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. Author summaryThe production of fatty acids and lipids in general creates energy reserves and provides essential building blocks for cellular membranes.
Oxidative stress, on the other hand, is a condition caused by increased concentration of oxidants, such as reactive oxygen species, which becomes harmful to the cells and triggers an oxidative stress response to mitigate damage. While these two processes are seemingly unrelated, we now provide evidence that there is actually a specific regulatory connection between fatty acid metabolism and cellular resistance to oxidative stress.
Using the fission Schizosaccharomyces pombe as a model, we show that multiple conditions that lower fatty acid production, including mutations of lipogenic enzymes and their regulators, or chemical inhibition of fatty acid synthesis, specifically boost the expression of a subset of stress-responsive genes, and increase cellular resistance to hydrogen peroxide. This regulatory link relies on histone acetyltransferases and is connected with promoter hyperacetylation at the affected genes.
Our findings highlight the intricate interconnections between the metabolic state of the cell and the regulation of gene expression.