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Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma
BACKGROUND: HOX genes are a family of developmental genes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained prol...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342872/ https://www.ncbi.nlm.nih.gov/pubmed/25622821 http://dx.doi.org/10.1186/s13059-015-0583-7 |
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author | Kurscheid, Sebastian Bady, Pierre Sciuscio, Davide Samarzija, Ivana Shay, Tal Vassallo, Irene Criekinge, Wim V Daniel, Roy T van den Bent, Martin J Marosi, Christine Weller, Michael Mason, Warren P Domany, Eytan Stupp, Roger Delorenzi, Mauro Hegi, Monika E |
author_facet | Kurscheid, Sebastian Bady, Pierre Sciuscio, Davide Samarzija, Ivana Shay, Tal Vassallo, Irene Criekinge, Wim V Daniel, Roy T van den Bent, Martin J Marosi, Christine Weller, Michael Mason, Warren P Domany, Eytan Stupp, Roger Delorenzi, Mauro Hegi, Monika E |
author_sort | Kurscheid, Sebastian |
collection | PubMed |
description | BACKGROUND: HOX genes are a family of developmental genes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe the epigenetic and genetic alterations and their interactions associated with the expression of this signature in glioblastoma. RESULTS: We observe prominent hypermethylation of the HOXA locus 7p15.2 in glioblastoma in contrast to non-tumoral brain. Hypermethylation is associated with a gain of chromosome 7, a hallmark of glioblastoma, and may compensate for tumor-driven enhanced gene dosage as a rescue mechanism by preventing undue gene expression. We identify the CpG island of the HOXA10 alternative promoter that appears to escape hypermethylation in the HOX-high glioblastoma. An additive effect of gene copy gain at 7p15.2 and DNA methylation at key regulatory CpGs in HOXA10 is significantly associated with HOX-signature expression. Additionally, we show concordance between methylation status and presence of active or inactive chromatin marks in glioblastoma-derived spheres that are HOX-high or HOX-low, respectively. CONCLUSIONS: Based on these findings, we propose co-evolution and interaction between gene copy gain, associated with a gain of chromosome 7, and additional epigenetic alterations as key mechanisms triggering a coordinated, but inappropriate, HOX transcriptional program in glioblastoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0583-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4342872 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-43428722015-02-28 Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma Kurscheid, Sebastian Bady, Pierre Sciuscio, Davide Samarzija, Ivana Shay, Tal Vassallo, Irene Criekinge, Wim V Daniel, Roy T van den Bent, Martin J Marosi, Christine Weller, Michael Mason, Warren P Domany, Eytan Stupp, Roger Delorenzi, Mauro Hegi, Monika E Genome Biol Research BACKGROUND: HOX genes are a family of developmental genes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe the epigenetic and genetic alterations and their interactions associated with the expression of this signature in glioblastoma. RESULTS: We observe prominent hypermethylation of the HOXA locus 7p15.2 in glioblastoma in contrast to non-tumoral brain. Hypermethylation is associated with a gain of chromosome 7, a hallmark of glioblastoma, and may compensate for tumor-driven enhanced gene dosage as a rescue mechanism by preventing undue gene expression. We identify the CpG island of the HOXA10 alternative promoter that appears to escape hypermethylation in the HOX-high glioblastoma. An additive effect of gene copy gain at 7p15.2 and DNA methylation at key regulatory CpGs in HOXA10 is significantly associated with HOX-signature expression. Additionally, we show concordance between methylation status and presence of active or inactive chromatin marks in glioblastoma-derived spheres that are HOX-high or HOX-low, respectively. CONCLUSIONS: Based on these findings, we propose co-evolution and interaction between gene copy gain, associated with a gain of chromosome 7, and additional epigenetic alterations as key mechanisms triggering a coordinated, but inappropriate, HOX transcriptional program in glioblastoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-015-0583-7) contains supplementary material, which is available to authorized users. BioMed Central 2015-01-27 2015 /pmc/articles/PMC4342872/ /pubmed/25622821 http://dx.doi.org/10.1186/s13059-015-0583-7 Text en © Kurscheid et al.; licensee BioMed Central. 2015 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 work is properly credited. 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. |
spellingShingle | Research Kurscheid, Sebastian Bady, Pierre Sciuscio, Davide Samarzija, Ivana Shay, Tal Vassallo, Irene Criekinge, Wim V Daniel, Roy T van den Bent, Martin J Marosi, Christine Weller, Michael Mason, Warren P Domany, Eytan Stupp, Roger Delorenzi, Mauro Hegi, Monika E Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma |
title | Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma |
title_full | Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma |
title_fullStr | Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma |
title_full_unstemmed | Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma |
title_short | Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma |
title_sort | chromosome 7 gain and dna hypermethylation at the hoxa10 locus are associated with expression of a stem cell related hox-signature in glioblastoma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342872/ https://www.ncbi.nlm.nih.gov/pubmed/25622821 http://dx.doi.org/10.1186/s13059-015-0583-7 |
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