促颗粒型星形细胞瘤去甲基化和转录图谱将 bZIP 转录因子与免疫反应联系起来。
Pilocytic astrocytoma demethylation and transcriptional landscapes link bZIP transcription factors to immune response.
机构信息
Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
Hopp Children's Cancer Center Heidelberg, Heidelberg, Germany.
出版信息
Neuro Oncol. 2020 Sep 29;22(9):1327-1338. doi: 10.1093/neuonc/noaa035.
BACKGROUND
Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. While genome and transcriptome landscapes are well studied, data of the complete methylome, tumor cell composition, and immune infiltration are scarce.
METHODS
We generated whole genome bisulfite sequence (WGBS) data of 9 PAs and 16 control samples and integrated available 154 PA and 57 control methylation array data. RNA sequence data of 49 PAs and 11 control samples as well as gene expression arrays of 248 PAs and 28 controls were used to assess transcriptional activity.
RESULTS
DNA-methylation patterns of partially methylated domains suggested high stability of the methylomes during tumorigenesis. Comparing tumor and control tissues of infra- and supratentorial location using methylation arrays revealed a site specific pattern. Analysis of WGBS data revealed 9381 significantly differentially methylated regions (DMRs) in PA versus control tissue. Enhancers and transcription factor (TF) motifs of five distinct TF families were found to be enriched in DMRs. Methylation together with gene expression data-based in silico tissue deconvolution analysis indicated a striking variation in the immune cell infiltration in PA. A TF network analysis showed a regulatory relation between basic leucine zipper (bZIP) transcription factors and genes involved in immune-related processes.
CONCLUSION
We provide evidence for a link of focal methylation differences and differential gene expression to immune infiltration.
背景
毛细胞型星形细胞瘤（PA）是最常见的儿童脑肿瘤。虽然基因组和转录组图谱已有深入研究，但完整甲基组、肿瘤细胞组成和免疫浸润的数据仍然匮乏。
方法
我们生成了 9 个 PA 和 16 个对照样本的全基因组亚硫酸氢盐测序（WGBS）数据，并整合了现有的 154 个 PA 和 57 个对照甲基化阵列数据。我们还使用了 49 个 PA 和 11 个对照样本的 RNA 序列数据以及 248 个 PA 和 28 个对照的基因表达阵列来评估转录活性。
结果
部分甲基化区域的 DNA 甲基化模式表明甲基组在肿瘤发生过程中具有高度稳定性。使用甲基化阵列比较幕上和幕下肿瘤和对照组织，揭示了一种特定的位置模式。WGBS 数据分析显示，PA 与对照组织之间存在 9381 个显著差异甲基化区域（DMRs）。五个不同 TF 家族的增强子和转录因子（TF）基序被发现富集在 DMRs 中。基于甲基化和基因表达数据的计算组织去卷积分析表明，PA 中的免疫细胞浸润存在显著差异。TF 网络分析表明，碱性亮氨酸拉链（bZIP）转录因子与免疫相关过程中涉及的基因之间存在调控关系。
结论
我们提供了证据表明，局部甲基化差异和差异基因表达与免疫浸润有关。
Zotero 插件