PMID:23382196

Citation	South, PF, Harmeyer, KM, Serratore, ND and Briggs, SD (2013) H3K4 methyltransferase Set1 is involved in maintenance of ergosterol homeostasis and resistance to Brefeldin A. Proc. Natl. Acad. Sci. U.S.A. 110:E1016-25
Abstract	Set1 is a conserved histone H3 lysine 4 (H3K4) methyltransferase that exists as a multisubunit complex. Although H3K4 methylation is located on many actively transcribed genes, few studies have established a direct connection showing that loss of Set1 and H3K4 methylation results in a phenotype caused by disruption of gene expression. In this study, we determined that cells lacking Set1 or Set1 complex members that disrupt H3K4 methylation have a growth defect when grown in the presence of the antifungal drug Brefeldin A (BFA), indicating that H3K4 methylation is needed for BFA resistance. To determine the role of Set1 in BFA resistance, we discovered that Set1 is important for the expression of genes in the ergosterol biosynthetic pathway, including the rate-limiting enzyme HMG-CoA reductase. Consequently, deletion of SET1 leads to a reduction in HMG-CoA reductase protein and total cellular ergosterol. In addition, the lack of Set1 results in an increase in the expression of DAN1 and PDR11, two genes involved in ergosterol uptake. The increase in expression of uptake genes in set1Δ cells allows sterols such as cholesterol and ergosterol to be actively taken up under aerobic conditions. Interestingly, when grown in the presence of ergosterol set1Δ cells become resistant to BFA, indicating that proper ergosterol levels are needed for antifungal drug resistance. These data show that H3K4 methylation impacts gene expression and output of a biologically and medically relevant pathway and determines why cells lacking H3K4 methylation have antifungal drug sensitivity.
Links	PubMed PMC3600464 Online version:10.1073/pnas.1215768110
Keywords	ATP-Binding Cassette Transporters/biosynthesis; ATP-Binding Cassette Transporters/genetics; Aerobiosis/drug effects; Aerobiosis/physiology; Antifungal Agents/pharmacology; Brefeldin A/pharmacokinetics; Drug Resistance, Fungal/drug effects; Drug Resistance, Fungal/physiology; Ergosterol/biosynthesis; Ergosterol/genetics; Gene Expression Regulation, Fungal/drug effects; Gene Expression Regulation, Fungal/physiology; Glycoproteins/biosynthesis; Glycoproteins/genetics; Histone-Lysine N-Methyltransferase/genetics; Histone-Lysine N-Methyltransferase/metabolism; Histones/genetics; Histones/metabolism; Homeostasis/drug effects; Homeostasis/physiology; Methylation/drug effects; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/metabolism; Saccharomyces cerevisiae Proteins/biosynthesis; Saccharomyces cerevisiae Proteins/genetics; Saccharomyces cerevisiae Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
YEAST:SET1		GO:0035961: positive regulation of ergosterol biosynthetic process by positive regulation of transcription from RNA polymerase II promoter	ECO:0000315:		P		Figure 2	complete CACAO 10989
YEAST:SET1		GO:0055092: sterol homeostasis	ECO:0000315:		P		Figure 4	complete CACAO 11011
YEAST:SET1		GO:1990872: negative regulation of sterol import by negative regulation of transcription from RNA polymerase II promoter	ECO:0000315:		P		Figure 5	complete CACAO 11012
YEAST:SET1		GO:0070452: positive regulation of ergosterol biosynthetic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Figure 2 Figure 4	complete CACAO 11056
YEAST:SET3		GO:0035961: positive regulation of ergosterol biosynthetic process by positive regulation of transcription from RNA polymerase II promoter	ECO:0000315:		P		Figure 6	complete CACAO 11010
YEAST:SET3		GO:0070452: positive regulation of ergosterol biosynthetic process	ECO:0000315:		P		Figure 6	complete CACAO 11055

References

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