Active medulloblastoma enhancers reveal subgroup-specific cellular origins

By Charles Y. Lin, S. Erkek, Y. Tong, L. Yin, Alexander J. Federation, M. Zapatka, P. Haldipur, D. Kawauchi, T. Risch, H. Warnatz and 29 more. Nature, 2016

360 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a3b549bb2e0a20ee74625dfc59ad7d381a1d09bb

Citations in the corpus

• The whole-genome landscape of medulloblastoma subtypes (2017, neutral): “A role for deregulated TGF β signalling in Group 3 has been suggested in our previous genomic/epigenomic studies 11,32 ; however, functional studies that further substantiate these observations are still lacking.”
• Transcriptional Addiction in Cancer (2017, neutral): “…many different mechanisms (Figure 5A) (Chapuy et al., 2013; Chipumuro et al., 2014; Christensen et al., 2014; Drier et al., 2016; Hnisz et al., 2013; Kennedy et al., 2015; Kwiatkowski et al., 2014; Lin et al., 2016; Loven et al., 2013; Tomazou et al., 2015; Wang et al., 2015; Yang et al., 2015).”