Regulation of alternative splicing of lipid metabolism genes in sepsis-induced liver damage by RNA-binding proteins

Abstract Background:RNA binding proteins (RBPs) have the potential for transcriptional regulation in sepsis-induced liver injury, but precise functions remain unclear. Aim: To conduct a genome-wide expression analysis of RBPs and illuminate changes in regulation of alternative splicing in sepsis-induced liver injury. Method: RNA-seq data on "sepsis and liver" from the publicly available NCBI dataset was analyzed, and differentially expressed RBPs and alternative splicing events (ASEs) in healthy and septic liver were identified. Co-expression analyses of sepsis-regulated RBPs and ASEs were performed. Models of sepsis were established to validate hepatic RBP gene expression patterns with different treatments. Result: Pairwise analysis of gene expression profiles of sham, cecum ligation puncture (CLP) and CLP with dichloroacetate (CLPDCA) mice allowed 1208 differentially expressed genes (DEGs), of which 800 were upregulated and 408 downregulated, to be identified. DEGs were similar in both CLP and CLPDCA mice. A further 67 upregulated and 58 downregulated DEGS were identified by comparison of sham and CLPDCA groups. GO functional analysis showed DEGs to be enriched in immune and inflammatory-related processes and KEGG analysis showed that lipid metabolism-related pathways were downregulated. Differences in lipid metabolism-related alternative splicing events, including A3SS, were also found in CLP and CLPDCA compared with sham mice. Thirty-seven RBPs, including S100a11, Ads2, Fndc3b, Fn1, Ddx28, Car2, Cisd1 and Ptms, were differentially expressed in CLP mice and shown to be enriched in lipid metabolic and immune /inflammatory-related processes by GO functional analysis. The models of sepsis were constructed with different treatment groups and S100a11 expression in the CLP group found to be higher than in the sham group, a change that was reversed by DCA. The alternative splicing ratio of Srebf1 and Cers2 decreased compared with the Sham group increased after DCA treatment. Conclusion: Abnormal profiles of gene expression and alternative splicing were associated with sepsis-induced liver injury. Unusual expression of RBPs, such as S100a11, may regulate alternative splicing of lipid metabolism-associated genes, such as Srebf1 and Cers2, in the septic liver. RBPs may constitute potential treatment targets for sepsis-induced liver injury.