomas.cech@colorado.edu.

Abstract

A mutation in the promoter of the Telomerase Reverse Transcriptase (TERT) gene is the most frequent noncoding mutation in cancer. The mutation drives unusual monoallelic expression of TERT, allowing immortalization. Here, we find that DNA methylation of the TERT CpG island (CGI) is also allele-specific in multiple cancers. The expressed allele is hypomethylated, which is opposite to cancers without TERT promoter mutations. The continued presence of Polycomb repressive complex 2 (PRC2) on the inactive allele suggests that histone marks of repressed chromatin may be causally linked to high DNA methylation. Consistent with this hypothesis, TERT promoter DNA containing 5-methyl-CpG has much increased affinity for PRC2 in vitro. Thus, CpG methylation and histone marks appear to collaborate to maintain the two TERT alleles in different epigenetic states in TERT promoter mutant cancers. Finally, in several cancers, DNA methylation levels at the TERT CGI correlate with altered patient survival.

KEYWORDS:

5-methylcytosine; CpG island; PRC2; Polycomb repressive complex 2; TERT promoter; allele-specific; cancer; monoallelic; telomerase

PMID:
29281820
PMCID:
PMC5747321
DOI:
10.1016/j.celrep.2017.12.001
[Indexed for MEDLINE]
Free PMC Article

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