Htz1 and Set1 Regulate Ergosterol Levels in Response to Environmental Stress

Abstract

ABSTRACTErgosterol is an essential isoprenoid for cellular integrity and proper membrane fluidity of fungi. Proper level of ergosterol is crucial for resistance to various stressful conditions, such as hypoxia, hypothermia, and hyperosmolarity. The isoprenoid building blocks of ergosterol are synthesized via the mevalonate pathway, which relies on the availability of many central metabolites, such as acetyl-coA and S-adenosyl methionine (SAM). The metabolic currencies are also the substrates for epigenetic modifications such as histone acetylation and methylation. To have a better understanding of how isoprenoid synthesis and these epigenetic mechanisms affect each other, we re-analyzed the results of our screen on Saccharomyces cerevisiae gene deletion collection for isoprenoid production and found a group of chromatin regulators with significant effects on isoprenoid production. More specifically, the canonical histone Htz1 (H2A.z), the SWR1 complex that loads Htz1 onto chromatin, and the histone demethylase Jhd2 inhibited, whereas the Htz1 unloading INO80 complex and histone methylase Set1 enhanced isoprenoid production. Further analysis of genome-wide expression data revealed that Htz1 and Set1 differentially regulate stress-response genes which presumably affect isoprenoid synthesis. Conversely, changes in isoprenoid production alters the transcription of the same set of genes. Further analysis of ergosterol levels in these gene deletions showed that htz1, set1 double deletion leads to accumulation of ergosterol beyond homeostatic levels and renders cells vulnerable to environmental stress. Our re-analysis of multiple published data and follow-up experiments revealed an epigenetic crosstalk mechanism between ergosterol levels and stress response genes that is essential for maintaining optimum concentration of ergosterol under various conditions.