Epigenetic gene silencing by heterochromatin primes fungal resistance

Abstract

Summary Genes embedded in H3 lysine 9 methylation (H3K9me)–dependent heterochromatin are transcriptionally silenced 1 – 3 . In fission yeast, Schizosaccharomyces pombe , H3K9me-mediated heterochromatin can be transmitted through cell division provided the counteracting demethylase Epe1 is absent 4 , 5 . Under certain conditions wild-type cells might utilize heterochromatin heritability to form epimutations, phenotypes mediated by unstable silencing rather than DNA changes 6 , 7 . Here we show that resistant heterochromatin-dependent epimutants arise in threshold levels of caffeine. Unstable resistant isolates exhibit distinct heterochromatin islands, which reduce expression of underlying genes, some of which confer resistance when mutated. Targeting synthetic heterochromatin to implicated loci confirms that resistance results from heterochromatin-mediated silencing. Our analyses reveal that epigenetic processes promote phenotypic plasticity, allowing wild-type cells to adapt to non-favorable environments without altering their genotype. In some isolates, subsequent or co-occurring gene amplification events augment resistance. Caffeine impacts two anti-silencing factors: Epe1 levels are downregulated, reducing its chromatin association; and Mst2 histone acetyltransferase expression switches to a shortened isoform. Thus, heterochromatin-dependent epimutant formation provides a bet-hedging strategy that allows cells to remain genetically wild-type but adapt transiently to external insults. Unstable caffeine-resistant isolates show cross-resistance to antifungal agents, suggesting that related heterochromatin-dependent processes may contribute to antifungal resistance in plant and human pathogenic fungi.

An enhancer screen identifies new suppressors of small-RNA-mediated epigenetic gene silencing

“…This is intriguing because Ssu72 and Dis2 are active phosphatases, letting us to speculate that inhibition of RNAi-mediated heterochromatin formation could be regulated by kinase signalling pathways. This is of particular interest in light of a recent report that described the isolation of heterochromatin-dependent epimutants that are resistant to caffeine, which is abolished in RNAi mutants [ 38 ]. A similar phenomenon had been described earlier in Mucor circinelloides , which can cause deadly fungal infections in humans.…”

Fission Yeast Schizosaccharomyces pombe: A Unicellular “Micromammal” Model Organism

“…Caffeine exposure of fission yeast strains induced epigenetic changes to convert a subset of genes from a euchromatin to a heterochromatin state. This resulted in previously caffeine-sensitive strains becoming caffeine resistant (Torres-Garcia et al, 2020). Intriguingly, the selective epigenetic silencing was identified as heritable (passed on through several rounds of cell division) and yet reversible.…”

The epigenetic origin of life history transitions in plants and algae

“…Only two types of histone modification-the methylated forms of H3K9 and H3K27-have been demonstrated to be transmissible through cell division (Zhu and Reinberg 2011). The mitotic heritability of H3K9 methylation has been demonstrated in fission yeast (Grewal and Klar 1996;Nakayama et al 2001;Grewal and Jia 2007;Audergon et al 2015;Torres-Garcia et al 2020), which involves a self-sustaining 'read-write' mechanism that is mediated by the recruitment of H3K9 methyltransferases to the replication fork (Reese et al 2003;Sarraf and Stancheva 2004;Estève et al 2006;Loyola et al 2009;Li et al 2011). In plants, H3K9me2 represents the equivalent of H3K9me3 and is catalyzed by KRYPTONITE (KYP)/SU(VAR)3-9 HOMOLOG 4 (SUVH4), SUVH5 and SUVH6 (Jackson et al 2002;Du et al 2012Du et al , 2014Du et al , 2015.…”