Allshire lab paper featured in Nature. Authors Image Illustration by Sito Torres-Garcia Torres-Garcia, S., Yaseen, I., Shukla, M., Audergon, P.N.C.B., White, S.A., Pidoux, A.L., and Allshire, R.C. Summary of Paper by Lori Koch Fungal infection poses a serious threat to human health, especially for those who are immune-compromised, however the rise of drug-resistant fungi means that fewer and fewer treatments will remain effective. Previously, it was thought that resistance resulted from changes in the DNA sequence of fungi. In their recent paper, published in Nature, researchers in the Allshire Lab (WCB) led by PhD student Sito Torres-Garcia demonstrate that resistance can arise in fungi through epigenetic changes alone without alteration to their DNA. Here, they treated the yeast Schizosaccharomyces pombe with caffeine, which inhibits growth of this wild-type fungus, and isolated yeast that were unstably resistant. These unstable isolates limped through the selection and could continue to grow in the presence of caffeine, but lost resistance when grown in the absence of caffeine. Whole genome sequencing revealed essentially no difference in the DNA sequence of these unstably resistant isolates compared to untreated yeast, however longer exposure to caffeine led to DNA sequence changes. Further analysis of the unstable isolates showed that chemical modifications, specifically methylation on histone H3 at lysine 9 (H3K9), accumulated on specific regions containing the hba1, cup1, mbx2 genes. H3K9 methylation is well known to trigger the assembly of a less accessible structure called heterochromatin that reduces gene expression. By artificially targeting Clr4 methyltransferase activity to add H3K9 methylation across these genes in otherwise normal yeast, the researchers showed that methylation of these regions reduced gene expression and allowed cells to gain resistance to caffeine and antifungal drugs. Additional experiments revealed that enzymes involved in counteracting H3K9 methylation influence the frequency of resistance. Thus, fungi hedge their bets and develop resistance by altering their epigenome while remaining genetically unchanged. These findings open many new avenues for future research into how fungi develop resistance to antifungal agents that may prove vital for tackling this important problem. Related links Journal Link Allshire Lab Website DOI This article was published on 2024-06-17
