Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
Department of Surgery, Columbia University Medical Center, New York, NY, USA.
Nat Commun. 2024 Apr 30;15(1):3635. doi: 10.1038/s41467-024-47943-9.
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.
尽管颅内肿瘤的肿瘤内异质性已经得到证实，但在细胞类型水平上的表观基因组改变在很大程度上仍未得到解决。为了确定儿童中枢神经系统肿瘤中胞嘧啶修饰的细胞类型特异性改变，我们利用一种多组学方法，将批量 DNA 胞嘧啶修饰数据（甲基化和羟甲基化）与批量和单细胞 RNA 测序数据相结合。我们证明，当考虑到肿瘤细胞类型组成时，肿瘤中显著差异修饰的胞嘧啶数量大大减少。在肿瘤的祖细胞样细胞类型中，我们发现大量差异 Cytosine-phosphate-Guanine 位点羟甲基化而不是甲基化。具有差异羟甲基化的基因，如组蛋白去乙酰化酶 4 和胰岛素样生长因子 1 受体，与肿瘤中基因表达的细胞类型特异性变化相关。我们的研究结果强调了祖细胞样细胞类型中表观基因组改变的重要性及其在儿童中枢神经系统肿瘤中细胞类型特异性转录调控中的作用。
