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Epigenetic gene silencing by heterochromatin primes fungal resistance

ABSTRACT: Genes embedded in H3 lysine 9 methylation (H3K9me)-dependent heterochromatin are transcriptionally silenced. In fission yeast, Schizosaccharomyces pombe, H3K9me-mediated heterochromatin silencing can be transmitted through cell division provided the counteracting demethylase Epe1 is absent. It is possible that under certain conditions wild-type cells might utilize heterochromatin heritability to form epimutations, phenotypes mediated by unstable silencing rather than DNA changes. Here we show that resistant heterochromatin-dependent epimutants are formed in response to threshold levels of caffeine. Unstable resistant isolates exhibit distinct heterochromatin islands, which reduce the expression of underlying genes, one of which is known to confer resistance when deleted. 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 fission yeast to adapt to non-favorable environments without altering their genotype. In some isolates, subsequent or co-occurring gene amplification events enhance resistance. Caffeine impacts two anti-silencing factors: levels of Epe1 are downregulated, reducing its chromatin association; and expression of the Mst2 histone acetyltransferase is switched to a shortened isoform. Thus, heterochromatin-dependent epimutant formation provides a bet-hedging strategy that allows cells to remain genetically wild-type but transiently adapt to external insults. As unstable caffeine-resistant isolates show cross-resistance to fungicides it is likely that related heterochromatin-dependent processes contribute to anti-fungal resistance in both plant and human pathogenic fungi.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE138436 | GEO | 2020/09/09

REPOSITORIES: GEO

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Project description:H3K9 methylation (H3K9me) is a conserved marker of heterochromatin, a transcriptionally silent chromatin structure. Knowledge of the mechanisms for regulating heterochromatin distribution is limited. The fission yeast JmjC domain-containing protein Epe1 localizes to heterochromatin mainly through its interaction with Swi6, a homologue of heterochromatin protein 1 (HP1), and directs JmjC-mediated H3K9me demethylation in vivo. Here, we found that loss of epe1 (epe1∆) induced a red-white variegated phenotype in a red-pigment accumulation background that generated uniform red colonies. Analysis of isolated red and white colonies revealed that silencing of genes involved in pigment accumulation by stochastic ectopic heterochromatin formation led to white colony formation. In addition, genome-wide analysis of red- and white-isolated clones revealed that epe1∆ resulted in a heterogeneous heterochromatin distribution among clones. We found that Epe1 had an N-terminal domain distinct from its JmjC domain, which activated transcription in both fission and budding yeasts. The N-terminal transcriptional activation (NTA) domain was involved in suppression of ectopic heterochromatin-mediated red-white variegation. We introduced a single copy of Epe1 into epe1∆ clones harboring ectopic heterochromatin, and found that Epe1 could reduce H3K9me from ectopic heterochromatin but some of the heterochromatin persisted. This persistence was due to a latent H3K9me source embedded in ectopic heterochromatin. Epe1H297A, a canonical JmjC mutant, suppressed red-white variegation, but entirely failed to remove already-established ectopic heterochromatin, suggesting that Epe1 prevented stochastic de novo deposition of ectopic H3K9me in an NTA-dependent but JmjC-independent manner, while its JmjC domain mediated removal of H3K9me from established ectopic heterochromatin. Our results suggest that Epe1 not only limits the distribution of heterochromatin but also controls the balance between suppression and retention of heterochromatin-mediated epigenetic diversification.

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Epigenetic gene silencing by heterochromatin primes fungal resistance

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