Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes
| Autor: | James C. Costello, Franklin W. Huang, Thomas R. Cech, Mahmoud Ghandi, Richard D. Paucek, Ronald Nwumeh, Josh Lewis Stern |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Transcription Genetic medicine.disease_cause telomerase Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cell Line Tumor Neoplasms medicine monoallelic Humans cancer Telomerase reverse transcriptase Enhancer of Zeste Homolog 2 Protein Epigenetics Promoter Regions Genetic 5-methylcytosine lcsh:QH301-705.5 Alleles Mutation biology Base Sequence allele-specific Polycomb repressive complex 2 DNA DNA Methylation Molecular biology Survival Analysis PRC2 Chromatin Histone Code 030104 developmental biology Histone CpG site lcsh:Biology (General) DNA methylation biology.protein CpG island TERT promoter CpG Islands Protein Binding |
| Zdroj: | Cell Reports, Vol 21, Iss 13, Pp 3700-3707 (2017) Cell Reports, Vol 31, Iss 8, Pp-(2020) Cell Rep |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2020.107718 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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