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

The nuclear envelope (NE) is important in maintaining genome organization. The role of lipids in the communication between the NE and telomere silencing was investigated, including how changes in lipid composition impact gene expression and overall nuclear architecture. For this purpose, yeast cells were treated with the non-metabolizable lysophosphatidylcholine analog edelfosine, known to accumulate at the perinuclear endoplasmic reticulum. Edelfosine treatment induced NE deformation and disrupted telomere clustering but not anchoring. In addition, the association of Sir4 at telomeres measured by ChIP decreased. RNA-seq analysis showed that the expression of sub-telomeric regions increased, which was 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 combined transcriptional programs resulted in higher levels of oleate and the formation of nuclear lipid droplets. Interestingly, cells lacking Sir proteins displayed resistance to oleate and edelfosine and this phenotype was dependent on Rap1 and histone H4K16 acetylation. GRAPHICAL ABSTRACT Summary The nuclear envelope (NE) is important for nuclear organization. This study shows that changes in NE lipid composition from lysolipid treatment disrupts SIR-mediated telomere silencing and triggers changes in transcriptional circuits regulated by membrane sensing factors.