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Enhancer profiling of glioblastoma uncovers core oncogenic dependency and therapeutic opportunity [RNA-seq]

ABSTRACT: Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across primary GBM biopsies, normal brain tissues, and cell line counterparts. Analysis of differentially regulated enhancers, especially super-enhancers between GBM and normal brain tissues, as well as among GBM samples with matched RNA-sequencing data, uncovered unrecognized layers of oncogenic core transcriptional dependency and inter-tumor heterogeneity. Moreover, we demonstrate the functional relevance of leading candidates of super-enhancer-driven transcriptional factors, long non-coding RNAs, and druggable targets in GBM. Through profiling of transcriptional enhancers, our integrative study provides clinically relevant insights into GBM molecular classification, pathogenesis, and therapeutic innovations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE145645 | GEO | 2021/05/05

REPOSITORIES: GEO

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Project description:<p>Non-coding elements in our genomes that play critical roles in complex disease are frequently marked by highly unstable RNA species. Sequencing nascent RNAs attached to an actively transcribing RNA polymerase complex can identify unstable RNAs, including those templated from gene-distal enhancers (eRNAs). However, nascent RNA sequencing techniques remain challenging to apply in some cell lines and especially to intact tissues, limiting broad applications in fields such as cancer genomics and personalized medicine. Here we report the development of chromatin run-on and sequencing (ChRO-seq), a novel run-on technology that maps the location of RNA polymerase using virtually any frozen tissue sample, including samples with degraded RNA that are intractable to conventional RNA-seq. We used ChRO-seq to develop the first maps of nascent transcription in 23 human glioblastoma (GBM) brain tumors and patient derived xenografts. Remarkably, >90,000 distal enhancers discovered using the signature of eRNA biogenesis within primary GBMs closely resemble those found in the normal human brain, and diverge substantially from GBM cell models. Despite extensive overall similarity, 12% of enhancers in each GBM distinguish normal and malignant brain tissue. These enhancers drive regulatory programs similar to the developing nervous system and are enriched for transcription factor binding sites that specify a stem-like cell fate. These results demonstrate that GBMs largely retain the enhancer landscape associated with their tissue of origin, but selectively adopt regulatory programs that are responsible for driving stem-like cell properties. We also identified enhancers and their associated transcription factors that regulate genes characteristic of each known GBM subtype, and discovered a core group of transcription factors that control the expression of genes associated with clinical outcomes. This study uncovers new insights into the molecular etiology of GBM and introduces ChRO-seq which can now be used to map regulatory programs contributing to a variety of complex diseases.</p>

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Enhancer profiling of glioblastoma uncovers core oncogenic dependency and therapeutic opportunity [RNA-seq]

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