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

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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Stern JL,Paucek RD,Huang FW,Ghandi M,Nwumeh R,Costello JC,Cech TR

doi

10.1016/j.celrep.2017.12.001

subject

Has Abstract

pub_date

2017-12-26 00:00:00

pages

3700-3707

issue

13

issn

2211-1247

pii

S2211-1247(17)31797-7

journal_volume

21

pub_type

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