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: 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, Paul A Northcott
• Journal: Nature (Nature) Vol. 530 Issue 7588 Pg. 57-62 (Feb 04 2016) ISSN: 1476-4687 [Electronic] England
• PMID: 26814967 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Transcription Factors

Topics

• Animals
• Cerebellar Neoplasms (classification, genetics, pathology)
• Enhancer Elements, Genetic (genetics)
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• Gene Regulatory Networks (genetics)
• Genes, Neoplasm (genetics)
• Genes, Reporter (genetics)
• Humans
• Male
• Medulloblastoma (classification, genetics, pathology)
• Mice
• Reproducibility of Results
• Transcription Factors (metabolism)
• Zebrafish (genetics)