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

Overview

1. Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC 3083, Australia
2. La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3083, Australia
3. School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
4. Epigenes Australia Pty Ltd, Melbourne, VIC 3138, Australia
5. School of Biological Sciences, Monash University, Clayton Campus, VIC 3800, Australia
6. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton Campus, VIC 3800, Australia

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 multitissue 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 h of daily fasting for 4 months and performed RNA-seq 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 the 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.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

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Data

Datasets cited

• geo:GSE290224, at NCBI GEO; found in “Data Availability”

Data Availability

The high-throughput RNA-seq data and tissue-specific gene-transposable element regulatory networks generated in this study have been deposited in the NCBI Gene Expression Omnibus under accession numbers GSE290224 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE290224) and GSE335823 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE335823).

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

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Version 2, 28 September 2026

• Funding: added National Health and Medical Research Council: 2019100

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 5 keywords, 50 references.

Cite

This paper

Cheng, X., Fan, Y., Peng, X., Tabassum, N. I., Jo, D.-G., Johns, T. G., Balasubramanian, S., Sureshkumar, S., & Arumugam, T. V. (2026). Intermittent fasting rewires tissue-specific gene-transposable element regulatory networks. PNAS nexus, 5(8), pgag254. https://doi.org/10.1093/pnasnexus/pgag254

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