Enhancer landscape of meningioma [ChIP-seq]

Meningiomas are the most common primary intracranial tumor. However, surgical resection and radiation frequently fail to eliminate high grade tumors, leading to significant morbidity and mortality. Predicting which tumors will recur rapidly is critical to effective treatment strategies. To address the prognostic challenges and dearth of therapeutic targets, we interrogated the enhancer landscape of a diverse cohort of meningiomas. Enhancers robustly stratified meningiomas into three biologically distinct groups and identified a subset of tumors with a poor prognosis, independent of histological grading. Integrating enhancer networks with transcriptional profiles revealed unique lineage transcriptional regulators associated with each subgroup. A strong hormonal epidemiologic association is well-characterized in meningiomas, but mechanistic insight remains lacking. We identified differential hormonal regulators that stratified between subgroups, and implicated progesterone receptor in maintaining the super enhancer network of a subset of tumors. Super enhancers marked critical and druggable dependencies across a panel of meningioma models. Overall design: 33 samples from snap frozen meningioma tissue and 3 arachnoid granulation models were analyzed with H3K27ac ChIP-seq with matching input sequencing. 13 samples have matched RNA-seq.脑膜瘤 (Meningiomas) 是最常见的原发性颅内肿瘤。然而，手术切除与放射治疗往往无法彻底清除高级别肿瘤，进而导致较高的致残率与死亡率。精准预测肿瘤的快速复发风险，对于制定高效的临床治疗策略至关重要。 为解决脑膜瘤预后评估难题与治疗靶点匮乏的现状，本研究对多队列脑膜瘤的增强子图谱 (enhancer landscape) 进行了系统解析。研究发现，增强子可稳定将脑膜瘤划分为3个生物学特性迥异的组别，并鉴定出一类预后不良的肿瘤亚群，该分类结果独立于组织学分级。将增强子网络与转录谱整合分析后，本研究揭示了与每个亚群相关的独特谱系特异性转录调控因子。 脑膜瘤与激素相关的流行病学关联已被充分阐明，但相关机制层面的认知仍存在空白。本研究鉴定出在各亚组间存在表达差异的激素调控因子，并证实孕激素受体 (progesterone receptor) 参与维持某一类肿瘤亚群的超级增强子 (super enhancer) 网络。此外，超级增强子可标记一组脑膜瘤模型中具有临床可靶向性的关键依赖通路。 实验整体设计：本研究对33份速冻脑膜瘤组织样本与3株蛛网膜颗粒模型样本开展了组蛋白H3赖氨酸27乙酰化染色质免疫共沉淀测序 (H3K27ac ChIP-seq)，并设置匹配的输入对照测序；其中13份样本配有匹配的转录组测序 (RNA-seq) 数据。