TY  - JOUR
AU  - Lin, Charles Y
AU  - Erkek, Serap
AU  - Tong, Yiai
AU  - Yin, Linlin
AU  - Federation, Alexander J
AU  - Zapatka, Marc
AU  - Haldipur, Parthiv
AU  - Kawauchi, Daisuke
AU  - Risch, Thomas
AU  - Warnatz, Hans-Jörg
AU  - Worst, Barbara
AU  - Ju, Bensheng
AU  - Orr, Brent A
AU  - Zeid, Rhamy
AU  - Polaski, Donald R
AU  - Segura-Wang, Maia
AU  - Waszak, Sebastian M
AU  - Jones, David
AU  - Kool, Marcel
AU  - Hovestadt, Volker
AU  - Buchhalter, Ivo
AU  - Sieber, Laura
AU  - Johann, Pascal
AU  - Chavez, Lukas
AU  - Gröschel, Stefan
AU  - Ryzhova, Marina
AU  - Korshunov, Andrey
AU  - Chen, Wenbiao
AU  - Chizhikov, Victor V
AU  - Millen, Kathleen J
AU  - Amstislavskiy, Vyacheslav
AU  - Lehrach, Hans
AU  - Yaspo, Marie-Laure
AU  - Eils, Roland
AU  - Lichter, Peter
AU  - Korbel, Jan O
AU  - Pfister, Stefan
AU  - Bradner, James E
AU  - Northcott, Paul A
TI  - Active medulloblastoma enhancers reveal subgroup-specific cellular origins.
JO  - Nature 
VL  - 530
IS  - 7588
SN  - 1476-4687
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2017-05061
SP  - 57 - 62
PY  - 2016
AB  - 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.
KW  - Transcription Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26814967
C2  - pmc:PMC5168934
DO  - DOI:10.1038/nature16546
UR  - https://inrepo02.dkfz.de/record/129056
ER  -