Recent single-cell transcriptomic studies report that IDH-mutant gliomas share a common hierarchy of cellular phenotypes, independent of genetic subtype. However, the genetic differences between IDH-mutant glioma subtypes are prognostic, predictive of response to chemotherapy, and correlate with distinct tumor microenvironments. To reconcile these findings, we profile 22 human IDH-mutant gliomas using scATAC-seq and scRNA-seq. We determine the cell-type-specific differences in transcription factor expression and associated regulatory grammars between IDH-mutant glioma subtypes. We find that while IDH-mutant gliomas do share a common distribution of cell types, there are significant differences in the expression and targeting of transcription factors that regulate glial identity and cytokine elaboration. We knock out the chromatin remodeler ATRX, which suffers loss-of-function alterations in most IDH-mutant astrocytomas, in an IDH-mutant immunocompetent intracranial murine model. We find that both human ATRX-mutant gliomas and murine ATRX-knockout gliomas are more heavily infiltrated by immunosuppressive monocytic-lineage cells derived from circulation than ATRX-intact gliomas, in an IDH-mutant background. ATRX knockout in murine glioma recapitulates gene expression and open chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. Through single-cell cleavage under targets and tagmentation assays and meta-analysis of public data, we show that ATRX loss leads to a global depletion in CCCTC-binding factor association with DNA, gene dysregulation along associated chromatin loops, and protection from therapy-induced senescence. These studies explain how IDH-mutant gliomas from different subtypes maintain distinct phenotypes and tumor microenvironments despite a common lineage hierarchy.

中文翻译：

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ATRX 调节 IDH 突变神经胶质瘤中的神经胶质特性和肿瘤微环境

最近的单细胞转录组学研究报告说，IDH 突变型胶质瘤具有共同的细胞表型层次结构，与遗传亚型无关。然而，IDH 突变型胶质瘤亚型之间的遗传差异是预后性的，可预测对化疗的反应，并与不同的肿瘤微环境相关。为了协调这些发现，我们使用 scATAC-seq 和 scRNA-seq 分析了 22 个人类 IDH 突变神经胶质瘤。我们确定了 IDH 突变神经胶质瘤亚型之间转录因子表达和相关调控语法的细胞类型特异性差异。我们发现，虽然 IDH 突变型胶质瘤确实具有共同的细胞类型分布，但调节胶质细胞特性和细胞因子加工的转录因子的表达和靶向存在显着差异。我们敲除染色质重塑剂 ATRX，在 IDH 突变免疫活性颅内鼠模型中，大多数 IDH 突变星形细胞瘤的功能丧失改变。我们发现，在 IDH 突变背景下，人类 ATRX 突变神经胶质瘤和鼠 ATRX 敲除神经胶质瘤比来自循环的免疫抑制性单核细胞系细胞浸润得更多。小鼠神经胶质瘤中的 ATRX 敲除概括了人类 ATRX 突变星形细胞瘤特有的基因表达和开放染色质特征，包括星形细胞谱系和免疫细胞趋化性的驱动因素。通过靶标下的单细胞切割和标记分析以及对公共数据的荟萃分析，我们表明 ATRX 丢失导致与 DNA 相关的 CCCTC 结合因子的全球消耗，沿相关染色质环的基因失调，和保护免受治疗引起的衰老。这些研究解释了来自不同亚型的 IDH 突变神经胶质瘤如何保持不同的表型和肿瘤微环境，尽管有共同的谱系层次结构。