Interplay between<i>TERT</i>promoter mutations and methylation culminates in chromatin accessibility and<i>TERT</i>expression

Salgado, Catarina; Roelse, Celine M.; Nell, Rogier J.; Gruis, Nelleke A.; Doorn, Remco van; Velden, Pieter van der

doi:10.1101/859892

Cited by 4 publications

(8 citation statements)

References 31 publications

(51 reference statements)

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“…The enrichment of TERT promoter mutations in certain tissues has inspired several explanations, and our findings in both the CCLE and TCGA suggest a specific epigenetic signature that may underlie this unique pathway of telomere maintenance. We found that in TERT promoter mutants, CpG islands were preferentially hypomethylated in PRC2-repressed regions located near telomeres, which may relate to previous reports of a long-range telomere position effect (W. Kim et al, 2016;Yuan et al, 2019) and of TERT expression necessitating specific chromatin states in promoter-wildtype and mutant samples (Salgado et al, 2019).…”

Section: Discussionsupporting

confidence: 83%

“…Absolute methylation of the remaining gene body was positively correlated with TERT expression in both promoter status contexts ( Supplementary Fig. 8d), which parallels previous reports of a positive correlation between TERT expression and methylation (Barthel et al, 2017;Salgado et al, 2019). Exon 1 methylation was elevated in nearly all cell lines with monoallelic TERT expression in both the mutant promoter context (P = 6.3×10 -3 , two-sided Mann-Whitney U test, n = 81) and the wildtype one (P = 1.6×10 -4 , two-sided Mann-Whitney U test, n = 98) compared to biallelic TERT expressors (Stern et al, 2017).…”

Section: Distinct Tertp Methylation Patterns At the Tert Locussupporting

confidence: 89%

“…Considering that normal tissues typically exhibit particularly low methylation of the TERT promoter (Salgado et al, 2019;Stern et al, 2017) and that PRC2 occupies the inactive allele in TERT promoter mutants (Stern et al, 2017), our genome-wide signature may relate to the latter part of the two-step mechanism proposed for TERTp mutation-driven telomerase upregulation (Chiba et al, 2017). Moreover, epigenetic mechanisms have been shown to produce synergistic effects with driver mutations in tumor evolution (Tao et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines

Ghandi

Huang

2021

Preprint

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In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1,299 cancer cell lines. We find that telomerase reverse transcriptase (TERT) expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance components. Increased dependencies of shelterin members are associated with wild-type TP53 status. Investigating the epigenetic regulation of TERT, we find widespread allele-specific expression in promoter-wildtype contexts. TERT promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality.

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Section: Discussionsupporting

confidence: 83%

Section: Distinct Tertp Methylation Patterns At the Tert Locussupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines

Ghandi

Huang

2021

Preprint

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“…The histone mark H3K27me3 maintains heterochromatin and recruitment of the polycomb repressor complex (PRC) for silenced genes (43). Alternatively, the H3K4me3 mark maintains actively transcribed genes in the open confirmation to enable access for transcriptional activators to bind (44). Telomerase negative primary cells exhibit high levels of the silencing H3K27me3 mark at the TERT promoter, compared to telomerase positive cancer cell lines (45), which exhibit the activating H3K4me3 mark (46).…”

Section: Tert Histone Mark Modificationsmentioning

confidence: 99%

Telomerase Reverse Transcriptase (TERT) Regulation in Thyroid Cancer: A Review

2020

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Telomerase reverse transcriptase (TERT) is the catalytic subunit of the enzyme telomerase and is essential for telomerase activity. Upregulation of TERT expression and resulting telomerase activity occurs in the large majority of malignancies, including thyroid cancer. This upregulation results in continued cellular proliferation and avoidance of cellular senescence and cell death. In this review we will briefly introduce TERT and telomerase activity as it pertains to thyroid cancer and, highlight the effects of TERT on cancer cells. We will also explore in detail the different TERT regulatory strategies and how TERT is reactivated in thyroid cancer cells, specifically. These regulatory mechanisms include both activating single base pair TERT promoter mutations and epigenetic changes at the promoter, including changes in CpG methylation and histone modifications that affect chromatin structure. Further, regulation includes the allele-specific regulation of the TERT promoter in thyroid cancer cells harboring the TERT promoter mutation. These entail allele-specific transcriptional activator binding, DNA methylation, histone modifications, and mono-allelic expression of TERT. Lastly, TERT copy number alterations and alternative splicing are also implicated. Both amplifications of the TERT locus and increased full-length transcripts and decreased inactive and dominant negative isoforms result in active telomerase. Finally, the clinical significance of TERT in thyroid cancer is also reviewed.

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“…For example, some allelic variants of the melanocortin 1 receptor (MC1R) can act as genetic modifiers by increasing the penetrance of cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations, doubling the risk of melanoma compared to those only harboring the CDKN2A mutation [9]. However, the hypothesis that heritable germinal epimutations may play a role in the formation of some familial clusters of melanoma, as shown for other neoplasms [10,11] is not supported by conclusive evidence [12].…”

Section: Introductionmentioning

confidence: 99%

Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management

Zocchi

Lontano

Merli

et al. 2021

JCM

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A family history of melanoma greatly increases the risk of developing cutaneous melanoma, a highly aggressive skin cancer whose incidence has been steadily increasing worldwide. Familial melanomas account for about 10% of all malignant melanomas and display an inheritance pattern consistent with the presence of pathogenic germline mutations, among which those involving CDKN2A are the best characterized. In recent years, a growing number of genes, such as MC1R, MITF, CDK4, POT1, TERT, ACD, TERF2IP, and BAP1, have been implicated in familial melanoma. The fact that individuals harboring these germline mutations along with their close blood relatives have a higher risk of developing multiple primary melanomas as well as other internal organ malignancies, especially pancreatic cancer, makes cascade genetic testing and surveillance of these families of the utmost importance. Unfortunately, due to a polygenic inheritance mechanism involving multiple low-risk alleles, genetic modifiers, and environmental factors, it is still very difficult to predict the presence of these mutations. It is, however, known that germline mutation carriers can sometimes develop specific clinical traits, such as high atypical nevus counts and specific dermoscopic features, which could theoretically help clinicians predict the presence of these mutations in prone families. In this review, we provide a comprehensive overview of the high- and intermediate-penetrance genes primarily linked to familial melanoma, highlighting their most frequently associated non-cutaneous malignancies and clinical/dermoscopic phenotypes.

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Interplay betweenTERTpromoter mutations and methylation culminates in chromatin accessibility andTERTexpression

Cited by 4 publications

References 31 publications

Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines

Integrated evaluation of telomerase activation and telomere maintenance across cancer cell lines

Telomerase Reverse Transcriptase (TERT) Regulation in Thyroid Cancer: A Review

Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management

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