ZFIN ID: ZDB-PUB-160226-24
Active medulloblastoma enhancers reveal subgroup-specific cellular origins
Lin, C.Y., Erkek, S., Tong, Y., Yin, L., Federation, A.J., Zapatka, M., Haldipur, P., Kawauchi, D., Risch, T., Warnatz, H.J., Worst, B.C., Ju, B., Orr, B.A., Zeid, R., Polaski, D.R., Segura-Wang, M., Waszak, S.M., Jones, D.T., Kool, M., Hovestadt, V., Buchhalter, I., Sieber, L., Johann, P., Chavez, L., Gröschel, S., Ryzhova, M., Korshunov, A., Chen, W., Chizhikov, V.V., Millen, K.J., Amstislavskiy, V., Lehrach, H., Yaspo, M.L., Eils, R., Lichter, P., Korbel, J.O., Pfister, S.M., Bradner, J.E., Northcott, P.A.
Date: 2016
Source: Nature   530: 57-62 (Journal)
Registered Authors: Chen, Wenbiao, Ju, Bensheng, Lehrach, Hans
Keywords: Cancer genomics, CNS cancer, Paediatric cancer, Gene regulatory networks, Chromatin immunoprecipitation
MeSH Terms:
  • Animals
  • Cerebellar Neoplasms/classification
  • Cerebellar Neoplasms/genetics*
  • Cerebellar Neoplasms/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*
  • Medulloblastoma/genetics
  • Medulloblastoma/pathology*
  • Mice
  • Reproducibility of Results
  • Transcription Factors/metabolism*
  • Zebrafish/genetics
PubMed: 26814967 Full text @ Nature
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.