Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

TY - JOUR

T1 - Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

AU - Hovestadt, Volker

AU - Jones, David T W

AU - Picelli, Simone

AU - Wang, Wei

AU - Kool, Marcel

AU - Northcott, Paul A

AU - Sultan, Marc

AU - Stachurski, Katharina

AU - Ryzhova, Marina

AU - Warnatz, Hans-Jörg

AU - Ralser, Meryem

AU - Brun, Sonja

AU - Bunt, Jens

AU - Jäger, Natalie

AU - Kleinheinz, Kortine

AU - Erkek, Serap

AU - Weber, Ursula D

AU - Bartholomae, Cynthia C

AU - von Kalle, Christof

AU - Lawerenz, Chris

AU - Eils, Jürgen

AU - Koster, Jan

AU - Versteeg, Rogier

AU - Milde, Till

AU - Witt, Olaf

AU - Schmidt, Sabine

AU - Wolf, Stephan

AU - Pietsch, Torsten

AU - Rutkowski, Stefan

AU - Scheurlen, Wolfram

AU - Taylor, Michael D

AU - Brors, Benedikt

AU - Felsberg, Jörg

AU - Reifenberger, Guido

AU - Borkhardt, Arndt

AU - Lehrach, Hans

AU - Wechsler-Reya, Robert J

AU - Eils, Roland

AU - Yaspo, Marie-Laure

AU - Landgraf, Pablo

AU - Korshunov, Andrey

AU - Zapatka, Marc

AU - Radlwimmer, Bernhard

AU - Pfister, Stefan M

AU - Lichter, Peter

PY - 2014/5/18

Y1 - 2014/5/18

N2 - 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.

AB - 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.

U2 - 10.1038/nature13268

DO - 10.1038/nature13268

M3 - SCORING: Journal article

C2 - 24847876

VL - 510

SP - 537

EP - 541

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7506

ER -