Insulin signaling regulates R2 retrotransposon expression to orchestrate transgenerational rDNA copy number maintenance

Jonathan O. Nelson (), Alyssa Slicko, Amelie A. Raz and Yukiko M. Yamashita ()
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Jonathan O. Nelson: Stony Brook University
Alyssa Slicko: Whitehead Institute for Biomedical Research
Amelie A. Raz: Whitehead Institute for Biomedical Research
Yukiko M. Yamashita: Whitehead Institute for Biomedical Research

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Preserving a large number of essential yet highly unstable ribosomal DNA (rDNA) repeats is critical for the germline to perpetuate the genome through generations. Spontaneous rDNA loss must be countered by rDNA copy number (CN) expansion. Germline rDNA CN expansion is best understood in Drosophila melanogaster, which relies on unequal sister chromatid exchange (USCE) initiated by DNA breaks at rDNA. The rDNA-specific retrotransposon R2 responsible for USCE-inducing DNA breaks is typically expressed only when rDNA CN is low to minimize the danger of DNA breaks; however, the underlying mechanism of R2 regulation remains unclear. Here we identify the insulin receptor (InR) as a major repressor of R2 expression, limiting unnecessary R2 activity. Through single-cell RNA sequencing, we find that male germline stem cells (GSCs), the major cell type that undergoes rDNA CN expansion, have reduced InR expression when rDNA CN is low. Reduced InR activity in turn leads to R2 expression and CN expansion. We further find that dietary manipulation alters R2 expression and rDNA CN expansion activity. This work reveals that the insulin pathway integrates rDNA CN surveying with environmental sensing, revealing a potential mechanism by which diet exerts heritable changes to genomic content.

Date: 2025
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DOI: 10.1038/s41467-024-55725-6

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