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CTCF loss mediates unique DNA hypermethylation landscapes in human cancers

BACKGROUND: The chromatin insulator CCCTC-binding factor (CTCF) displays tissue-specific DNA binding sites that regulate transcription and chromatin organization. Despite evidence linking CTCF to the protection of epigenetic states through barrier insulation, the impact of CTCF loss on genome-wide D...

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Autores principales: Damaschke, Nathan A., Gawdzik, Joseph, Avilla, Mele, Yang, Bing, Svaren, John, Roopra, Avtar, Luo, Jian-Hua, Yu, Yan P., Keles, Sunduz, Jarrard, David F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275597/
https://www.ncbi.nlm.nih.gov/pubmed/32503656
http://dx.doi.org/10.1186/s13148-020-00869-7
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author Damaschke, Nathan A.
Gawdzik, Joseph
Avilla, Mele
Yang, Bing
Svaren, John
Roopra, Avtar
Luo, Jian-Hua
Yu, Yan P.
Keles, Sunduz
Jarrard, David F.
author_facet Damaschke, Nathan A.
Gawdzik, Joseph
Avilla, Mele
Yang, Bing
Svaren, John
Roopra, Avtar
Luo, Jian-Hua
Yu, Yan P.
Keles, Sunduz
Jarrard, David F.
author_sort Damaschke, Nathan A.
collection PubMed
description BACKGROUND: The chromatin insulator CCCTC-binding factor (CTCF) displays tissue-specific DNA binding sites that regulate transcription and chromatin organization. Despite evidence linking CTCF to the protection of epigenetic states through barrier insulation, the impact of CTCF loss on genome-wide DNA methylation sites in human cancer remains undefined. RESULTS: Here, we demonstrate that prostate and breast cancers within The Cancer Genome Atlas (TCGA) exhibit frequent copy number loss of CTCF and that this loss is associated with increased DNA methylation events that occur preferentially at CTCF binding sites. CTCF sites differ among tumor types and result in tissue-specific methylation patterns with little overlap between breast and prostate cancers. DNA methylation and transcriptome profiling in vitro establish that forced downregulation of CTCF leads to spatially distinct DNA hypermethylation surrounding CTCF binding sites, loss of CTCF binding, and decreased gene expression that is also seen in human tumors. DNA methylation inhibition reverses loss of expression at these CTCF-regulated genes. CONCLUSION: These findings establish CTCF loss as a major mediator in directing localized DNA hypermethylation events in a tissue-specific fashion and further support its role as a driver of the cancer phenotype.
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spelling pubmed-72755972020-06-08 CTCF loss mediates unique DNA hypermethylation landscapes in human cancers Damaschke, Nathan A. Gawdzik, Joseph Avilla, Mele Yang, Bing Svaren, John Roopra, Avtar Luo, Jian-Hua Yu, Yan P. Keles, Sunduz Jarrard, David F. Clin Epigenetics Research BACKGROUND: The chromatin insulator CCCTC-binding factor (CTCF) displays tissue-specific DNA binding sites that regulate transcription and chromatin organization. Despite evidence linking CTCF to the protection of epigenetic states through barrier insulation, the impact of CTCF loss on genome-wide DNA methylation sites in human cancer remains undefined. RESULTS: Here, we demonstrate that prostate and breast cancers within The Cancer Genome Atlas (TCGA) exhibit frequent copy number loss of CTCF and that this loss is associated with increased DNA methylation events that occur preferentially at CTCF binding sites. CTCF sites differ among tumor types and result in tissue-specific methylation patterns with little overlap between breast and prostate cancers. DNA methylation and transcriptome profiling in vitro establish that forced downregulation of CTCF leads to spatially distinct DNA hypermethylation surrounding CTCF binding sites, loss of CTCF binding, and decreased gene expression that is also seen in human tumors. DNA methylation inhibition reverses loss of expression at these CTCF-regulated genes. CONCLUSION: These findings establish CTCF loss as a major mediator in directing localized DNA hypermethylation events in a tissue-specific fashion and further support its role as a driver of the cancer phenotype. BioMed Central 2020-06-05 /pmc/articles/PMC7275597/ /pubmed/32503656 http://dx.doi.org/10.1186/s13148-020-00869-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Damaschke, Nathan A.
Gawdzik, Joseph
Avilla, Mele
Yang, Bing
Svaren, John
Roopra, Avtar
Luo, Jian-Hua
Yu, Yan P.
Keles, Sunduz
Jarrard, David F.
CTCF loss mediates unique DNA hypermethylation landscapes in human cancers
title CTCF loss mediates unique DNA hypermethylation landscapes in human cancers
title_full CTCF loss mediates unique DNA hypermethylation landscapes in human cancers
title_fullStr CTCF loss mediates unique DNA hypermethylation landscapes in human cancers
title_full_unstemmed CTCF loss mediates unique DNA hypermethylation landscapes in human cancers
title_short CTCF loss mediates unique DNA hypermethylation landscapes in human cancers
title_sort ctcf loss mediates unique dna hypermethylation landscapes in human cancers
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275597/
https://www.ncbi.nlm.nih.gov/pubmed/32503656
http://dx.doi.org/10.1186/s13148-020-00869-7
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