The Role of Nuclear Envelope Lipids in Nuclear Shape and Transcription
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Date
2023-04-23
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Abstract
The nuclear envelope (NE) is a double membrane structure contiguous with the endoplasmic reticulum (ER) encompassing the nucleus. The NE is important in maintaining genome organization, as silenced domains are sequestered at the nuclear periphery, while active domains associate with the nuclear pore complex for rapid export of mRNA. Budding yeast in particular tether silenced telomeres at the NE to prevent aberrant recombination of the chromosome ends. In this thesis, 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 cells were treated with the non-metabolizable lysophosphatidylcholine analog edelfosine, a lipid drug known to accumulate at the perinuclear ER. Edelfosine induced NE deformation and disrupted telomere clustering but not anchoring. In addition, the association of Sir4 of the Silent Information Regulator complex with telomeres decreased. RNA-seq analysis showed upregulation of Sir-dependent genes located at sub-telomeric regions, and downregulation of ribosomal protein genes. Transcriptomic analysis also revealed that two lipid metabolic circuits are 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 edelfosine and unsaturated fatty acids. Characterization of the edelfosine mechanism of toxicity in cells lacking SIR4 found that while these cells display similar NE deformations and formation of nuclear lipid droplets as seen in wild type cells, they have less internalization of sterols from the plasma membrane, with a concomitant maintenance of the proton pump Pma1 at the plasma membrane and a reduced acidification of the cytosol. Altogether this body of work presents evidence supporting a cross-talk between NE lipids and nuclear architecture and function.
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biochemistry, nucleus, lipids, genome organization
Citation
Sosa Ponce, M. L. (2023). The role of nuclear envelope lipids in nuclear shape and transcription (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.