Mild oxidative stress and dietary epigenetic modulators direct DNA methylation remodeling toward stress-resilience...

Although hepatic epigenetic plasticity in response to diet is well established, the factors that bias methylation remodeling toward adaptive gene networks remain unresolved. We hypothesized that mild oxidative stress acts as a contextual cue directing dietary epigenetic modulators toward DNA methylation remodeling of stress-resilience pathways. To evaluate this model, we analyzed hepatic transcriptional and methylation responses to a genistein plus vitamin C diet in seabream.

RNA-seq identified 146 differentially expressed genes (DEGs), with upregulated genes involved in SAM metabolism, chromatin remodeling, protein catabolism, and mitochondrial activity, and downregulated genes linked to glucose and lipid metabolism, intracellular trafficking, and signaling. Weighted gene co-expression network analysis revealed a modular transcriptomic organization associated with physiological traits, but only one module strongly correlated with diet. This module is related with metabolic activation and apoptosis control. Reduced representation bisulfite sequencing (RRBS) revealed 16,300 differentially methylated cytosines and 354 differentially methylated regions, primarily in gene bodies and intergenic regions. Functional Epigenetic Module analysis with remodeled promoters showed directed DNA methylation affecting epigenetic regulation, oxidative and metabolic stress, and stress adaptation, consistent with targeted remodeling. Functional in vivo validation revealed that the treatment reduces reactive oxygen species levels under oxidative stress.

These findings demonstrate that induced mild oxidative stress combined with dietary epigenetic modulators produces a selective epigenetic remodeling of the liver. We propose that mild oxidative stress may act as a contextual signal that guides dietary epigenetic modulators to reshape DNA methylation landscapes in a pathway-directed manner.