Intermittent fasting rewires tissue-specific gene-transposable element regulatory networks

Abstract Intermittent fasting (IF) is a dietary intervention known to promote systemic health benefits, yet its impact on genome-wide transcriptional regulatory networks, particularly those involving transposable elements (TEs), remains poorly understood. This study investigates the multi-tissue transcriptomic response to chronic IF in mice, focusing on TE regulation and its integration with host gene networks. We subjected C57BL/6 mice to 16 hours of daily fasting for four months and performed RNA sequencing on liver, skeletal muscle, and cortex tissues. Using locus-specific TE quantification, we found that IF induces profound, tissue-specific changes in TE expression, with the liver showing the strongest response (5,359 differentially expressed TEs), followed by skeletal muscle (620), while minimal changes were observed in the cortex. Integrated co-expression network analysis (WGCNA) in liver and muscle revealed IF-responsive TEs that co-vary with nearby genes, forming distinct co-expression modules. Functional enrichment of genes proximal to co-expressed TEs within these modules highlighted clear tissue-specific regulatory programs. In the liver, the enriched terms were predominantly associated with translation and metabolism, whereas in skeletal muscle, the enriched pathways were involved in muscle contraction, mitochondrial organization, and chromatin modification. Furthermore, correlation analysis revealed strong, significant co-expression between TEs and their proximal genes within these modules, suggesting that TEs may exert potential cis-regulatory effects on adjacent genes. Taken together, our results provide a high-resolution atlas of TE regulation under IF and demonstrate that TEs are integral components of tissue-specific transcriptional networks reshaped by fasting. These findings offer new insights into how dietary interventions influence gene regulatory systems.