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Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression

The telomerase reverse transcriptase (TERT) gene is responsible for telomere maintenance in germline and stem cells, and is re-expressed in 90% of human cancers. CpG methylation in the TERT promoter (TERTp) was correlated with TERT mRNA expression. Furthermore, two hotspot mutations in TERTp, dubbed...

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Autores principales: Salgado, Catarina, Roelse, Celine, Nell, Rogier, Gruis, Nelleke, van Doorn, Remco, van der Velden, Pieter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141627/
https://www.ncbi.nlm.nih.gov/pubmed/32267900
http://dx.doi.org/10.1371/journal.pone.0231418
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author Salgado, Catarina
Roelse, Celine
Nell, Rogier
Gruis, Nelleke
van Doorn, Remco
van der Velden, Pieter
author_facet Salgado, Catarina
Roelse, Celine
Nell, Rogier
Gruis, Nelleke
van Doorn, Remco
van der Velden, Pieter
author_sort Salgado, Catarina
collection PubMed
description The telomerase reverse transcriptase (TERT) gene is responsible for telomere maintenance in germline and stem cells, and is re-expressed in 90% of human cancers. CpG methylation in the TERT promoter (TERTp) was correlated with TERT mRNA expression. Furthermore, two hotspot mutations in TERTp, dubbed C228T and C250T, have been revealed to facilitate binding of transcription factor ETS/TCF and subsequent TERT expression. This study aimed to elucidate the combined contribution of epigenetic (promoter methylation and chromatin accessibility) and genetic (promoter mutations) mechanisms in regulating TERT gene expression in healthy skin samples and in melanoma cell lines (n = 61). We unexpectedly observed that the methylation of TERTp was as high in a subset of healthy skin cells, mainly keratinocytes, as in cutaneous melanoma cell lines. In spite of the high promoter methylation fraction in wild-type (WT) samples, TERT mRNA was only expressed in the melanoma cell lines with either high methylation or intermediate methylation in combination with TERT mutations. TERTp methylation was positively correlated with chromatin accessibility and TERT mRNA expression in 8 melanoma cell lines. Cooperation between epigenetic and genetic mechanisms were best observed in heterozygous mutant cell lines as chromosome accessibility preferentially concerned the mutant allele. Combined, these results suggest a complex model in which TERT expression requires either a widely open chromatin state in TERTp-WT samples due to high methylation throughout the promoter or a combination of moderate methylation fraction/chromatin accessibility in the presence of the C228T or C250T mutations.
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spelling pubmed-71416272020-04-09 Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression Salgado, Catarina Roelse, Celine Nell, Rogier Gruis, Nelleke van Doorn, Remco van der Velden, Pieter PLoS One Research Article The telomerase reverse transcriptase (TERT) gene is responsible for telomere maintenance in germline and stem cells, and is re-expressed in 90% of human cancers. CpG methylation in the TERT promoter (TERTp) was correlated with TERT mRNA expression. Furthermore, two hotspot mutations in TERTp, dubbed C228T and C250T, have been revealed to facilitate binding of transcription factor ETS/TCF and subsequent TERT expression. This study aimed to elucidate the combined contribution of epigenetic (promoter methylation and chromatin accessibility) and genetic (promoter mutations) mechanisms in regulating TERT gene expression in healthy skin samples and in melanoma cell lines (n = 61). We unexpectedly observed that the methylation of TERTp was as high in a subset of healthy skin cells, mainly keratinocytes, as in cutaneous melanoma cell lines. In spite of the high promoter methylation fraction in wild-type (WT) samples, TERT mRNA was only expressed in the melanoma cell lines with either high methylation or intermediate methylation in combination with TERT mutations. TERTp methylation was positively correlated with chromatin accessibility and TERT mRNA expression in 8 melanoma cell lines. Cooperation between epigenetic and genetic mechanisms were best observed in heterozygous mutant cell lines as chromosome accessibility preferentially concerned the mutant allele. Combined, these results suggest a complex model in which TERT expression requires either a widely open chromatin state in TERTp-WT samples due to high methylation throughout the promoter or a combination of moderate methylation fraction/chromatin accessibility in the presence of the C228T or C250T mutations. Public Library of Science 2020-04-08 /pmc/articles/PMC7141627/ /pubmed/32267900 http://dx.doi.org/10.1371/journal.pone.0231418 Text en © 2020 Salgado et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Salgado, Catarina
Roelse, Celine
Nell, Rogier
Gruis, Nelleke
van Doorn, Remco
van der Velden, Pieter
Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression
title Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression
title_full Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression
title_fullStr Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression
title_full_unstemmed Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression
title_short Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression
title_sort interplay between tert promoter mutations and methylation culminates in chromatin accessibility and tert expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141627/
https://www.ncbi.nlm.nih.gov/pubmed/32267900
http://dx.doi.org/10.1371/journal.pone.0231418
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