The Shape of Silence: A Role for the Nuclear Envelope in Transcriptional Regulation

Abstract

The lipid drug edelfosine integrates into the nuclear envelope (NE) of S. cerevisiae (budding yeast) and results in its morphological deformation. As biologists we are guided by a central tenant that form and function are inextricably linked. This is true for the thumb on a hand and a protein produced in a cell. We hypothesized that this will also be true for the organelles inside a eukaryotic cell, wherein changes in nuclear shape would lead to changes in nuclear functions, like alterations in gene expression and protein localization. Using live cell imaging combined with yeast genetics and biochemical approaches, we found that edelfosine treatment led to dispersion of the membrane‐associated SIR complex and triggered processing of the membrane‐sensing transcription factors, Mga2 and Spt23. By a complementary approach of RNA‐seq followed by transcriptomic analysis, we identified that targets of Mga2 as well as subtelomeric regions were upregulated in response to edelfosine, while ribosomal protein targets of Rap1 were downregulated. Our work suggests that disruption of the nuclear membrane is sufficient to trigger changes in membrane‐associated transcription factors and chromatin remodellers. Our data indicate that nuclear membrane integrity is linked to transcriptional regulation. The NE could be a novel target for chemotherapeutics as lipid drugs like edelfosine do not cause DNA damage and would likely not pose mutagenic threats.