Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

Volker Hovestadt, David T.W. Jones, Simone Picelli, Wei Wang, Marcel Kool, Paul A. Northcott, Marc Sultan, Katharina Stachurski, Marina Ryzhova, Hans Jörg Warnatz, Meryem Ralser, Sonja Brun, Jens Bunt, Natalie Jäger, Kortine Kleinheinz, Serap Erkek, Ursula D. Weber, Cynthia C. Bartholomae, Christof Von Kalle, Chris LawerenzJürgen Eils, Jan Koster, Rogier Versteeg, Till Milde, Olaf Witt, Sabine Schmidt, Stephan Wolf, Torsten Pietsch, Stefan Rutkowski, Wolfram Scheurlen, Michael D. Taylor, Benedikt Brors, Jörg Felsberg, Guido Reifenberger, Arndt Borkhardt, Hans Lehrach, Robert J. Wechsler-Reya, Roland Eils, Marie Laure Yaspo, Pablo Landgraf, Andrey Korshunov, Marc Zapatka, Bernhard Radlwimmer, Stefan M. Pfister, Peter Lichter

Research output: Contribution to journalArticlepeer-review

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. © 2014 Macmillan Publishers Limited.
Original languageEnglish
Pages (from-to)537-541
Number of pages5
JournalNature
Volume510
Issue number7506
DOIs
Publication statusPublished - 2014

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