Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes
Josh Lewis Stern,
Richard D. Paucek,
Franklin W. Huang,
Mahmoud Ghandi,
Ronald Nwumeh,
James C. Costello,
Thomas R. Cech
Affiliations
Josh Lewis Stern
BioFrontiers Institute, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80303, USA
Richard D. Paucek
BioFrontiers Institute, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80303, USA
Franklin W. Huang
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Mahmoud Ghandi
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Ronald Nwumeh
BioFrontiers Institute, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80303, USA
James C. Costello
Department of Pharmacology and University of Colorado Comprehensive Cancer Center, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
Thomas R. Cech
BioFrontiers Institute, Department of Chemistry and Biochemistry, and Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO 80303, USA
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.
