Abstract
Super-enhancer–regulated transcription factors give insight into cell of origin of medulloblastoma subtypes.
Major finding: Super-enhancer–regulated transcription factors give insight into cell of origin of medulloblastoma subtypes.
Approach: H3K27ac and BRD4 ChIP-seq with DNA methylation and transcriptome data identify active enhancers.
Impact: Core regulatory circuitry mapping aids in the understanding and treatment of medulloblastoma.
Medulloblastomas can be separated into four distinct molecular subtypes: WNT, SHH, Group 3, and Group 4. While the differences between subtypes can be partially explained by known mutations and differences in signaling, subtype-specific epigenetic programs have not been well characterized. Lin, Erkek, and colleagues performed chromatin immunoprecipitation sequencing (ChIP-seq) for acetylated histone 3 lysine 27 (H3K27ac) and bromodomain containing 4 (BRD4) to identify active enhancers in primary medulloblastoma tumors and cell lines. The ChIP-seq data was compared with DNA methylation and transcriptome data to identify 78,516 active medulloblastoma enhancers, 20,406 of which were differentially active among the four subtypes. The enhancers were assigned to the genes they regulate, which revealed diversity in differential enhancer-promoter interactions and potential subtype-specific dependencies. TGFβ emerged as an important oncogenic driver in Group 3, and a number of subtype-specific super-enhancers were also identified, including ALK in the WNT subtype, SMO and NTRK3 in SHH, LMO1, LMO2, and MYC in Group 3, and ETV4 and PAX5 in Group 4, indicating that differential active super-enhancers distinguished the different subgroups. The subtype-specific super-enhancers were validated in vivo using transposon-mediated zebrafish reporter assays, which resulted in a 45% validation rate and identified a zebrafish hindbrain-specific MYC super-enhancer that was active in WNT and Group 3 medulloblastoma. Furthermore, computational analysis of super-enhancer–regulated transcription factors identified medulloblastoma subtype-specific regulatory networks, including LMX1A as a master regulator of Group 4 and cerebellar upper rhombic lip transcriptional programming, suggesting a potential cell-of-origin for these tumors. Taken together, this study identified a number of active enhancers and super-enhancers specific to medulloblastoma subtypes, which provide insights into inter-subgroup heterogeneity in cis-regulatory elements and putative cells-of-origin.
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