Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

Hovestadt, Volker, Jones, David T. W., Picelli, Simone, Wang, Wei, Kool, Marcel, Northcott, Paul A., Sultan, Marc, Stachurski, Katharina, Ryzhova, Marina, Warnatz, Hans-Jorg, Ralser, Meryem, Brun, Sonja, Bunt, Jens, Jager, Natalie, Kleinheinz, Kortine, Erkek, Serap, Weber, Ursula D., Bartholomae, Cynthia C., von Kalle, Christof, Lawerenz, Chris, Eils, Jurgen, Koster, Jan, Versteeg, Rogier, Milde, Till, Witt, Olaf, Schmidt, Sabine, Wolf, Stephan, Pietsch, Torsten, Rutkowski, Stefan, Scheurlen, Wolfram, Taylor, Michael D., Brors, Benedikt, Felsberg, Jorg, Reifenberger, Guido, Borkhardt, Arndt, Lehrach, Hans, Wechsler-Reya, Robert J., Eils, Roland, Yaspo, Marie-Laure, Landgraf, Pablo, Korshunov, Andrey, Zapatka, Marc, Radlwimmer, Bernhard, Pfister, Stefan M. and Lichter, Peter (2014) Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature, 510 7506: 537-541. doi:10.1038/nature13268

Author Hovestadt, Volker
Jones, David T. W.
Picelli, Simone
Wang, Wei
Kool, Marcel
Northcott, Paul A.
Sultan, Marc
Stachurski, Katharina
Ryzhova, Marina
Warnatz, Hans-Jorg
Ralser, Meryem
Brun, Sonja
Bunt, Jens
Jager, Natalie
Kleinheinz, Kortine
Erkek, Serap
Weber, Ursula D.
Bartholomae, Cynthia C.
von Kalle, Christof
Lawerenz, Chris
Eils, Jurgen
Koster, Jan
Versteeg, Rogier
Milde, Till
Witt, Olaf
Schmidt, Sabine
Wolf, Stephan
Pietsch, Torsten
Rutkowski, Stefan
Scheurlen, Wolfram
Taylor, Michael D.
Brors, Benedikt
Felsberg, Jorg
Reifenberger, Guido
Borkhardt, Arndt
Lehrach, Hans
Wechsler-Reya, Robert J.
Eils, Roland
Yaspo, Marie-Laure
Landgraf, Pablo
Korshunov, Andrey
Zapatka, Marc
Radlwimmer, Bernhard
Pfister, Stefan M.
Lichter, Peter
Title Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing
Journal name Nature   Check publisher's open access policy
ISSN 1476-4687
Publication date 2014-06-26
Year available 2014
Sub-type Article (original research)
DOI 10.1038/nature13268
Open Access Status
Volume 510
Issue 7506
Start page 537
End page 541
Total pages 5
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2015
Language eng
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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2015 Collection
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Citation counts: TR Web of Science Citation Count  Cited 67 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 66 times in Scopus Article | Citations
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