Although intratumoral heterogeneity has been established in pediatric central nervous system tumors, epigenomic alterations at the cell type level have largely remained unresolved. To identify cell type-specific alterations to cytosine modifications in pediatric central nervous system tumors, we utilize a multi-omic approach that integrated bulk DNA cytosine modification data (methylation and hydroxymethylation) with both bulk and single-cell RNA-sequencing data. We demonstrate a large reduction in the scope of significantly differentially modified cytosines in tumors when accounting for tumor cell type composition. In the progenitor-like cell types of tumors, we identify a preponderance differential Cytosine-phosphate-Guanine site hydroxymethylation rather than methylation. Genes with differential hydroxymethylation, like histone deacetylase 4 and insulin-like growth factor 1 receptor, are associated with cell type-specific changes in gene expression in tumors. Our results highlight the importance of epigenomic alterations in the progenitor-like cell types and its role in cell type-specific transcriptional regulation in pediatric central nervous system tumors.

尽管在儿科中枢神经系统肿瘤中已经建立了瘤内异质性，但细胞类型水平的表观基因组改变在很大程度上仍未得到解决。为了识别儿科中枢神经系统肿瘤中胞嘧啶修饰的细胞类型特异性改变，我们利用多组学方法，将大量 DNA 胞嘧啶修饰数据（甲基化和羟甲基化）与大量和单细胞 RNA 测序数据相整合。我们证明，当考虑肿瘤细胞类型组成时，肿瘤中显着差异修饰的胞嘧啶的范围大大减少。在肿瘤的类祖细胞类型中，我们发现了优势差异胞嘧啶-磷酸-鸟嘌呤位点羟甲基化而不是甲基化。具有差异羟甲基化的基因，如组蛋白脱乙酰酶 4 和胰岛素样生长因子 1 受体，与肿瘤中细胞类型特异性的基因表达变化相关。我们的结果强调了类祖细胞类型中表观基因组改变的重要性及其在儿科中枢神经系统肿瘤细胞类型特异性转录调节中的作用。