Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, 3520E MSRB 1, 1150 W. Medical Center, Ann Arbor, MI, 41804, USA.
Chad Carr Pediatric Tumor Center, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
Acta Neuropathol Commun. 2023 Feb 9;11(1):25. doi: 10.1186/s40478-023-01514-z.
Globally decreased histone 3, lysine 27 tri-methylation (H3K27me3) is a hallmark of H3K27-altered diffuse midline gliomas (DMGs) and group-A posterior fossa ependymomas (PFAs). H3K27-altered DMGs are largely characterized by lysine-to-methionine mutations in histone 3 at position 27 (H3K27M). Most PFAs overexpress EZH inhibitory protein (EZHIP), which possesses a region of similarity to the mutant H3K27M. Both H3K27M and EZHIP inhibit the function of the polycomb repressive complex 2 (PRC2) responsible for H3K27me3 deposition. These tumors often arise in neighboring regions of the brainstem and posterior fossa. In rare cases PFAs harbor H3K27M mutations, and DMGs overexpress EZHIP. These findings together raise the possibility that certain cell populations in the developing hindbrain/posterior fossa are especially sensitive to modulation of H3K27me3 states. We identified shared molecular features by comparing genomic, bulk transcriptomic, chromatin-based profiles, and single-cell RNA-sequencing (scRNA-seq) data from the two tumor classes. Our approach demonstrated that 1q gain, a key biomarker in PFAs, is prognostic in H3.1K27M, but not H3.3K27M gliomas. Conversely, Activin A Receptor Type 1 (ACVR1), which is associated with mutations in H3.1K27M gliomas, is overexpressed in a subset of PFAs with poor outcome. Despite diffuse H3K27me3 reduction, previous work shows that both tumors maintain genomic H3K27me3 deposition at select sites. We demonstrate heterogeneity in shared patterns of residual H3K27me3 for both tumors that largely segregated with inferred anatomic tumor origins and progenitor populations of tumor cells. In contrast, analysis of genes linked to H3K27 acetylation (H3K27ac)-marked enhancers showed higher expression in astrocytic-like tumor cells. Finally, common H3K27me3-marked genes mapped closely to expression patterns in the human developing hindbrain. Overall, our data demonstrate developmentally relevant molecular similarities between PFAs and H3K27M DMGs and support the overall hypothesis that deregulated mechanisms of hindbrain development are central to the biology of both tumors.
全球性的组蛋白 3、赖氨酸 27 三甲基化（H3K27me3）减少是 H3K27 改变的弥漫中线胶质瘤（DMG）和 A 组后颅窝室管膜瘤（PFAs）的标志。H3K27 改变的 DMG 主要特征是组蛋白 3 第 27 位赖氨酸到蛋氨酸的突变（H3K27M）。大多数 PFAs 过度表达 EZH 抑制蛋白（EZHIP），它具有与突变的 H3K27M 相似的区域。H3K27M 和 EZHIP 都抑制了负责 H3K27me3 沉积的多梳抑制复合物 2（PRC2）的功能。这些肿瘤通常发生在脑干和后颅窝的邻近区域。在罕见情况下，PFAs 携带 H3K27M 突变，而 DMG 过度表达 EZHIP。这些发现共同提出了这样一种可能性，即发育中的后脑/后颅窝中的某些细胞群对 H3K27me3 状态的调节特别敏感。我们通过比较这两种肿瘤类型的基因组、批量转录组、基于染色质的图谱和单细胞 RNA 测序（scRNA-seq）数据，确定了共享的分子特征。我们的方法表明，1q 增益是 PFAs 的一个关键生物标志物，在 H3.1K27M 中具有预后意义，但在 H3.3K27M 神经胶质瘤中则不然。相反，与 H3.1K27M 神经胶质瘤相关的激活素 A 受体类型 1（ACVR1）在预后不良的 PFAs 亚组中过度表达。尽管弥漫性 H3K27me3 减少，但先前的研究表明，这两种肿瘤都在选择部位保持基因组 H3K27me3 沉积。我们证明了两种肿瘤在共享残留 H3K27me3 模式方面存在异质性，这些模式在很大程度上与推断的肿瘤起源和肿瘤细胞祖细胞群体分离。相比之下，分析与 H3K27 乙酰化（H3K27ac）标记增强子相关的基因显示出星形胶质样肿瘤细胞中更高的表达。最后，共同的 H3K27me3 标记基因与人类发育后脑的表达模式密切相关。总的来说，我们的数据表明 PFAs 和 H3K27M DMG 之间存在与发育相关的分子相似性，并支持这样一种总体假设，即后脑发育失调的机制是这两种肿瘤生物学的核心。
