title: Active medulloblastoma enhancers reveal subgroup-specific cellular origins.
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.
authors.affiliation: Medical Oncology, Dana Farber Cancer Institute (DFCI), Boston, Massachusetts 02215, USA.
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.|Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Serap
authors.initials: S
authors.lastname: Erkek
authors.affiliation: Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Yiai
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA.
authors.forename: Linlin
authors.initials: L
authors.lastname: Yin
authors.affiliation: Medical Oncology, Dana Farber Cancer Institute (DFCI), Boston, Massachusetts 02215, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Federation
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98105, USA.
authors.forename: Parthiv
authors.initials: P
authors.lastname: Haldipur
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kawauchi
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Risch
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Warnatz
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Worst
authors.affiliation: Department of Bone Marrow Transplantation &Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Bensheng
authors.initials: B
authors.lastname: Ju
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Orr
authors.affiliation: Medical Oncology, Dana Farber Cancer Institute (DFCI), Boston, Massachusetts 02215, USA.
authors.forename: Rhamy
authors.initials: R
authors.lastname: Zeid
authors.affiliation: Medical Oncology, Dana Farber Cancer Institute (DFCI), Boston, Massachusetts 02215, USA.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Polaski
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
authors.forename: Maia
authors.initials: M
authors.lastname: Segura-Wang
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Waszak
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Buchhalter
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Sieber
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Pascal
authors.initials: P
authors.lastname: Johann
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Chavez
authors.affiliation: Department of Translational Oncology, NCT Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gröschel
authors.affiliation: Department of Neuropathology, NN Burdenko Neurosurgical Institute, 125047 Moscow, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Ryzhova
authors.affiliation: German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, 69120 Heidelberg, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: Department of Molecular Physiology &Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA.
authors.forename: Wenbiao
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163, USA.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Chizhikov
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98105, USA.|Department of Pediatrics, Genetics Division, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Millen
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Amstislavskiy
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Yaspo
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Institute of Pharmacy and Molecular Biotechnology and BioQuant, University of Heidelberg, 69117 Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.|Department of Pediatrics, University of Heidelberg, 69117 Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Medical Oncology, Dana Farber Cancer Institute (DFCI), Boston, Massachusetts 02215, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
mesh_terms: D000818:Animals; D002528:Cerebellar Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000145:classification* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics
chemical_list: D014157:Transcription Factors
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