Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer

Abstract Tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the...

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Autores principales:	Jean S. Fain, Axelle Loriot, Anna Diacofotaki, Aurélie Van Tongelen, Charles De Smet
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/13c815e52ba34a6ab5ae1ab31236669e
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spelling	oai:doaj.org-article:13c815e52ba34a6ab5ae1ab31236669e2021-12-02T15:28:46ZTranscriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer10.1038/s41598-021-96844-02045-2322https://doaj.org/article/13c815e52ba34a6ab5ae1ab31236669e2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96844-0https://doaj.org/toc/2045-2322Abstract Tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark deposited during transcriptional elongation and known to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of regional DNA hypermethylation. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo/hypermethylation, and some of these included tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.Jean S. FainAxelle LoriotAnna DiacofotakiAurélie Van TongelenCharles De SmetNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jean S. Fain Axelle Loriot Anna Diacofotaki Aurélie Van Tongelen Charles De Smet Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer
description	Abstract Tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark deposited during transcriptional elongation and known to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of regional DNA hypermethylation. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo/hypermethylation, and some of these included tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.
format	article
author	Jean S. Fain Axelle Loriot Anna Diacofotaki Aurélie Van Tongelen Charles De Smet
author_facet	Jean S. Fain Axelle Loriot Anna Diacofotaki Aurélie Van Tongelen Charles De Smet
author_sort	Jean S. Fain
title	Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer
title_short	Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer
title_full	Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer
title_fullStr	Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer
title_full_unstemmed	Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer
title_sort	transcriptional overlap links dna hypomethylation with dna hypermethylation at adjacent promoters in cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/13c815e52ba34a6ab5ae1ab31236669e
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Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer

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