Integrative Analysis of DNA Methylation and Gene Expression Reveals Key Molecular Signatures in Spatial Memory Impairment of Sepsis‐Associated Encephalopathy

Sepsis-associated encephalopathy (SAE) is a life-threatening neurological syndrome caused by sepsis and characterized by diffuse brain dysfunction. Previous research has indicated a role for DNA methylation in sepsis. However, its involvement in SAE remains underexplored. In this study, a sepsis model was established in adult male C57BL/6J mice through intraperitoneal injection of lipopolysaccharide (LPS) at a dose of 5 mg/kg to explore the relationship between DNA methylation and spatial memory impairment associated with SAE. Following LPS administration, the mice exhibited impaired learning and spatial memory. RNA sequencing of hippocampal tissues from SAE mouse models revealed differential gene expression, with 797 upregulated and 510 downregulated genes in the hippocampus 24 h post-LPS administration. Both GO and KEGG analyses indicated an enrichment of inflammation-related pathways. MeDIP-seq of the hippocampus identified 1628 hyper-methylated and 2245 hypo-methylated genes, with the latter being primarily enriched in synapse-related pathways. Seventy-one genes exhibited transcription trends opposite to their 5mC levels. RT-qPCR was used to validate the mRNA expression and methylation patterns of six genes, revealing that Apmap exhibited reduced promoter region methylation, accompanied by increased mRNA expression, while its overexpression alleviated these deficits. These findings suggest that Apmap may play a protective role in spatial memory impairment in SAE. The results present promising epigenetic biomarkers for early clinical diagnosis and potential therapeutic targets in SAE.