Pervasive promoter hypermethylation of silenced TERT alleles in human cancers
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ORIGINAL PAPER
Pervasive promoter hypermethylation of silenced TERT alleles in human cancers David Esopi 1,2 & Mindy Kim Graham 1,3 & Jacqueline A. Brosnan-Cashman 1,4 & Jennifer Meyers 1 & Ajay Vaghasia 1 & Anuj Gupta 1 & Balasubramanian Kumar 5 & Michael C. Haffner 1,6,7 & Christopher M. Heaphy 1,6,8 & Angelo M. De Marzo 1,6,9 & Alan K. Meeker 1,6,9 & William G. Nelson 1,6,9,3 & Sarah J. Wheelan 1,10,11 & Srinivasan Yegnasubramanian 1,6,9,3 Accepted: 6 May 2020 # The Author(s) 2020
Abstract Background In cancers, maintenance of telomeres often occurs through activation of the catalytic subunit of telomerase, encoded by TERT. Yet, most cancers show only modest levels of TERT gene expression, even in the context of activating hotspot promoter mutations (C228T and C250T). The role of epigenetic mechanisms, including DNA methylation, in regulating TERT gene expression in cancer cells is as yet not fully understood. Methods Here, we have carried out the most comprehensive characterization to date of TERT promoter methylation using ultradeep bisulfite sequencing spanning the CpG island surrounding the core TERT promoter in 96 different human cell lines, including primary, immortalized and cancer cell types, as well as in control and reference samples. Results In general, we observed that immortalized and cancer cell lines were hypermethylated in a region upstream of the recurrent C228T and C250T TERT promoter mutations, while non-malignant primary cells were comparatively hypomethylated in this region. However, at the allele-level, we generally found that hypermethylation of promoter sequences in cancer cells is associated with repressed expression, and the remaining unmethylated alleles marked with open chromatin are largely responsible for the observed TERT expression in cancer cells. Conclusions Our findings suggest that hypermethylation of the TERT promoter alleles signals transcriptional repression of those alleles, leading to attenuation of TERT activation in cancer cells. This type of fine tuning of TERT expression may account for the modest activation of TERT expression in most cancers. Keywords Telomeres and telomerase . Cancer . DNA methylation . Telomerase regulation . TERT promoter mutation . Epigenetics . High-throughput sequencing
1 Introduction D Esopi and MK Graham are co-first authors. D Esopi and MK Graham contributed equally to this work. This article is present on a university repository website and can be accessed on https://www.biorxiv.org/content/10.1101/2020.01.29. 925552v1. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13402-020-00531-7) contains supplementary material, which is available to authorized users. * Sarah J. Wheelan [email protected] * Srinivasan Yegnasubramanian [email protected] Extended author information available on the last page of the article
At the terminal ends of human chromosomes are telomere nucleoproteins, consisting of a hexameric DNA repeat, 5′-TTAGGG, coated by a complex of six shelterin proteins [1]. Telomeres fun
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