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Nature. 2016 Feb 4;530(7588):57-62. doi: 10.1038/nature16546. Epub 2016 Jan 27.

Active medulloblastoma enhancers reveal subgroup-specific cellular origins.

Author information

1
Medical Oncology, Dana Farber Cancer Institute (DFCI), Boston, Massachusetts 02215, USA.
2
Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
3
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
4
Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
5
Department of Molecular Physiology &Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA.
6
Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
7
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98105, USA.
8
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
9
Department of Bone Marrow Transplantation &Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
10
Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
11
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
12
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
13
Department of Translational Oncology, NCT Heidelberg, 69120 Heidelberg, Germany.
14
Department of Neuropathology, NN Burdenko Neurosurgical Institute, 125047 Moscow, Russia.
15
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, 69120 Heidelberg, Germany.
16
Department of Anatomy and Neurobiology, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163, USA.
17
Department of Pediatrics, Genetics Division, University of Washington, Seattle, Washington 98195, USA.
18
Institute of Pharmacy and Molecular Biotechnology and BioQuant, University of Heidelberg, 69117 Heidelberg, Germany.
19
Department of Pediatrics, University of Heidelberg, 69117 Heidelberg, Germany.

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.

PMID:
26814967
PMCID:
PMC5168934
DOI:
10.1038/nature16546
[Indexed for MEDLINE]
Free PMC Article

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