Perturbed fatty-acid metabolism is linked to localized chromatin hyperacetylation, increased stress-response gene expression and resistance to oxidative stress

Abstract

Oxidative stress is associated with cardiovascular and neurodegenerative diseases, diabetes, cancer, psychiatric disorders and aging. In order to counteract, eliminate and/or adapt to the sources of stress, cells possess elaborate stress-response mechanisms, which also operate at the level of regulating transcription. Interestingly, it is becoming apparent that the metabolic state of the cell and certain metabolites can directly control the epigenetic information and gene expression. In the fission yeast Schizosaccharomyces pombe, the conserved Sty1 stress-activated protein kinase cascade is the main pathway responding to most types of stresses, and regulates the transcription of hundreds of genes via the Atf1 transcription factor. Here we report that fission yeast cells defective in fatty acid synthesis (cbf11, mga2 and ACC/cut6 mutants; FAS inhibition) show increased expression of a subset of stress-response genes. This altered gene expression depends on Sty1-Atf1, the Pap1 transcription factor, and the Gcn5 and Mst1 histone acetyltransferases, is associated with increased acetylation of histone H3 at lysine 9 in the corresponding gene promoters, and results in increased cellular resistance to oxidative stress. We propose that changes in lipid metabolism can regulate the chromatin and transcription of specific stress-response genes, which in turn might help cells to maintain redox homeostasis.

Cbf11 and Mga2 function as a single regulatory entity to activate transcription of lipid metabolism genes and promote mitotic fidelity in fission yeast

“…Cells lacking the cbf11 and/or mga2 gene display similar, non-additive growth and cellular defects Deletion of the cbf11 or mga2 transcription factor gene leads to impaired growth (Burr et al, 2016;Převorovský et al, 2009). Moreover, we have recently shown that both Δcbf11 and Δmga2 mutants exhibit increased expression of stress genes and are resistant to H2O2 (Princová et al, 2023). To investigate any potential genetic interactions between cbf11 and mga2, we first created Δcbf11 and Δmga2 single, and Δmga2 Δcbf11 double deletion strains in an isogenic background.…”

“…To avoid as many confounding variables as possible, we used isogenic scarless TAP knock-in strains constructed using CRISPR/Cas9. The C-terminally tagged Cbf11-TAP strain has been described previously (Marešová et al, 2024; Princová et al, 2023). Inactive, membrane-bound Mga2 undergoes proteolytic activation that liberates its N-terminal part, which can then regulate transcription in the nucleus (Burr et al, 2017).…”

“…Constructions of the Δcbf11 and Δmga2 single deletion strains were published elsewhere (Převorovský et al, 2015; Princová et al, 2023). To create the Δmga2 Δcbf11 , Cbf11-TAP Δmga2 , and TAP-Mga2 Δcbf11 strains, the pClone system was used for deletion of the cbf11 and/or mga2 genes (Gregan et al, 2006).…”

“…Constructions of the Δcbf11 and Δmga2 single deletion strains were published elsewhere (Převorovský et al, 2015;Princová et al, 2023). To create the Δmga2 Δcbf11, Cbf11-TAP Δmga2, and TAP-Mga2…”

Proteolytic activation of fatty acid synthase signals pan-stress resolution

“…Lipid biosynthesis itself has an intriguing function in activating stress responses. Compromised de novo fatty acid synthesis by mutation of fasn-1 enhanced the expression of anti-microbial genes in C. elegans 22 and oxidative stress response genes in yeast 28 . However, lipid biosynthesis by FASN-1 was shown to be required to initiate the mitochondria-to-cytosolic stress response triggering HSF-1 and DVE-1 transcriptional programs 29 .…”