Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Somatic mutations in the TERT gene promoter are the most frequent noncoding mutations observed in various cancers.
• These mutations are hypothesized to activate telomerase, a key factor in achieving proliferative immortality in cancer cells.
• The precise molecular mechanisms underlying TERT activation by these promoter mutations remain largely undefined.

Purpose of the Study:

• To elucidate the molecular events driving TERT activation in cancer.
• To investigate the epigenetic changes associated with mutant TERT promoters.
• To understand the mechanism of monoallelic expression in mutant TERT alleles.

Main Methods:

• Analysis of multiple cancer cell lines.
• Chromatin immunoprecipitation assays to detect histone modifications (H3K4me2/3 and H3K27me3).
• Assessment of transcription factor recruitment (GABPA/B1) to TERT promoter regions.
• Evaluation of transcriptional activity of wild-type and mutant TERT alleles.

Main Results:

• Mutant TERT promoters display the H3K4me2/3 histone mark, indicative of active chromatin.
• The GABPA/B1 transcription factor is specifically recruited to the mutant TERT promoters.
• Wild-type TERT alleles retain the H3K27me3 mark, associated with epigenetic silencing.
• Transcriptional activity is exclusively observed in the mutant TERT promoters, not the wild-type ones.

Conclusions:

• A single-base-pair mutation in the TERT promoter can induce a significant epigenetic switch.
• This switch leads to the recruitment of specific transcription factors and marks of active chromatin.
• The findings explain the monoallelic transcriptional activation of the mutant TERT allele, contributing to cancer development.