RAGE-mediated functional DNA methylated modification contributes to cigarette smoke-induced airway inflammation in mice.

Ping Li,Lei Chen,Jun Chen,Mei Chen,Yongchun Shen,Tao Wang

doi:10.1042/bsr20210308

Abstract

Our previous study indicated knockout of receptor for advanced glycation end-products (RAGE) significantly attenuated cigarette smoke (CS)-induced airway inflammation in mice. In the present study, we aim to further detect the mediatory effects of RAGE in DNA methylated modification in CS-induced airway inflammation. Lung tissues from the CS-exposed mouse model of airway inflammation were collected for profiling of DNA methylation by liquid hybridization capture-based bisulfite sequencing, which were used for conjoint analysis with our previous data of gene expression by cDNA microarray to identify functional methylated genes, as well as hub genes selected by protein–protein interaction (PPI) network analysis, and functional enrichment analyses were then performed. After RAGE knockout, 90 genes were identified by intersection of the differentially methylated genes and differentially expressed genes. According to the reversed effects of methylation in promoters on gene transcription, 14 genes with functional methylated modification were further identified, among which chemokine (C–X–C motif) ligand 1 (CXCL1), Toll-like receptor 6 (TLR6) and oncostatin M (OSM) with hypomethylation in promoters, were selected as the hub genes by PPI network analysis. Moreover, functional enrichment analyses showed the 14 functional methylated genes, including the 3 hub genes, were mainly enriched in immune-inflammatory responses, especially mitogen-activated protein kinase, tumor necrosis factor, TLRs, interleukin (IL)-6 and IL-17 pathways. The present study suggests that RAGE mediates functional DNA methylated modification in a cluster of 14 targeted genes, particularly hypomethylation in promoters of CXCL1, TLR6 and OSM, which might significantly contribute to CS-induced airway inflammation via a network of signaling pathways.

Highlights

Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation that are associated with persistent airway inflammation induced by cigarette smoke (CS), a major causative factor for COPD [1].Receptor for advanced glycation end-products (RAGE), a membrane protein from the immunoglobulin superfamily, has been implicated in the pathogenesis of COPD [2]
The present study suggests that RAGE mediates functional DNA methylated modification in a cluster of 14 targeted genes, hypomethylation in promoters of chemokine ligand 1 (CXCL1), Toll-like receptor 6 (TLR6) and oncostatin M (OSM), which might significantly contribute to CS-induced airway inflammation via a network of signaling pathways
90 overlapping candidate genes were identified via the intersection of differential methylated gene (DMG) with differentially expressed gene (DEG) (Supplementary Table S1)

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation that are associated with persistent airway inflammation induced by cigarette smoke (CS), a major causative factor for COPD [1]. Receptor for advanced glycation end-products (RAGE), a membrane protein from the immunoglobulin superfamily, has been implicated in the pathogenesis of COPD [2]. Overexpression of RAGE contributed to airway inflammation in CS-associated COPD [3]. Our previous study further indicated knockout (KO) of RAGE gene significantly attenuated CS-induced airway inflammation in a mouse model [4]. The mechanisms regarding the effects of RAGE on airway inflammation in COPD remain not clear. Some evidences implied DNA methylation, an epigenetic regulation, played important

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