SIR telomere silencing depends on nuclear envelope lipids and modulates sensitivity to a lysolipid

The nuclear envelope (NE) is important for nuclear organization. This study shows that changes in NE lipid composition from treatment with a lysolipid drug decreases Sir4 association with telomeres, their clustering at the NE, and triggers lipid-specific transcriptional circuits regulated by membrane-sensing factors resulting in the formation of nuclear lipid droplets. The nuclear envelope (NE) is important in maintaining genome organization. The role of lipids in communication between the NE and telomere regulation was investigated, including how changes in lipid composition impact gene expression and overall nuclear architecture. Yeast was treated with the non-metabolizable lysophosphatidylcholine analog edelfosine, known to accumulate at the perinuclear ER. Edelfosine induced NE deformation and disrupted telomere clustering but not anchoring. Additionally, the association of Sir4 at telomeres decreased. RNA-seq analysis showed altered expression of Sir-dependent genes located at sub-telomeric (0-10 kb) regions, consistent with Sir4 dispersion. Transcriptomic analysis revealed that two lipid metabolic circuits were activated in response to edelfosine, one mediated by the membrane sensing transcription factors, Spt23/Mga2, and the other by a transcriptional repressor, Opi1. Activation of these transcriptional programs resulted in higher levels of unsaturated fatty acids and the formation of nuclear lipid droplets. Interestingly, cells lacking Sir proteins displayed resistance to unsaturated-fatty acids and edelfosine, and this phenotype was connected to Rap1.

Automated summary

This study shows that changes in nuclear envelope (NE) lipid composition disrupt telomere clustering, decrease Sir4 association with telomeres, and trigger the formation of nuclear lipid droplets. The study also reveals the activation of lipid metabolic circuits regulated by membrane-sensing factors and a transcriptional repressor, resulting in altered gene expression and higher levels of unsaturated fatty acids. Cells lacking Sir proteins show resistance to unsaturated fatty acids and edelfosine, which is connected to Rap1.