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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 5-Methylcytosine / metabolism
  • Alleles*
  • Base Sequence
  • Cell Line, Tumor
  • CpG Islands / genetics
  • DNA / genetics
  • DNA Methylation / genetics*
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Histone Code / genetics*
  • Humans
  • Mutation / genetics*
  • Neoplasms / genetics
  • Polycomb Repressive Complex 2 / metabolism
  • Promoter Regions, Genetic*
  • Protein Binding
  • Survival Analysis
  • Telomerase / genetics*
  • Transcription, Genetic


  • 5-Methylcytosine
  • DNA
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • TERT protein, human
  • Telomerase