Intermittent Fasting Rewires Gene Regulation Through Transposable Elements
A 4-month IF study in mice reveals thousands of tissue-specific transposable element changes that reshape liver metabolism and muscle mitochondrial networks.
Summary
Intermittent fasting is known to improve metabolic health, but its effects on transposable elements have been largely unexplored. Transposable elements are repetitive stretches of DNA once dismissed as junk that can influence nearby genes. In this study, mice fasted 16 hours a day for four months. Their liver showed 5,359 changed elements and their skeletal muscle 620, while the brain cortex showed only minimal changes. The changed elements moved in step with neighboring genes. In the liver these genes involved translation and metabolism. In muscle they involved contraction, mitochondrial organization, and chromatin modification. The authors suggest TEs may contribute to fasting's physiological benefits. The work is correlational and was done only in male mice.
Detailed Summary
Intermittent fasting (IF) is among the best-studied dietary strategies for extending healthspan. Its documented benefits include autophagy induction, mitochondrial biogenesis, and metabolic switching. Prior work, including the authors' own, showed that IF alters gene expression, the proteome, and the epigenetic landscape. However, the role of IF-responsive transposable elements (TEs) remained unresolved. TEs are repetitive sequences that make up a vast portion of the mammalian genome and were once dismissed as junk DNA. TE-derived sequences can dictate enhancer and promoter activity and transcription factor binding sites, influencing nearby genes in cis.
Researchers at La Trobe University placed male C57BL/6 mice on either ad libitum feeding (n = 8) or daily fasting from 16:00 to 08:00 (n = 8) for 4 months, starting at 6 weeks of age. These were the parental animals of a cohort previously reported by Fan et al. In that report, IF mice gained less weight and had lower blood glucose, higher ketones, and lower HbA1c. The team performed strand-specific 150-bp paired-end RNA sequencing (about 12 Gb per sample) on liver, skeletal muscle, and whole cortex. They quantified TEs at individual genomic loci with the SQuIRE pipeline against mm39 and tested differential expression with DESeq2 (Padj < 0.05).
The response was strongly tissue dependent. The liver had 5,359 differentially expressed TEs and skeletal muscle 620, while the cortex showed minimal changes.
The authors then built signed weighted co-expression networks (WGCNA) for liver and muscle. Each network used the 8,000 most variable genes plus the 8,000 most variable TEs. IF-responsive TEs co-varied with nearby genes, forming distinct co-expression modules. Genes proximal to co-expressed TEs showed tissue-specific enrichment. In the liver, enriched terms were mainly translation and metabolism. In muscle, they were muscle contraction, mitochondrial organization, and chromatin modification.
Correlation analysis showed strong, significant co-expression between TEs and their proximal genes within these modules. This is consistent with potential cis-regulatory effects. The authors position TEs as integral components of tissue-specific transcriptional networks reshaped by fasting, and suggest TEs may contribute to IF's physiological benefits. Any use as biomarkers or therapeutic targets remains speculative.
Important caveats apply. The data are mouse-only and male-only. IF mice were sampled in the fasted state while controls were fed, so acute fasting effects cannot be fully separated from chronic adaptation. Co-expression is correlational, and the portions of the paper reviewed describe no functional validation. Sample sizes were modest at n = 8 per group.
Key Findings
- Liver showed 5,359 differentially expressed TEs after 4 months of 16-hour daily fasting (Padj < 0.05), the strongest response of the three tissues
- Skeletal muscle had 620 differentially expressed TEs, while the cortex showed minimal changes, indicating a strongly tissue-specific effect
- In WGCNA co-expression networks for liver and muscle, IF-responsive TEs co-varied with nearby genes to form distinct modules
- Genes proximal to co-expressed TEs were enriched for translation and metabolism in liver, and for muscle contraction, mitochondrial organization, and chromatin modification in muscle
- TEs and their proximal genes showed strong, significant correlations, suggesting potential cis-regulatory effects
Methodology
Male C57BL/6 mice were randomized at 6 weeks to ad libitum feeding (n = 8) or 16-hour daily fasting (16:00 to 08:00; n = 8) for 4 months. Tissues came from the parental cohort of Fan et al. Liver, skeletal muscle, and whole cortex underwent strand-specific 150-bp paired-end RNA-seq (Illumina NovaSeq 6000, about 12 Gb per sample). TEs were quantified at the locus level with SQuIRE/STAR against mm39, with exon-overlapping TEs removed. Differential expression was tested with DESeq2 (Padj < 0.05). Signed WGCNA networks (8,000 genes plus 8,000 TEs per tissue, bicor, minModuleSize = 30) were built for liver and muscle. Functional enrichment and correlation analyses were then run on genes proximal to co-expressed TEs.
Study Limitations
The study used only male mice, with n = 8 per group, so findings may not generalize to females or humans. IF mice were sampled while fasting and controls while fed, which confounds acute fasting with chronic adaptation. Co-expression with proximal genes is correlational and suggests but does not prove cis-regulation. Whole cortex was analyzed rather than specific cell types or subregions, and no conflicts of interest were identified in the text reviewed.
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