Article

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.

Creator

• Costello, James C
• Paucek, Richard D
• Stern, Josh Lewis
• Nwumeh, Ronald
• Cech, Thomas R
• Ghandi, Mahmoud
• Huang, Franklin W

Date Issued

• 2017-12-26

Academic Affiliation

• Chemical and Biological Engineering

Journal Title

• Cell Reports

Journal Issue/Number

• 13

Journal Volume

• 21

File Extent

• 3700-3707

Subject

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

Last Modified

• 2019-12-05

Identifier

• PubMed ID: 29281820

Resource Type

• Article

Rights Statement

• In Copyright

DOI

•  https://doi.org/10.1016/j.celrep.2017.12.001

ISSN

• 2211-1247

Language

• English [eng]

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