THE ROLE OF SET1 MEDIATED HISTONE H3K4 METHYLATION IN ANTIFUNGAL DRUG RESISTANCE AND FUNGAL PATHOGENESIS IN CANDIDA SPECIES

Fungal pathogens are an increasing threat to humans, plants, and animals worldwide. Death and disease caused by fungal pathogens results in the loss of over 1.5 million lives, 12 million tons of crops, and even entire species every year. Candida species are the leading cause of invasive fungal species lead by Candida albicans, and Candida glabrata in second. Candida glabrata intrinsically has a low susceptibility to azole treatment, and multidrug resistant isolates are becoming more common. Additionally, new emerging Candida species have been found, and most clinical isolates are resistant to one or more drugs. There is a critical need to better understand drug resistance and pathogenesis to generate new therapies. 

Drug resistance can be caused by several different genetic factors, but until recently epigenetic factors have been frequently overlooked. Epigenetic research has revolutionized the treatment and detection of many cancers. And now, early research has shown epigenetic mechanisms play a role in drug resistance and pathogenesis in fungal species. Limited resources exist to combat fungal infections and understanding the epigenetic mechanisms that contribute to drug resistance and pathogenicity will provide new drug targets for future treatment.

Previous publications from the Briggs’ lab showed Set1-mediated histone H3K4 methylation was necessary for proper ergosterol homeostasis and Brefeldin A resistance. One of the three classes of antifungals, azoles, target the ergosterol pathway. The ergosterol connection resulted into this thesis project, investigating the role of Set1-mediated histone H3K4 methylation in drug resistance and pathogenicity in Saccharomyces cerevisiae, Candida glabrata, Candida albicans, and Candida auris. This research was the first to characterize the Set1 complex in C. glabrata and show it is the sole histone H3K4 methyltransferase in C. glabrata and C. auris. Additionally, it shows loss of SET1 in C. glabrata and C. auris reduces pathogenicity and alters drug efficacy. Interestingly, although the loss of SET1 seems to cause a similar pathogenic defect in all three Candida species, the role Set1 plays in drug efficacy including which drug and severity varies amongst species and isolates. Altogether, this research project provides new possible drug targets for fungal treatment and knowledge added to the scientific community on the role of epigenetics in fungal pathogens.