Active medulloblastoma enhancers reveal subgroup-specific cellular origins

Abstract

Summary 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. Using H3K27ac and BRD4 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 are responsible for subgroup divergence and implicate 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.

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

“…Analogous to Lin et al 8 ., H3K27ac peak finding was performed using MACS1.4 with default parameter settings except setting a P -value threshold of 1 × 10 −9 . Peak finding for each ependymoma was performed separately and as a control background for each H3K27ac ChIP-seq sample, its matched genomic DNA was used where available.…”

“…Subgroup specific transcription factor regulatory networks were constructed as previously described with only few amendments 8,25 . H3K27ac data of the samples within the same subgroup were combined.…”

“…These differences are captured by the characterization of variant enhancer and SE loci, in addition to the reverse engineering of core transcriptional regulatory circuitries in tumours. Finally, as shown in ependymoma and other tumours, knowledge of core and subgroup-specific TFs reveals a molecular basis for the oncogenic transcriptional programs of cancer, and provides insight into lineage programs that persist in the neoplastic state 8 .…”

“…While many significant TF motifs were enriched across shared enhancers of ependymoma, such as FOSL1, FOSL2, SOX9, RFX2, and SOX2 (Fig. 3a, Supplementary Table 18), we sought to identify the principal TFs of ependymoma that govern ependymoma cell identity across subgroups using core regulatory circuitry analysis 8,14 (Fig. 3b, Extended Data Fig.…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…50 For example, H3K27ac-and BRD4-DNA interactions have been found to strongly correlate at active medulloblastoma enhancer loci. 51 Interestingly, BRD4 inhibition has been reported to decrease cell viability in medulloblastoma cell lines and xenografts. 52,53 In addition to these epigenetic changes occurring in medulloblastoma, reprogramming of DNA methylation patterns in these tumors shows focal regions of low methylation linked to transcription-factor-binding sites, shedding light on differential transcriptional networks between subgroups.…”