Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer

Abstract Epigenetic deregulation is of importance in tumorigenesis. In particular CpG islands (CGI), are frequently hypermethylated. Here, genome-wide DNA-methylation profiles of 480,000 CpGs in lung cancer cells were generated. It was observed that intra- and intergenic CGI exhibited higher methyla...

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Autores principales:	Steffen Kiehl, Tobias Zimmermann, Rajkumar Savai, Soni S. Pullamsetti, Werner Seeger, Marek Bartkuhn, Reinhard H. Dammann
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/345716730072453da0e6f7e9e2f438eb
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spelling	oai:doaj.org-article:345716730072453da0e6f7e9e2f438eb2021-12-02T15:05:30ZEpigenetic silencing of downstream genes mediated by tandem orientation in lung cancer10.1038/s41598-017-04248-w2045-2322https://doaj.org/article/345716730072453da0e6f7e9e2f438eb2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04248-whttps://doaj.org/toc/2045-2322Abstract Epigenetic deregulation is of importance in tumorigenesis. In particular CpG islands (CGI), are frequently hypermethylated. Here, genome-wide DNA-methylation profiles of 480,000 CpGs in lung cancer cells were generated. It was observed that intra- and intergenic CGI exhibited higher methylation compared to normal cells. The functional annotation of hypermethylated CGI revealed that the hypermethylation was associated with homeobox domain genes and targets marked by repressive histone modifications. The strongest methylation variation was observed in transitional areas of CGI, termed shores. 5′-shores of promoter-associated CGI in lung cancer cell lines were higher methylated than 3′-shores. Within two tandem-oriented genes, a significant hypermethylation of the downstream-located CGI promoters was revealed. Hypermethylation correlates with the length of the intergenic region between such tandem genes. As the RASSF1A tumor suppressor gene represents such a downstream tandem gene, its silencing was analyzed using an inducible system. It was determined that the induction of an upstream gene led to a repression of RASSF1A through a process involving histone deacetylases and CPSF1. A tumor-specific increase in expression of histone deacetylases and CPSF1 was detected in lung cancer. Our results suggest that the downstream gene could be susceptible to epigenetic silencing when organized in a tandem orientation.Steffen KiehlTobias ZimmermannRajkumar SavaiSoni S. PullamsettiWerner SeegerMarek BartkuhnReinhard H. DammannNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Steffen Kiehl Tobias Zimmermann Rajkumar Savai Soni S. Pullamsetti Werner Seeger Marek Bartkuhn Reinhard H. Dammann Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer
description	Abstract Epigenetic deregulation is of importance in tumorigenesis. In particular CpG islands (CGI), are frequently hypermethylated. Here, genome-wide DNA-methylation profiles of 480,000 CpGs in lung cancer cells were generated. It was observed that intra- and intergenic CGI exhibited higher methylation compared to normal cells. The functional annotation of hypermethylated CGI revealed that the hypermethylation was associated with homeobox domain genes and targets marked by repressive histone modifications. The strongest methylation variation was observed in transitional areas of CGI, termed shores. 5′-shores of promoter-associated CGI in lung cancer cell lines were higher methylated than 3′-shores. Within two tandem-oriented genes, a significant hypermethylation of the downstream-located CGI promoters was revealed. Hypermethylation correlates with the length of the intergenic region between such tandem genes. As the RASSF1A tumor suppressor gene represents such a downstream tandem gene, its silencing was analyzed using an inducible system. It was determined that the induction of an upstream gene led to a repression of RASSF1A through a process involving histone deacetylases and CPSF1. A tumor-specific increase in expression of histone deacetylases and CPSF1 was detected in lung cancer. Our results suggest that the downstream gene could be susceptible to epigenetic silencing when organized in a tandem orientation.
format	article
author	Steffen Kiehl Tobias Zimmermann Rajkumar Savai Soni S. Pullamsetti Werner Seeger Marek Bartkuhn Reinhard H. Dammann
author_facet	Steffen Kiehl Tobias Zimmermann Rajkumar Savai Soni S. Pullamsetti Werner Seeger Marek Bartkuhn Reinhard H. Dammann
author_sort	Steffen Kiehl
title	Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer
title_short	Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer
title_full	Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer
title_fullStr	Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer
title_full_unstemmed	Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer
title_sort	epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/345716730072453da0e6f7e9e2f438eb
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Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer

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