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
N1 - Funding Information:
Acknowledgements We thank the members of the ICGC PedBrain Tumor Project, the German Cancer Research Center (DKFZ) Genomics and Proteomics Core Facility, the European Molecular Biology Laboratory (EMBL) Genomics Core Facility, M. Schick, R.Fischer,M.Bewerunge-Hudler,M.Knopf,R.Kabbe,A.Benner,R.Volckmanand P.van Sluis for technical support and helpful discussion. Active Motif, Inc. is acknowledgedfor ChIP and library preparation. We also thank C. Plass for critical reading of the manuscript. This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and the German Federal Ministry of Education and Research (BMBF, grants #01KU1201A, MedSys #0315416C and NGFNplus #01GS0883). Additional support came from the DKFZ-Heidelberg Center for Personalized Oncology (DKFZ-HIPO), the Dutch Cancer Foundations KWF (2010-4713) and KIKA (M.Ko.), and the German Research Foundation (DFG; grant LA2983/2-1 to P.La.).
PY - 2014
Y1 - 2014
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. © 2014 Macmillan Publishers Limited.
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. © 2014 Macmillan Publishers Limited.
UR - https://www.mendeley.com/catalogue/413b218f-6342-3eca-8847-3b914f9c69fe/
U2 - 10.1038/nature13268
DO - 10.1038/nature13268
M3 - Article
C2 - 24847876
SN - 0028-0836
VL - 510
SP - 537
EP - 541
JO - Nature
JF - Nature
IS - 7506
ER -