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

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Ribosomal DNA (rDNA) repeat preservation is vital for germline genome perpetuation.
• Spontaneous rDNA loss necessitates copy number (CN) expansion, primarily via unequal sister chromatid exchange (USCE) in Drosophila melanogaster.
• The R2 retrotransposon initiates USCE-inducing DNA breaks, but its regulation, especially during low rDNA CN, is unclear.

Purpose of the Study:

• To elucidate the regulatory mechanism of R2 retrotransposon expression in germline rDNA copy number expansion.
• To identify factors that link rDNA copy number status to R2 activity.
• To investigate the role of the insulin pathway in integrating environmental cues with genomic content regulation.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) to analyze gene expression in male germline stem cells (GSCs).
• Investigation of insulin receptor (InR) function in regulating R2 expression.
• Dietary manipulation experiments to assess effects on R2 expression and rDNA CN expansion.

Main Results:

• The insulin receptor (InR) was identified as a key repressor of R2 retrotransposon expression.
• Male GSCs exhibit reduced InR expression when rDNA CN is low, leading to R2 activation and rDNA CN expansion.
• Dietary changes were shown to influence R2 expression and rDNA CN expansion activity.

Conclusions:

• The insulin pathway acts as a sensor for rDNA CN, modulating R2 activity to maintain genomic stability.
• Dietary interventions can impact R2 expression and rDNA CN expansion, suggesting a mechanism for diet-induced heritable changes in genomic content.
• This study reveals a novel link between metabolic status, gene regulation, and germline genome integrity.