Systematic Chromatin Accessibility Analysis Based on Different Immunological Subtypes of Clear Cell Renal Cell Carcinoma

Shiqiang Zhang; Wenzhong Zheng; Donggen Jiang; Haiyun Xiong; Guolong Liao; Xiangwei Yang; He Ma; Jun Li; Miaojuan Qiu; Binbin Li; Chunhui Sun; Jing Zhao; Liling Wang; Jun Pang

doi:10.3389/fonc.2021.575425

Systematic Chromatin Accessibility Analysis Based on Different Immunological Subtypes of Clear Cell Renal Cell Carcinoma

Front Oncol. 2021 Apr 16:11:575425. doi: 10.3389/fonc.2021.575425. eCollection 2021.

Authors

Shiqiang Zhang¹, Wenzhong Zheng², Donggen Jiang¹, Haiyun Xiong¹, Guolong Liao¹, Xiangwei Yang¹, He Ma¹, Jun Li¹, Miaojuan Qiu³, Binbin Li³, Chunhui Sun³, Jing Zhao³, Liling Wang⁴, Jun Pang¹

Affiliations

¹ Department of Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
² Department of Urology, Fujian Medical University Union Hospital, Fuzhou, China.
³ Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
⁴ Maternal and Child Health Research Institute, Baoan Women's and Children's Hospital, Jinan University, Shenzhen, China.

Abstract

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 de novo 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 via NFKB. High KLF12 expression negatively correlates with interferon gamma response, IL2-STAT5 signaling, TNF-alpha signaling via NFKB, IL6-JAK-STAT3 signaling.

Conclusion: The abnormality of chromatin accessibility may play an important regulatory role in ccRCC immunity.

Keywords: chromatin accessibility; clear cell renal cell carcinoma; immune cell infiltration; the tumor microenvironment; transcription factor.