Proteasome-dependent truncation of the negative heterochromatin regulator Epe1 mediates antifungal resistance
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ABSTRACT:
PROVIDER: PRJNA786560 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17143041_1.fastq.gz | Fastqsanger.gz | |||
| SRR17143041_2.fastq.gz | Fastqsanger.gz | |||
| SRR17143042_1.fastq.gz | Fastqsanger.gz | |||
| SRR17143042_2.fastq.gz | Fastqsanger.gz | |||
| SRR17143043_1.fastq.gz | Fastqsanger.gz |
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Project description:Epe1 histone demethylase restricts H3K9-methylation-dependent heterochromatin, preventing it from spreading over, and silencing, gene-containing regions in fission yeast. External stress induces an adaptive response allowing heterochromatin island formation that confers resistance on surviving wild-type lineages. Here we investigate the mechanism by which Epe1 is regulated in response to stress. Exposure to caffeine or antifungals results in Epe1 ubiquitylation and proteasome-dependent removal of the N-terminal 150 residues from Epe1, generating truncated tEpe1 which accumulates in the cytoplasm. Constitutive tEpe1 expression increases H3K9 methylation over several chromosomal regions, reducing expression of underlying genes and enhancing resistance. Reciprocally, constitutive non-cleavable Epe1 expression decreases resistance. tEpe1-mediated resistance requires a functional JmjC demethylase domain. Moreover, caffeine-induced Epe1-to-tEpe1 cleavage is dependent on an intact cell-integrity MAP kinase stress signalling pathway, mutations in which alter resistance. Thus, environmental changes provoke a mechanism that curtails the function of this key epigenetic modifier, allowing heterochromatin to reprogram gene expression, thereby bestowing resistance to some cells within a population. H3K9me-heterochromatin components are conserved in human and crop plant fungal pathogens for which a limited number of antifungals exist. Our findings reveal how transient heterochromatin-dependent antifungal resistant epimutations develop and thus inform on how they might be countered.
2022-05-04 | GSE190267 | GEO
Project description:Epe1 histone demethylase restricts H3K9-methylation-dependent heterochromatin, preventing it from spreading over, and silencing, gene-containing regions in fission yeast. External stress induces an adaptive response allowing heterochromatin island formation that confers resistance on surviving wild-type lineages. Here we investigate the mechanism by which Epe1 is regulated in response to stress. Exposure to caffeine or antifungals results in Epe1 ubiquitylation and proteasome-dependent removal of the N-terminal 150 residues from Epe1, generating truncated tEpe1 which accumulates in the cytoplasm. Constitutive tEpe1 expression increases H3K9 methylation over several chromosomal regions, reducing expression of underlying genes and enhancing resistance. Reciprocally, constitutive non-cleavable Epe1 expression decreases resistance. tEpe1-mediated resistance requires a functional JmjC demethylase domain. Moreover, caffeine-induced Epe1-to-tEpe1 cleavage is dependent on an intact cell-integrity MAP kinase stress signalling pathway, mutations in which alter resistance. Thus, environmental changes provoke a mechanism that curtails the function of this key epigenetic modifier, allowing heterochromatin to reprogram gene expression, thereby bestowing resistance to some cells within a population. H3K9me-heterochromatin components are conserved in human and crop plant fungal pathogens for which a limited number of antifungals exist. Our findings reveal how transient heterochromatin-dependent antifungal resistant epimutations develop and thus inform on how they might be countered.
2022-10-13 | PXD030205 | Pride
Project description:Epe1 histone demethylase restricts H3K9-methylation-dependent heterochromatin, preventing it from spreading over, and silencing, gene-containing regions in fission yeast. External stress induces an adaptive response allowing heterochromatin island formation that confers resistance on surviving wild-type lineages. Here we investigate the mechanism by which Epe1 is regulated in response to stress. Exposure to caffeine or antifungals results in Epe1 ubiquitylation and proteasome-dependent removal of the N-terminal 150 residues from Epe1, generating truncated Epe1 (tEpe1) which accumulates in the cytoplasm. Constitutive tEpe1 expression increases H3K9 methylation over several chromosomal regions, reducing expression of underlying genes and enhancing resistance. Reciprocally, constitutive non-cleavable Epe1 expression decreases resistance. tEpe1-mediated resistance requires a functional JmjC demethylase domain. Moreover, caffeine-induced Epe1-to-tEpe1 cleavage is dependent on an intact cell integrity MAP kinase stress signaling pathway, mutations in which alter resistance. Thus, environmental changes elicit a mechanism that curtails the function of this key epigenetic modifier, allowing heterochromatin to reprogram gene expression, thereby bestowing resistance to some cells within a population. H3K9me-heterochromatin components are conserved in human and crop-plant fungal pathogens for which a limited number of antifungals exist. Our findings reveal how transient heterochromatin-dependent antifungal resistant epimutations develop and thus inform on how they might be countered.
| S-EPMC7613290 | biostudies-literature
Project description:The epigenetic landscape of a cell frequently changes in response to fluctuations in nutrient levels, but the mechanistic link is not well understood. In fission yeast, the JmjC domain protein Epe1 is critical for maintaining the heterochromatin landscape. Loss of Epe1 results in heterochromatin expansion and overexpression of Epe1 leads to defective heterochromatin. Through a genetic screen, we found that mutations in genes of the cAMP signaling pathway suppress the heterochromatin defects associated with Epe1 overexpression. We further demonstrated that the activation of Pka1, the downstream effector of cAMP signaling, is required for the efficient translation of epe1+ mRNA to maintain Epe1 overexpression. Moreover, inactivating the cAMP-signaling pathway, either through genetic mutations or glucose deprivation, leads to the reduction of endogenous Epe1 and corresponding heterochromatin changes. These results reveal the mechanism by which the cAMP signaling pathway regulates heterochromatin landscape in fission yeast.
2022-01-10 | GSE181263 | GEO
Project description:The non-proteolytic role of the proteasome in heterochromatin regulation
2019-06-16 | GSE103336 | GEO
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.
2019-04-24 | GSE108448 | GEO
Project description:The non-proteolytic role of the proteasome in heterochromatin regulation
2018-02-16 | GSE97865 | GEO
Project description:We report global occupancy of H3K9me2 and H3K4me3 in wild-type S. pombe and two mutant backgrounds - the deletion of heterochromatin antagonist epe1 and the double mutant absent epe1 and the H3K4 methyltransferase set1
2020-08-24 | GSE140067 | GEO
Project description:Stress can spur the redistribution of histone modifications to establish novel phenotypes. We do not understand how cells leverage existing epigenetic pathways to establish and maintain new gene expression states that enhance fitness and cell survival. H3K9 methylation promotes epigenetic silencing in fission yeast (S. pombe). Heterochromatin establishment depends on the H3K9 methyltransferase, Clr4 and is opposed by two major two heterochromatin regulators, Epe1, a putative H3K9 demethylase and Mst2, an H3K14 acetyltransferase. We designed an inducible system in mst2D cells to toggle Epe1 availability on-demand and trigger heterochromatin misregulation thus initiating an adaptive epigenetic response. Following Epe1 depletion, we mapped transcriptome and H3K9me3 changes as a function of time. Although Epe1 could be removed in ~30 minutes, the population of cells took two orders of magnitude longer to establish an adaptive phenotype. Similarly, re-expressing Epe1 did not switch cells back to their initial state. Instead, cells exhibit unique transcriptional signatures during recovery that encode adaptive memory that is both reversible and tunable. Our results reveal that the slow kinetics of chromatin state changes enable bet-hedging for cells to identify optimal adaptive solutions while hysteresis within the gene regulatory network encodes cellular memory.
2023-07-11 | GSE235807 | GEO
Project description:Stress can spur the redistribution of histone modifications to establish novel phenotypes. We do not understand how cells leverage existing epigenetic pathways to establish and maintain new gene expression states that enhance fitness and cell survival. H3K9 methylation promotes epigenetic silencing in fission yeast (S. pombe). Heterochromatin establishment depends on the H3K9 methyltransferase, Clr4 and is opposed by two major two heterochromatin regulators, Epe1, a putative H3K9 demethylase and Mst2, an H3K14 acetyltransferase. We designed an inducible system in mst2D cells to toggle Epe1 availability on-demand and trigger heterochromatin misregulation thus initiating an adaptive epigenetic response. Following Epe1 depletion, we mapped transcriptome and H3K9me3 changes as a function of time. Although Epe1 could be removed in ~30 minutes, the population of cells took two orders of magnitude longer to establish an adaptive phenotype. Similarly, re-expressing Epe1 did not switch cells back to their initial state. Instead, cells exhibit unique transcriptional signatures during recovery that encode adaptive memory that is both reversible and tunable. Our results reveal that the slow kinetics of chromatin state changes enable bet-hedging for cells to identify optimal adaptive solutions while hysteresis within the gene regulatory network encodes cellular memory.
2023-07-11 | GSE235806 | GEO