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

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. Overall design: ChIP-seq and RNA-seq were performed on GBM samples

本研究通过绘制组蛋白H3赖氨酸27乙酰化（H3K27ac）的沉积图谱，分析了原发性胶质母细胞瘤（GBM）活检组织、正常脑组织及其对应细胞系的活性调控景观。针对差异调控增强子——尤其是胶质母细胞瘤与正常脑组织之间、以及带有配对RNA测序（RNA-seq）数据的胶质母细胞瘤样本之间的超级增强子——开展的分析，揭示了此前未被阐明的致癌核心转录依赖层级与肿瘤间异质性。此外，本研究还验证了胶质母细胞瘤中超级增强子调控的转录因子、长链非编码RNA（lncRNA）以及可药物靶向靶点的关键候选分子的功能相关性。通过转录增强子谱分析，本整合研究为胶质母细胞瘤的分子分型、发病机制以及治疗创新提供了具有临床相关性的见解。实验设计概述：本研究对胶质母细胞瘤样本开展了染色质免疫共沉淀测序（ChIP-seq）与RNA测序（RNA-seq）实验。