DNA methylation and gene expression patterns across brain regions following chronic social defeat stress

Background Chronic social stress induces persistent behavioral and molecular alterations, but how epigenetic and transcriptional responses are coordinated across stress-responsive brain regions remains unclear. Methods We integrated genome-wide DNA methylation and transcriptomic profiles from the hippocampus (HP), nucleus accumbens (NAc), and prefrontal cortex in a mouse model of chronic social defeat stress. Exploratory analyses included identification of candidate differentially methylated probes (DMPs) and differentially expressed genes (DEGs), gene locus-level integration, network-based analyses, and mediation analysis adjusted for experimental stress exposure. Results Candidate methylation and expression changes were identified in each region, with limited overlap among regional candidate lists. Gene locus-level integration identified eight DMP-associated genes in the NAc and one in the HP that also met the criteria for candidate DEGs. A hippocampal co-expression module was significantly associated with individual variation in social avoidance after false discovery rate correction, whereas a co-methylation module showed a nominal association with the same behavioral measure. The eigengenes of these modules were positively correlated, and their shared genes showed nominal Gene Ontology enrichment for interleukin-1 production and regulation of long-lasting synaptic potentiation. Exploratory mediation analysis suggested a possible indirect association between the hippocampal methylation module and social avoidance through the expression module after adjustment for experimental stress exposure. Conclusion These findings describe methylation and expression patterns across three brain regions and highlight hippocampal molecular networks associated with social avoidance. Integrating epigenomic and transcriptomic information may provide complementary insights into the molecular basis of individual differences in stress-related behavior and generate hypotheses for future investigation.