Chromatin Accessibility Regulates Gene Expression and Correlates With Tumor-Infiltrating Immune Cells in Gastric Adenocarcinoma

Chenshen Huang,Qi Huang,Zhizhan Ni,Zongqiang Huang,Hong Chen,Bujun Ge,Runzhi Huang

doi:10.3389/fonc.2020.609940

Abstract

BackgroundWe explored key molecules affecting the prognosis of gastric adenocarcinoma (STAD) using co-analysis of chromatin accessibility (ATAC-seq), mRNA expression (RNA-seq), and overall survival.MethodsWe used the assay for transposase-accessible chromatin using sequencing (ATAC-seq) profiles to identify genes with chromatin accessibilities in their promoter regions. The RNA-seq profiles were processed for differentially expressed genes (DEGs) at mRNA level. The DEGs with chromatin accessibilities in promoter regions were further filtered using the Pearson correlation with TP53 expression. After co-analysis, genes were identified for the prognostic value using Kaplan–Meier method, followed by Pearson correlation analysis with significant pathways. For verification, we acquired clinical samples for qPCR and immunohistochemistry (IHC). Multidimensional database validations were performed to prevent the bias introduced by the use of a single database.ResultsWe identified 11,557 DEGs and 57 genes with chromatin accessibilities. The co-analysis of ATAC-seq, RNA-seq, and clinical survival data revealed that interleukin-18 binding protein (IL18BP), with significant chromatin accessibility in its promoter region and differential mRNA expression, might be directly regulated by TP53 and influence STAD prognosis. Further, gene set variation analysis indicated that IL18BP may impact the survival of STAD patients in an immune-related manner. According to the CIBERSORT algorithm and Pearson correlation, the integration of IL18BP and CD4+ T memory cells may play an important role in the prognosis of STAD patients.ConclusionIL18BP, regulated by TP53, may serve as a key molecule affecting STAD prognosis. And the mechanism is proposed to be the interaction between IL18BP and CD4+ T cells.

Highlights

Gastric cancer, a malignant tumor type, is the fifth most common cancer, and the third leading cause of cancer deaths worldwide [1]
We found that IL18BP, regulated by TP53, had significant chromatin accessibilities in the promoter region and was differentially expressed in STAD
The chromatin accessibility landscape of patients with STAD was derived from the ATAC-seq profile of 21 tumor samples from TCGA database

Summary

Introduction

A malignant tumor type, is the fifth most common cancer, and the third leading cause of cancer deaths worldwide [1]. Gastric adenocarcinoma (STAD) is the most common (approximately 95% of all cases) pathological subtype of gastric cancer [2]. The prognosis of patients with advanced STAD remains poor. A better understanding of the key molecules of STAD prognosis through integrated bioinformatics is warranted. TP53 encodes the p53 protein, an important factor in cancer development, and is one of the most frequently mutated genes in STAD. As a transcription factor (TF), mutant p53 had been proposed to be associated with chromatin states [3]. We inferred that p53 might affect STAD prognosis at the epigenetic level. We acquired ATAC-seq profiles and explored the genes that might be directly regulated by p53. We explored key molecules affecting the prognosis of gastric adenocarcinoma (STAD) using co-analysis of chromatin accessibility (ATAC-seq), mRNA expression (RNA-seq), and overall survival

Objectives

Methods

Results

Conclusion