TY  - JOUR
AU  - Gartlgruber, Moritz
AU  - Sharma, Ashwini Kumar
AU  - Quintero, Andrés
AU  - Dreidax, Daniel
AU  - Jansky, Selina
AU  - Park, Young-Gyu
AU  - Kreth, Sina
AU  - Meder, Johanna
AU  - Doncevic, Daria
AU  - Saary, Paul
AU  - Toprak, Umut H.
AU  - Ishaque, Naveed
AU  - Afanasyeva, Elena
AU  - Wecht, Elisa
AU  - Koster, Jan
AU  - Versteeg, Rogier
AU  - Grünewald, Thomas
AU  - Jones, David T. W.
AU  - Pfister, Stefan M.
AU  - Henrich, Kai-Oliver
AU  - van Nes, Johan
AU  - Herrmann, Carl
AU  - Westermann, Frank
TI  - Super enhancers define regulatory subtypes and cell identity in neuroblastoma
JO  - Nature cancer
VL  - 2
SN  - 2662-1347
CY  - London
PB  - Nature Research
M1  - DKFZ-2020-02785
SP  - 114–128
PY  - 2021
N1  - #EA:B087#LA:B087# VOL 2 | JANUARy 2021 | 114–128
AB  - Half of the children diagnosed with neuroblastoma (NB) have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from NB are lacking. Here, using genome-wide H3K27ac profiles across 60 NBs, covering the different clinical and molecular subtypes, we identified four major super-enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups; namely, MYCN-amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk NBs. The fourth subtype, exhibiting mesenchymal characteristics, shared cellular identity with multipotent Schwann cell precursors, was induced by RAS activation and was enriched in relapsed disease. Notably, CCND1, an essential gene in NB, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Overall, this study reveals subtype-specific super-enhancer regulation in NBs.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1038/s43018-020-00145-w
UR  - https://inrepo02.dkfz.de/record/166292
ER  -