Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.1/17348 |
Resumo: | Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allelespecific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer. |
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Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancerDuplo papel de hipermetilação de DNA específica de alelo dentro do TERT no câncerMutações do promotorMetilaçãoExpressãoTelômerosAberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allelespecific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer.American Soc Clinical Investigation IncSapientiaLee, Donghyun D.Komosa, MartinSudhaman, SumedhaLeão, RicardoZhang, Cindy H.Apolonio, Joana D.Hermanns, ThomasWild, Peter J.Klocker, HelmutNassiri, FarshadZadeh, GelarehDiplas, Bill H.Yan, HaiGallinger, StevenPugh, Trevor J.Ramaswamy, VijayTaylor, Michael D.Castelo-Branco, PedroNunes, Nuno MiguelTabori, Uri2021-11-23T16:23:07Z2021-11-012021-11-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/17348eng10.1172/JCI1469151558-8238info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-24T10:29:29Zoai:sapientia.ualg.pt:10400.1/17348Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:07:20.437999Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer Duplo papel de hipermetilação de DNA específica de alelo dentro do TERT no câncer |
title |
Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer |
spellingShingle |
Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer Lee, Donghyun D. Mutações do promotor Metilação Expressão Telômeros |
title_short |
Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer |
title_full |
Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer |
title_fullStr |
Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer |
title_full_unstemmed |
Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer |
title_sort |
Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer |
author |
Lee, Donghyun D. |
author_facet |
Lee, Donghyun D. Komosa, Martin Sudhaman, Sumedha Leão, Ricardo Zhang, Cindy H. Apolonio, Joana D. Hermanns, Thomas Wild, Peter J. Klocker, Helmut Nassiri, Farshad Zadeh, Gelareh Diplas, Bill H. Yan, Hai Gallinger, Steven Pugh, Trevor J. Ramaswamy, Vijay Taylor, Michael D. Castelo-Branco, Pedro Nunes, Nuno Miguel Tabori, Uri |
author_role |
author |
author2 |
Komosa, Martin Sudhaman, Sumedha Leão, Ricardo Zhang, Cindy H. Apolonio, Joana D. Hermanns, Thomas Wild, Peter J. Klocker, Helmut Nassiri, Farshad Zadeh, Gelareh Diplas, Bill H. Yan, Hai Gallinger, Steven Pugh, Trevor J. Ramaswamy, Vijay Taylor, Michael D. Castelo-Branco, Pedro Nunes, Nuno Miguel Tabori, Uri |
author2_role |
author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Sapientia |
dc.contributor.author.fl_str_mv |
Lee, Donghyun D. Komosa, Martin Sudhaman, Sumedha Leão, Ricardo Zhang, Cindy H. Apolonio, Joana D. Hermanns, Thomas Wild, Peter J. Klocker, Helmut Nassiri, Farshad Zadeh, Gelareh Diplas, Bill H. Yan, Hai Gallinger, Steven Pugh, Trevor J. Ramaswamy, Vijay Taylor, Michael D. Castelo-Branco, Pedro Nunes, Nuno Miguel Tabori, Uri |
dc.subject.por.fl_str_mv |
Mutações do promotor Metilação Expressão Telômeros |
topic |
Mutações do promotor Metilação Expressão Telômeros |
description |
Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allelespecific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-11-23T16:23:07Z 2021-11-01 2021-11-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.1/17348 |
url |
http://hdl.handle.net/10400.1/17348 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
10.1172/JCI146915 1558-8238 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
American Soc Clinical Investigation Inc |
publisher.none.fl_str_mv |
American Soc Clinical Investigation Inc |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799133317708120064 |