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  Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

Hovestadt, V., Jones, D., Picelli, S., Wang, W., Kool, M., Northcott, P. A., et al. (2014). Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature, 26(510), 537-541. doi:10.1038/nature13268.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-6122-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-6123-E
Genre: Journal Article

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Hovestadt , V, Author
Jones , D, Author
Picelli , S, Author
Wang , W, Author
Kool , M, Author
Northcott , P A, Author
Sultan, Marc1, Author              
Stachurski , K, Author
Ryzhova , M, Author
Warnatz, Hans Joerg2, Author              
Ralser, Markus3, Author              
Brun , S, Author
Bunt , J, Author
Jäger , N, Author
Kleinheinz , K, Author
Erkek , S, Author
Weber , U D, Author
Bartholomae, C C, Author
von Kalle , C, Author
Lawerenz , C, Author
Eils , J, Author Koster , J, AuthorVersteeg , R, AuthorMilde , T, AuthorWitt , O, AuthorSchmidt , S, AuthorWolf , S, AuthorPietsch , T, AuthorRutkowski, S, AuthorScheurlen , W, AuthorTaylor , M B, AuthorBrors , B, AuthorFelsberg , J, AuthorReifenberger , G, AuthorBorkhardt , A, AuthorLehrach, H.3, Author              Wechsler-Reya , R, AuthorEils , R, AuthorYaspo, Marie-Laure4, Author              Landgraf , P, AuthorKorshunov , A, AuthorZapatka , M, AuthorRadlwimmer , B, AuthorPfister , S M, AuthorLichter , P, Author more..
Affiliations:
1Human Chromosome 21 (Marie-Laure Yaspo), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479652              
2Department of Biomedical Optics, Max Planck Institute for Medical Research, Max Planck Society, ou_1497699              
3Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              
4Gene Regulation and Systems Biology of Cancer (Marie-Laure Yaspo), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117287              

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 Abstract: Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.

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Language(s): eng - English
 Dates: 2014-05-18
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/nature13268
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Title: Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 26 (510) Sequence Number: - Start / End Page: 537 - 541 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238