Epigenetic regulation of the telomerase gene promoters
Epigenetic mechanisms have been implicated in the regulation of telomerase gene expression and here we show that specific modifications within the chromatin environment of the hTR and hTERT promoters correlate with expression of hTR and hTERT in ALT, normal and telomerase-positive tumour cell lines. Lack of expression of hTR and hTERT is associated with repressive histone modification, while, hTR and hTERT expression is associated permissive histone modifications. Methylation of lysine 20 H4 was not linked to gene expression but instead was specific to the hTR and hTERT promoters of ALT cells providing an insight into the differences between ALT and telomerase-positive cells as well as a novel marker for the ALT phenotype. Basal transcription machinery dynamics were also shown to be different between normal and cancer cells at the telomerase gene promoters. Modulation of the chromatin environment was also shown to cause re-expression or increased expression of hTR and hTERT further supporting the role of the chromatin environment in controlling telomerase gene expression. Epigenetic mechanisms are also shown to be involved in the repression of hTERT transcription in human mesenchymal stem cell (hMSCs) and modulation of the chromatin environment is shown to allow re-expression of hTERT expression, while the disruption of telomerase gene expression in human haematopoietic stem cells (hHSCs) in chronic myeloid leukaemia (CML) and the role of the chromatin environment was also studied. These data establishes how epigenetic mechanisms can contribute to transcriptional regulation of telomerase and also highlights the potential importance of epigenetics in senescence and tumourigenicity.