Abstract
AimN6-methyladenosine (m6A) modification has been demonstrated to play an important part in hepatitis B virus (HBV) infection and immune response. This study aims to further investigate whether m6A modification plays an important role in the progression of HBV-related liver fibrosis through the regulation of immune cell infiltration.MethodsIn this study, 124 chronically HBV infected cases were obtained from the Gene Expression Omnibus database. In total, 489 m6A-and-stage related genes were selected to be associated with the m6A modification and the stage of liver fibrosis. Based on these genes, we identified two distinct gene clusters, gene clusterA and gene clusterB. The immune characteristics of the two clusters were comprehensively compared. The m6A-S score was constructed as quantification of individual m6A status. The correlations between m6A regulators and infiltrating immune cells were examined and compared in different pairs of groups with various m6A traits.ResultsBiological functions, immune cell infiltration, and cytokines expression were compared between the two gene clusters proving that the gene clusterB was more immune active and had a more advanced liver fibrosis stage. The m6A-S score was associated with immune infiltration and the progression of liver fibrosis. Five different grouping conditions with different m6A traits were set up. According to the intersection of significant genes and cells, ALKBH5 interacting with macrophage and WTAP interacting with nature killer T cells may be key points in the progress of liver fibrosis.ConclusionsN6-methyladenosine modification is closely related to the immune cell infiltration and the fibrosis stage of chronic HBV-infected liver tissue. It provides us a better understanding of the progression of liver cirrhosis via evaluating the m6A modification pattern and immune infiltration characteristics.
Highlights
More than 150 RNA modifications have been found in eukaryotes, such as 5-methylcytosine, N1-methyladenosine, uridine to pseudouridine, and N6-methyladenosine (m6A) [7]
The methylation of the sixth position N of adenine on mRNA is catalyzed by the methyltransferase complex composed of METTL3, METTL14, and WTAP assisted by other functionally related molecules [10, 11], while the reverse process is mediated by demethylases, FTO, and ALKBH5 [12]
ALKBH5 interacting with macrophage and WTAP interacting with natural killer T cell were considered key points of m6A modification regulation in the progression of liver fibrosis (Figure 4; Supplementary Figure 1)
Summary
Almost one-third of the human population has been infected by HBV at some point in their lives according to the WHO data [1]. M6A, the most abundant and prominent modification of cellular RNAs, is a dynamic and reversible process regulated by methyltransferases (“writers”), demethylases (“erasers”), and binding proteins (“readers”) [8, 9]. The dynamic balance of the sites of m6A modification can be recognized by RNA binding proteins, which affects the subsequent biological processes [12, 13]. M6A modification has been confirmed to play essential roles in numerous biological responses, such as immune responses, metabolic disorders, viral infection, and cancer development [13–23]. It remains uncertain whether m6A modifications mediated by these regulators take part in the progress of HBV-related liver fibrosis
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