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

Publication date: 26 December 2017
Source:Cell Reports, Volume 21, Issue 13
Author(s): Josh Lewis Stern, Richard D. Paucek, Franklin W. Huang, Mahmoud Ghandi, Ronald Nwumeh, James C. Costello, Thomas R. Cech
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.

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Teaser

The promoter for a telomerase gene (TERT) is the third most frequently mutated site in cancer. These mutations drive unusual expression of TERT from a single allele, allowing unceasing cell division. Stern et al. identify modifications of the promoter that appear to collaborate to maintain this expression pattern in these cancers.


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