Active medulloblastoma enhancers reveal subgroup-specific cellular origins

Charles Y. Lin, Serap Erkek, Yiai Tong, Linlin Yin, Alexander J. Federation, Marc Zapatka, Parthiv Haldipur, Daisuke Kawauchi, Thomas Risch, Hans-Jörg Warnatz, Barbara C. Worst, Bensheng Ju, Brent A. Orr, Rhamy Zeid, Donald R. Polaski, Maia Segura-Wang, Sebastian M. Waszak, David T. W. Jones, Marcel Kool, Volker Hovestadt, Ivo Buchhalter, Laura Sieber, Pascal Johann, Lukas Chavez, Stefan Gröschel, Marina Ryzhova, Andrey Korshunov, Wenbiao Chen, Victor V. Chizhikov, Kathleen J. Millen, Vyacheslav Amstislavskiy, Hans Lehrach, Marie-Laure Yaspo, Roland Eils, Peter Lichter, Jan O. Korbel, Stefan M. Pfister (), James E. Bradner () and Paul A. Northcott ()
Additional contact information
Charles Y. Lin: Medical Oncology, Dana Farber Cancer Institute (DFCI)
Serap Erkek: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Yiai Tong: Developmental Neurobiology, St Jude Children’s Research Hospital
Linlin Yin: Vanderbilt University School of Medicine
Alexander J. Federation: Medical Oncology, Dana Farber Cancer Institute (DFCI)
Marc Zapatka: German Cancer Research Center (DKFZ)
Parthiv Haldipur: Center for Integrative Brain Research, Seattle Children’s Research Institute
Daisuke Kawauchi: German Cancer Research Center (DKFZ)
Thomas Risch: Max Planck Institute for Molecular Genetics
Hans-Jörg Warnatz: Max Planck Institute for Molecular Genetics
Barbara C. Worst: German Cancer Research Center (DKFZ)
Bensheng Ju: St Jude Children’s Research Hospital
Brent A. Orr: St Jude Children’s Research Hospital
Rhamy Zeid: Medical Oncology, Dana Farber Cancer Institute (DFCI)
Donald R. Polaski: Medical Oncology, Dana Farber Cancer Institute (DFCI)
Maia Segura-Wang: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Sebastian M. Waszak: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
David T. W. Jones: German Cancer Research Center (DKFZ)
Marcel Kool: German Cancer Research Center (DKFZ)
Volker Hovestadt: German Cancer Research Center (DKFZ)
Ivo Buchhalter: German Cancer Research Center (DKFZ)
Laura Sieber: German Cancer Research Center (DKFZ)
Pascal Johann: German Cancer Research Center (DKFZ)
Lukas Chavez: German Cancer Research Center (DKFZ)
Stefan Gröschel: NCT Heidelberg
Marina Ryzhova: NN Burdenko Neurosurgical Institute
Andrey Korshunov: German Cancer Consortium (DKTK)
Wenbiao Chen: Vanderbilt University School of Medicine
Victor V. Chizhikov: University of Tennessee Health Sciences Center
Kathleen J. Millen: Center for Integrative Brain Research, Seattle Children’s Research Institute
Vyacheslav Amstislavskiy: Max Planck Institute for Molecular Genetics
Hans Lehrach: Max Planck Institute for Molecular Genetics
Marie-Laure Yaspo: Max Planck Institute for Molecular Genetics
Roland Eils: German Cancer Research Center (DKFZ)
Peter Lichter: German Cancer Research Center (DKFZ)
Jan O. Korbel: Genome Biology Unit, European Molecular Biology Laboratory (EMBL)
Stefan M. Pfister: German Cancer Research Center (DKFZ)
James E. Bradner: Medical Oncology, Dana Farber Cancer Institute (DFCI)
Paul A. Northcott: German Cancer Research Center (DKFZ)

Nature, 2016, vol. 530, issue 7588, 57-62

Abstract: Abstract Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.

Date: 2016
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DOI: 10.1038/nature16546

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