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

Abstract

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.

Dual activities of a silencing information regulator complex in yeast transcriptional regulation and DNA‐damage response

“…When the nuclear envelope structure is distorted, Sir4 interaction with telomeric regions and subsequent hyperclustering is disrupted, resulting in loss of transcriptional silencing. A recent study investigated the impact of Sir4/telomere interaction disruption and found that ribosomal protein gene expression was notably downregulated due to accumulative rDNA compaction 49 . The telomeric silencing by Sir proteins is shown to be dependent on nuclear envelope lipid content, where links between chromatin remodeling and lipid metabolism have been previously established.…”

“…The telomeric silencing by Sir proteins is shown to be dependent on nuclear envelope lipid content, where links between chromatin remodeling and lipid metabolism have been previously established. Modification of the nuclear envelope altered telomeric SIR clustering and resulted in a partial loss of complex silencing at subtelomeric genes 49 .…”

Anomalous lateral diffusion of lipids during the fluid/gel phase transition of a lipid membrane

“…Homeoviscous adaptation (HA) is the most well-known strategy. 50–66 In HA, depending on the temperature the saturated to unsaturated lipid ratio changes. With decreasing temperature, some of the lipids with saturated fatty acid tails are converted to unsaturated lipids with the help of desaturase enzymes.…”