Topography of transcriptionally active chromatin in glioblastoma

Molecular profiling of the most aggressive brain tumor glioblastoma (GBM) on the basis of gene expression, DNA methylation, and genomic variations advances both cancer research and clinical diagnosis. The enhancer architectures and regulatory circuitries governing tumor-intrinsic transcriptional diversity and subtype identity are still elusive. Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across 95 GBM biopsies, 12 normal brain tissues, and 38 cell line counterparts. Analyses of differentially regulated enhancers and super-enhancers uncovered previously unrecognized layers of intertumor heterogeneity. Integrative analysis of variant enhancer loci and transcriptome identified topographies of transcriptional enhancers and core regulatory circuitries in four molecular subtypes of primary tumors: AC1-mesenchymal, AC1-classical, AC2-proneural, and AC3-proneural. Moreover, this study reveals core oncogenic dependency on super-enhancer-driven transcriptional factors, long noncoding RNAs, and druggable targets in GBM. Through profiling of transcriptional enhancers, we provide clinically relevant insights into molecular classification, pathogenesis, and therapeutic intervention of GBM.

Automated summary

This study investigates the role of enhancer landscapes in governing transcriptional diversity and subtype identity in GBM, uncovering previously unrecognized layers of intertumor heterogeneity. The research also reveals the topographies of transcriptional enhancers and core regulatory circuitries in four molecular subtypes of primary tumors, as well as the core oncogenic dependency on super-enhancer-driven factors in GBM. The findings provide insights into molecular classification, pathogenesis, and therapeutic interventions for GBM through profiling of transcriptional enhancers.