基于透明细胞肾细胞癌不同免疫亚型的系统性染色质可及性分析
Systematic Chromatin Accessibility Analysis Based on Different Immunological Subtypes of Clear Cell Renal Cell Carcinoma.
作者信息
Zhang Shiqiang, Zheng Wenzhong, Jiang Donggen, Xiong Haiyun, Liao Guolong, Yang Xiangwei, Ma He, Li Jun, Qiu Miaojuan, Li Binbin, Sun Chunhui, Zhao Jing, Wang Liling, Pang Jun
机构信息
Department of Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
Department of Urology, Fujian Medical University Union Hospital, Fuzhou, China.
出版信息
Front Oncol. 2021 Apr 16;11:575425. doi: 10.3389/fonc.2021.575425. eCollection 2021.
BACKGROUND
Recent research of clear cell renal cell carcinoma (ccRCC) is focused on the tumor immune microenvironment (TIME). Chromatin accessibility is critical for regulation of gene expression. However, its role in different immunological subtypes of ccRCC based on immune cell infiltration has not been systematically studied.
METHODS
Five hundred thirty patient data from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) were adopted to estimate immune cell infiltration. Twenty-four types of immune cells were evaluated with single-sample Gene Set Enrichment Analysis (ssGSEA). Patients were divided into two clusters based on immune cell infiltration. Systematic chromatin accessibility analysis was conducted based on the two clusters.
RESULTS
We compared the relative expression of the immune gene signatures among 530 patients of TCGA-KIRC using ssGSEA. Overall survival (OS) analysis revealed 10 types of immune cells were significantly associated with prognosis. Patients were divided into two clusters based on 24 types of immune cell infiltration. Immune cell signals as well as PD-1/PD-L1 signal were higher in cluster 1. Among the two clusters, 2,400 differential peaks were found in TCGA-KIRC Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) data. The distribution of differential peaks and prognosis-related immune cells in 23 chromosomes are essentially the same. There is no peak distribution downstream. The proportion of peaks upstream of the 5' transcription start site decreases, and both sides of binding regions of the TSS 0.1-1 kb becomes smaller. Enrichment analysis of GO and KEGG of these differential peaks showed that they are remarkably related to the immune regulation in tumor microenvironment. Known motifs and motifs were found by linking motif annotations to different peaks. Survival analysis of related motif transcription factors were prognostic. The GSEA enrichment analysis showed that high SP1 expression positively correlates with TGF-beta signaling and inflammatory response, while negatively correlates with TNF-alpha signaling NFKB. High KLF12 expression negatively correlates with interferon gamma response, IL2-STAT5 signaling, TNF-alpha signaling NFKB, IL6-JAK-STAT3 signaling.
CONCLUSION
The abnormality of chromatin accessibility may play an important regulatory role in ccRCC immunity.
背景
肾透明细胞癌（ccRCC）的最新研究聚焦于肿瘤免疫微环境（TIME）。染色质可及性对于基因表达调控至关重要。然而，其在基于免疫细胞浸润的ccRCC不同免疫亚型中的作用尚未得到系统研究。
方法
采用来自癌症基因组图谱肾透明细胞癌（TCGA-KIRC）的530例患者数据来评估免疫细胞浸润。用单样本基因集富集分析（ssGSEA）评估24种免疫细胞。基于免疫细胞浸润将患者分为两个聚类。基于这两个聚类进行系统的染色质可及性分析。
结果
我们使用ssGSEA比较了TCGA-KIRC的530例患者中免疫基因特征的相对表达。总生存（OS）分析显示10种免疫细胞与预后显著相关。基于24种免疫细胞浸润将患者分为两个聚类。聚类1中的免疫细胞信号以及PD-1/PD-L1信号更高。在两个聚类中，利用高通量测序转座酶可及染色质（ATAC-seq）数据在TCGA-KIRC中发现了2400个差异峰。23条染色体上差异峰和预后相关免疫细胞的分布基本相同。下游没有峰分布。5'转录起始位点上游峰的比例降低，TSS 0.1 - 1 kb结合区域两侧变小。这些差异峰的GO和KEGG富集分析表明它们与肿瘤微环境中的免疫调节显著相关。通过将基序注释与不同峰关联发现了已知基序和基序。相关基序转录因子的生存分析具有预后意义。基因集富集分析（GSEA）显示，高SP1表达与TGF-β信号传导和炎症反应呈正相关，而与TNF-α信号传导-NFKB呈负相关。高KLF12表达与干扰素γ反应、IL2-STAT5信号传导、TNF-α信号传导-NFKB、IL6-JAK-STAT3信号传导呈负相关。
结论
染色质可及性异常可能在ccRCC免疫中发挥重要调节作用。
Zotero 插件