Robin Allshire

Epigenetic mechanisms mediating fungicide and antifungal resistance.

Robin’s interest in chromosome structure and function began during his PhD research at the MRC Mammalian Genome Unit at the University of Edinburgh, which he joined in 1981. Under the supervision of Chris Bostock and Edwin Southern, he investigated the use of bovine papillomavirus as a chassis for constructing mammalian artificial chromosomes, completing his PhD in 1985. 

As a post-doctoral researcher with Nick Hastie at the MRC Human Genetics Unit he demonstrated that human telomeres are composed of simple repeats and showed that their length decreases with age and is altered in cancers. 

portrait photo of Robin Allshire
Robin Allshire

As an independent investigator at Cold Spring Harbor and the MRC Human Genetics Unit, he and his laboratory first demonstrated that fission yeast centromeres contain heterochromatin and went on to demonstrate that this heterochromatin plays a pivotal role in ensuring sister-centromere cohesion, promoting CENP-A chromatin and thus, kinetochore assembly, and accurate chromosome segregation. More recently his lab demonstrated that H3K9 methylation can act as a bona fide epigenetic mark allowing the transmission of information though both mitotic and meiotic divisions.

In 2002 Robin joined the Wellcome Centre for Cell Biology and the University of Edinburgh and a Wellcome Trust Principal Research Fellow and Professor of Chromosome Biology.  He is currently investigating the role of epigenetics in mediating Fungicide and Antifungal resistance.

Awards: 

1988: Elected EMBO member
2005: Elected Fellow of The Royal Society of Edinburgh.
2011: Elected Fellow of The Royal Society, London. 
2013: Genetics Society Medal 2013. 
2020: Elected Fellow of The Academy of Medical Sciences.

Other current roles: 

2024-present: Member of Council of the Royal Society, London.
2013-present: Board of Trustees for the Darwin Trust of Edinburgh. 

Felix Dewornu, Vishnu Priya Krishnan, Mengyuan Li, Nakul Panchal, Alison Pidoux, Severina Pociunaite, Paresh Rana, Mahima Sagar Sahu, Bilal Shah, Manu Shukla, Pin Tong, Ane Valera and Sharon White.


Antifungal resistance is increasing in prevalence, raising fungal-borne disease frequencies in humans and crops important for human well-being.  The survival of fungi in harsh environments involves stress-sensing pathways that reprogram their proteomes. New environmental conditions, including global heating, can push opportunistic fungi to colonise novel niches, thus increasing their potential to become harmful pathogens. Effective antifungal treatments are limited in number precisely because fungi are adept at resisting challenges.

Resistance to fungicides/antifungal compounds can result from genetic mutations, however, it was unknown if resistance might also arise from heritable epigenetic changes mediated by post-translational modifications carried on histones in chromatin.  Using the model fission yeast (Schizosaccharomyces pombe) fungal system, we discovered that heterochromatin island-mediated ‘epimutations’ confer resistance following exposure to external insults (Torres-Garcia et al. 2020; Figure A). Heterochromatin islands are formed by addition of methyl groups to lysine 9 of histone H3 (H3K9me) over regions of chromatin resulting in reduced expression of underlying genes. Epimutation-mediated repression of the cup1+ or ppr4+ genes results in mitochondrial dysfunction which appears to activate the oxidative stress response, consequently increasing efflux and drug resistance (Fellas et al. 2025 in press; Figure B). Thus, wild-type cells utilise epimutations that impose mitochondrial function to bypass external insults such as antifungal compounds

Unlike genetic mutations, such epimutations are unstable - causative heterochromatin islands, associated gene repression and resistance are lost in the absence of antifungal selection. Thus, epigenetic processes promote phenotypic plasticity so that wild-type cells adapt to unfavourable environments without irreversible genetic alterations.

We are exploiting fission yeast to define the mechanisms of epigenetic regulation that govern adaptation to challenging environments. We are also exploring if related epigenetic-mediated processes contribute to the frequent emergence of fungicide-antifungal resistance in divergent human and cereal crop plant fungal such as Cryptococcus neoformans and Zymoseptoria tritici.


Investigating fungicide resistance in S.pombe

Figure legend.

A. Resistant isolates arise in fission yeast after insult exposure. Resistance can be mediated by changes in DNA (resistant mutants) or reversible, heterochromatin-based epimutations (resistant epimutants). Upon insult removal unstable epimutants lose heterochromatin islands, gene repression and resistance, reverting to wild-type (sensitive) whereas genetic mutants continue to exhibit the resistant phenotype.

B. Mutation or heterochromatin-mediated repression of cup1+ or ppr4+ (encode mitochrondrial proteins) causes mitochondrial electron transport chain dysfunction increasing reactive oxygen species levels (ROS; red stars). This activates the Pap1-dependent oxidative stress response, elevating nuclear Pap1 (red arrow) and expression of Pap1-dependent genes encoding transmembrane transporters that lead to increased efflux of insults such as caffeine or azole-based antifungals.  The mitonuclear retrograde response is also activated leading to decreased expression of nuclear-encoded mitochondrial proteins (black arrow).

*Fellas, A., *$Pidoux, A.L., Tong, P., Hewes, H.H., Wallace, E.C., and $Allshire, R.C. (BioRxiv Preprint/ EMBO J. in press 2025). Heterochromatin epimutations impose mitochondrial dysfunction to confer antifungal resistance. bioRxiv 10.1101/2024.11.13.623381. (*joint 1st authors; $joint corresponding authors

*Yaseen, I., *White, S.A,, Torres-Garcia, S., Spanos, C., Lafos, M., Gaberdiel, E., Yeboah, R., El Karoui, M., Rappsilber, J., Pidoux, A.L., Allshire, R.C. (2022) Proteasome-dependent truncation of the negative heterochromatin regulator Epe1 mediates antifungal resistance. Nature Structure & Molecular Biology 29:745-758. doi: 10.1038/s41594-022-00801-y. (*joint 1st authors)

Torres-Garcia, S., Yaseen, I., Shukla, M., Audergon, P.N.C.B., White, S.A., Pidoux, A.L., Allshire, R.C. (2020). Epigenetic gene silencing by heterochromatin primes fungal resistance. Nature 585, 453-458. doi: 10.1038/s41586-020-2706-x.


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