Research Projects

Fungal infections are rising, but effective drugs are in short supply and increasingly ineffective due to resistance. Drug resistance due to genetic mutations has been extensively studied, but little attention has been paid to the non-genetic mechanisms (like epigenetic modifications) responsible for drug resistance. Due to their unstable nature, they are often difficult to detect. Here, we aim to identify such epigenetic mechanisms in C. albicans and, subsequently, the epigenetic drivers responsible for their occurrence. In other fungi, identified epimutations are transcriptionally repressive, but we believe that transcriptionally activating epimutations also play a role in drug resistance. In C. albicans, the chromosomal or segmental aneuploidy is known to be responsible for drug resistance. Segmental aneuploidy increases the number of copies of that gene, which is responsible for more gene expression and drives drug resistance. This indirectly supports our hypothesis that the same output is expected from transcriptionally activating epimutations. Our initial effort has led us to identify unstable resistant isolates, and we saw a robust increase in H3K4me3 in these unstable resistant isolates compared to wild-type or stable resistant isolates, suggesting its role in driving unstable drug resistance. We hypothesize that the heritability of H3K4me3 modifications drives drug resistance. Understanding the differential regulation of H3K4 methyltransferase Set1, which generates the epimutations, will help us understand the generation mechanism of these unstable resistant isolates (epimutants). The project will help us establish the system, and then later, we will also include other fungal pathogens like fungi that are responsible for the damage to crops.