Insulin signaling regulates R2 retrotransposon expression to orchestrate transgenerational rDNA copy number maintenance.
Insulin signaling regulates R2 retrotransposon expression to orchestrate transgenerational rDNA copy number maintenance.
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胰岛素信号传导调节 R2 逆转录转座子表达，以协调跨代 rDNA 拷贝数维持。
DOI：
10.1101/2024.02.28.582629
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Yamashita,YukikoM
中科院分区：
文献类型：
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作者：
Nelson,JonathanO;Slicko,Alyssa;Raz,AmelieA;Yamashita,YukikoM
保留大量必需但高度不稳定的核糖体DNA （rDNA）重复序列对于生殖系使基因组代代相传至关重要。自发的rDNA损失必须通过rDNA拷贝数（CN）的增加来弥补。生殖系rDNA CN扩增在果蝇中得到了最好的理解，它依赖于rDNA DNA断裂引发的不平等姐妹染色单体交换（USCE）。负责usce诱导DNA断裂的rDNA特异性反转录转座子R2通常仅在rDNA CN较低时表达，以尽量减少DNA断裂的危险；然而，R2调控的潜在机制尚不清楚。在这里，我们发现胰岛素受体（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（GSCs）是rDNA CN扩增的主要细胞类型，当rDNA CN较低时，其表达会减少。InR活性降低导致R2表达和CN扩增。我们进一步发现饮食操纵改变了R2表达和rDNA CN扩增活性。这项工作揭示了胰岛素通路将rDNA CN测量与环境感知相结合，揭示了饮食对基因组内容施加遗传变化的潜在机制。
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 inDrosophila 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 reducedInRexpression 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.