Based on studies of primary human cells that lack transcription of the TERT gene, it has been inferred that during differentiation TERT is transcriptionally silenced, in part, by accumulation and maintenance of H3K27me3 and to a lesser extent H3K9me3. Another epigenetic mark of transcriptional silencing is 5-methyl-cytosine (5mC). The role of 5mC in regulatory regions of TERT in many cancers appears to be atypical, suggesting a complex interplay between transcription factors and methyltransferases and demethylases for both histones and DNA. And although enhancers have been reported for TERT, so far these do not appear operate across a broad range of cell types making it difficult to ascertain unifying themes in enhancer-mediated TERT regulation.
TERT promoters that have activating mutations drive unusual monoallelic expression of the TERT mRNA. This can be deduced from the nucleotide variants in the coding region of the TERT gene: only a single variant is transcribed and these variants can be traced back to the alleles bearing the promoter mutations. Thus, in these cells, there are co-residing active and silent copies of the TERT gene.
The existence of mutations in the TERT promoter appears to have dramatic consequences for the overall regulatory landscape at TERT. Cancers without these mutations display a distinct epigenetic landscape compared to those with mutations. One possible explanation for these differences are the specific transcription factors that are recruited to these different TERT genes. Another possibility is that these tumors were derived from cells with different origins or environments.
Dozens of transcription factors are reported to bind to the TERT promoter in various contexts but it’s not known which factors are lost or gained from the promoter during differentiation, or how these changes lead to transcriptional silencing. Likewise, during induction of pluripotency, almost nothing is known about what pioneer factors reactivate TERT, and whether this process is in anyway similar to TERT reactivation in oncogenesis. In cancer, rearrangements and viral integrations have been implicated in TERT reactivation, but data suggest that these situations do not encompass the majority of cancers. Other hypotheses suggest that some cancers arise from cells with stem cell-like properties, i.e. cells that have not differentiated, and therefore have simply avoided TERT repression. Given the critical importance of TERT to oncogenesis, embryogenesis, senescence, aging, tissue regeneration, and telomere based diseases, these gaps in our knowledge lead to the following questions and represent a major research endeavor:
What represses TERT upon differentiation of pluripotent cells to mature cell types?
What factors are required to de-repress TERT during induction of pluripotency and oncogenesis?
1. Stern J.L., Paucek R.D., Huang F.W., Ghandi M., Nwumeh R., Costello J., Cech T.R. Allele-specific DNA methylation and its interplay with repressive histone marks at promoter-mutant TERT genes. Cell Reports (2017). https://doi.org/10.1016/j.celrep.2017.12.001
2. Stern J.L., Theodorescu D., Vogelstein B., Papadopoulos N., Cech T.R. Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers. Genes Dev. 29, 2219-24 (2015). http://www.genesdev.org/cgi/doi/10.1101/gad.269498.115
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