Construction of m7G subtype classification on heterogeneity of sepsis

Abstract

Sepsis is a highly heterogeneous disease and a major factor in increasing mortality from infection. N7-Methylguanosine (m7G) is a widely RNA modification in eukaryotes, which involved in regulation of different biological processes. Researchers have found that m7G methylation contributes to a variety of human diseases, but its research in sepsis is still limited. Here, we aim to establish the molecular classification of m7G gene-related sepsis, reveal its heterogeneity and explore the underlying mechanism. We first identified eight m7G related prognostic genes, and identified two different molecular subtypes of sepsis through Consensus Clustering. Among them, the prognosis of C2 subtype is worse than that of C1 subtype. The signal pathways enriched by the two subtypes were analyzed by ssGSEA, and the results showed that the amino acid metabolism activity of C2 subtype was more active than that of C1 subtype. In addition, the difference of immune microenvironment among different subtypes was explored through CIBERSORT algorithm, and the results showed that the contents of macrophages M0 and NK cells activated were significantly increased in C2 subtype, while the content of NK cells resting decreased significantly in C2 subtype. We further explored the relationship between immune regulatory genes and inflammation related genes between C2 subtype and C1 subtype, and found that C2 subtype showed higher expression of immune regulatory genes and inflammation related genes. Finally, we screened the key genes in sepsis by WGCNA analysis, namely NUDT4 and PARN, and verified their expression patterns in sepsis in the datasets GSE131761 and GSE65682. The RT-PCR test further confirmed the increased expression of NUDTA4 in sepsis patients. In conclusion, sepsis clustering based on eight m7G-related genes can well distinguish the heterogeneity of sepsis patients and help guide the personalized treatment of sepsis patients.