Sepsis is one of the most important diseases leading to death in ICU. Early diagnosis and early application of antibiotics can reduce morbidity and mortality. Therefore, the screening and validation of reliable biomarkers and the improvement of the accuracy and efficiency of sepsis prediction have been the goals of experts and scholars at home and abroad. RNA modifications play a critical role in regulating molecular events and diseases, and miRNAs have been shown to be closely associated[10] not only with epigenetics[11] but also with sepsis heterogeneity and prognosis. m6A is an important methylation modification, and m6A methylation plays a role in transcription by affecting RNA splicing, export, translation, and stability. First, mRNA is spliced into mature transcripts and exported from the nucleus to the cytoplasm before translation. The splicing and export process is regulated by m6A[2]. Most studies on m6A methylation have been limited to tumor-related directions[12], with the focus on single genes associated with single diseases or with specific immune cells. Further understanding of the relationship between m6A regulation and sepsis may provide a new way for clinical morbidity prediction and molecular diagnosis, and further guide clinical treatment. In this study, we isolated HNRNPC, LRPPRC, FTO and ELAVL1 genes associated with sepsis in children. Sepsis in children was divided into two subtypes. The two groups showed significantly different genetic status and immune status. HNRNPC, LRPPRC,ELAVL1 are m6A related readers, FTO are related erasers, which provide direction for further research on gene and sepsis related mechanism.
These results suggest that HNRNPC has the best diagnostic value in childhood sepsis and may be a potentially important gene in early sepsis. HNRNPC plays a splicing role in m6A modification. Two HNRNPC proteins, HNRNPG and HNRNPC 11, do not bind directly to m6A but functionally regulate m6A RNA transcripts[13]. HNRNPC, i.e. heterogeneous nuclear ribonucleoprotein C1/C2, is a protein composed of 306 amino acids and localized in the nucleus[10]. HNRNPC is spliced at the early stages of spliceome assembly and pre-mRNA[11], and is found to be upregulated in many tumors. It is considered to be one of the important genes regulating cancer-specific alternative lysis and polyadenylation, and can influence tumor metastasis and cell death in combination with other proteins. Furthermore, HNRNPC regulates the stability and translational level of binding molecules. More recently, it has been reported that m6A affects RNA secondary structure, while HNRNPC can regulate mRNA abundance and splicing of m6A after recognition, known as the "m6A switch."
LRPPRC is a leucine-rich pentapeptide repeat protein, mainly distributed in mitochondria, belonging to a family of proteins containing PPR motifs. This family of proteins binds to RNA and regulates transcription. It plays an important role in RNA processing, splicing, stability, editing and translation, mainly manifested in strong inhibitionof autophagy [14]and complex interaction with apoptosis. LRPPRC has been shown to play an important regulatory role in many diseases. It is specifically overexpressed in lung adenocarcinoma[15]. It can also be associated with other proteins, thereby negatively regulating mitochondrial mediated antiviral immunity[16]. In an animal experiment, LRPPRC knockout resulted in impaired mitochondrial respiration, decreased ATP production, and increased hyperpolarization and mitochondrial reactive oxygen species production in mouse hearts, possibly due to LRPPRC inhibition of ATPIF1-related mRNA translation[17], suggesting that LRPPRC expression may promote ATP production. At the same time, numerous studies have shown that mitochondrial dysfunction in cells with LRPPRC defects is impaired in their ability to maintain energy homeostasis, especially under conditions of inflammation and nutritional stress[18, 19]. This suggests that when sepsis patients are in a state of systemic inflammatory dysfunction and organ tissue ischemia and hypoxia, cells in LRPPRC deficient patients are more likely to be ATP deficient and thus more vulnerable to damage.
ELAVL1: RNA-binding proteinHuR,also a protein that regulates post-transcription products, is overexpressed and overexpressed in most cancers.This dysregulation of HuR enables itto participate inthe translation of messenger RNA (mRNA) in many cancers andvarious disease pathogenesis. HuR can increase the stability of some transcription products and also promote the translation of some target mRNAs. In hypoxia environment, HuR can significantly increase the expression of VEGF and HIF-1α, which may be related to the repair and angiogenesis after hypoxia induced cell damage. By altering the pattern of protein expression,HuR can influence major cellular processes such as proliferation, differentiation, carcinogenesis, senescence, apoptosis, and responses to immune and environmental stress[20]. In this study, we foundthat differences amongthe three readers involved autophagy and apoptosis, infection, and cell damage and repair under stress conditions. However, ourstudy of m6A regulators was limited to bioinformatics analysis, and its underlying mechanisms need to be further explored.
FTO: Originally reported as an in vitro demethylase of N3-methylformamide in single-stranded DNA83 and[21] N3-methyluridine in single-stranded RNA, FTO was first found to be associated with weight gain and obesity in humans[22, 23]. It is widely expressed in all adult and fetal tissues, with highest expression in the brain. FTO has been shown to play an oncogene role in leukemia[25], glioblastoma, and renal clear cell carcinoma.[26] FTO expression is abnormally upregulated by oncoproteins in some subtypes of AML, with a corresponding decrease in fat mass and obesity-related protein (FTO, m6A demethylase) expression. These changes were related to the significant increase of IL-6, TNF-a and IL-1b expression and the decrease of left ventricular function[2].METTL3/14/16,RBM15, WTAP,YTHDF2, HNRNPC, LRPPRC,ELAVL1 and FTO were significantly different among10The association of these genes with sepsis remains to be studied. Our study suggests that these genes may be key targets for m6A regulators, which may trigger new treatment strategies for sepsis. However, further research is needed to clarify their role in sepsis diagnosis and treatment.