The Set1 Histone H3K4 Methyltransferase Contributes to Azole Susceptibility in a Species-Specific Manner by Differentially Altering the Expression of Drug Efflux Pumps and the Ergosterol Gene Pathway.

Fungal infections are a major health concern because of limited antifungal drugs and development of drug resistance. can develop azole drug resistance by overexpression of drug efflux pumps or mutating , the target of azoles. However, the role of epigenetic histone modifications in azole-induced gene expression and drug resistance is poorly understood in Candida glabrata. In this study, we show that Set1 mediates histone H3K4 methylation in C. glabrata. In addition, loss of and histone H3K4 methylation increases azole susceptibility in both C. glabrata and S. cerevisiae. This increase in azole susceptibility in S. cerevisiae and C. glabrata strains lacking is due to distinct mechanisms. For S. cerevisiae, loss of decreased the expression and function of the efflux pump Pdr5, but not expression under azole treatment. In contrast, loss of in C. glabrata does not alter expression or function of efflux pumps. However, RNA sequencing revealed that C. glabrata Set1 is necessary for azole-induced expression of all 12 genes in the late ergosterol biosynthesis pathway, including and Furthermore, chromatin immunoprecipitation analysis shows histone H3K4 trimethylation increases upon azole-induced gene expression. In addition, high performance liquid chromatography analysis indicated Set1 is necessary for maintaining proper ergosterol levels under azole treatment. Clinical isolates lacking were also hypersusceptible to azoles which is attributed to reduced expression but not defects in drug efflux. Overall, Set1 contributes to azole susceptibility in a species-specific manner by altering the expression and consequently disrupting pathways known for mediating drug resistance.