Nelson Jonathan O, Slicko Alyssa, Raz Amelie A, Yamashita Yukiko M
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
Nat Commun. 2025 Jan 4;16(1):399. doi: 10.1038/s41467-024-55725-6.
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.
保留大量至关重要但高度不稳定的核糖体DNA（rDNA）重复序列对于生殖系通过世代延续基因组至关重要。rDNA拷贝数（CN）的扩增必须抵消自发的rDNA丢失。生殖系rDNA CN扩增在黑腹果蝇中得到了最好的理解，它依赖于由rDNA处的DNA断裂引发的不等姐妹染色单体交换（USCE）。负责引发USCE的DNA断裂的rDNA特异性逆转录转座子R2通常仅在rDNA CN较低时表达，以将DNA断裂的危险降至最低；然而，R2调控的潜在机制仍不清楚。在这里，我们确定胰岛素受体（InR）是R2表达的主要抑制因子，限制了不必要的R2活性。通过单细胞RNA测序，我们发现雄性生殖系干细胞（GSC）是经历rDNA CN扩增的主要细胞类型，当rDNA CN较低时，其InR表达降低。InR活性降低反过来导致R2表达和CN扩增。我们进一步发现饮食操作会改变R2表达和rDNA CN扩增活性。这项工作揭示了胰岛素途径将rDNA CN监测与环境感知整合在一起，揭示了饮食对基因组内容产生可遗传变化的潜在机制。
