Diseases caused by fungi are a growing global health threat, with a mortality rate higher than that of malaria and breast cancer. Fungal infections are particularly dangerous for people with compromised immune systems, including those with HIV and cancer, and they also destroy up to a third of all crops worldwide every year. While there is a limited amount of antifungal drugs that can combat these infections, fungi can develop resistance to them. Until recently, this resistance was thought to be driven by changes in the DNA sequence of the fungi, but new evidence from a group at the University of Edinburgh suggests otherwise.
The researchers treated a type of yeast called Schizosaccharomyces pombe with caffeine. Since caffeine is toxic to these yeast, it can mimic an antifungal drug. By using small doses of caffeine, they were able to detect the first changes that allowed certain cells to become resistant. Surprisingly, they found that the yeast that had developed resistance didn’t have any changes in their DNA sequence. The resistant yeast did, however, have changes in their epigenetics — the way that the DNA is organized and regulated. In particular, more of their DNA was in a tightly packed, condensed form called heterochromatin than the DNA of non-resistant yeast. This formation effectively silences many genes, altering the way cells function without changing their DNA sequence. Importantly, these epigenetic changes could be passed on when the cells replicated, giving resistance to new generations of yeast.
These findings could change the way that antifungal resistance is diagnosed and treated. Tests that look only at the DNA sequence of fungi might miss these epigenetic resistance mechanisms. Additionally, drugs that target epigenetic structures like heterochromatin might be an effective treatment against fungal infections. Understanding how antifungal resistance develops is an important step in combating fungal infections worldwide.
Sito Torres-Garcia is a Darwin Trust Ph.D. Student at the University of Edinburgh. Dr. Robin Allshire is a Professor of Chromosome Biology at the University of Edinburgh. The Allshire Lab is part of the Wellcome Center for Cell Biology in the Institute of Cell Biology in the School of Biological Sciences at the University of Edinburgh.
Managing Correspondent: Jaclyn Long
Original Article: Epigenetic gene silencing by heterochromatin primes fungal resistance
Image credit: CCO public domain