Epigenetic gene silencing by heterochromatin primes fungal resistance
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ABSTRACT:
PROVIDER: PRJNA575857 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10231400_1.fastq.gz | Fastqsanger.gz | |||
| SRR10231400_2.fastq.gz | Fastqsanger.gz | |||
| SRR10231401_1.fastq.gz | Fastqsanger.gz | |||
| SRR10231401_2.fastq.gz | Fastqsanger.gz | |||
| SRR10231402_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2020-09-09 | GSE138436 | GEO
Project description:Heterochromatin that depends on histone H3 lysine 9 methylation (H3K9me) renders embedded genes transcriptionally silent1-3. In the fission yeast Schizosaccharomyces pombe, H3K9me heterochromatin can be transmitted through cell division provided the counteracting demethylase Epe1 is absent4,5. Heterochromatin heritability might allow wild-type cells under certain conditions to acquire epimutations, which could influence phenotype through unstable gene silencing rather than DNA change6,7. Here we show that heterochromatin-dependent epimutants resistant to caffeine arise in fission yeast grown with threshold levels of caffeine. Isolates with unstable resistance have distinct heterochromatin islands with reduced expression of embedded genes, including some whose mutation confers caffeine resistance. Forced heterochromatin formation at implicated loci confirms that resistance results from heterochromatin-mediated silencing. Our analyses reveal that epigenetic processes promote phenotypic plasticity, letting wild-type cells adapt to unfavourable environments without genetic alteration. In some isolates, subsequent or coincident gene-amplification events augment resistance. Caffeine affects two anti-silencing factors: Epe1 is downregulated, reducing its chromatin association, and a shortened isoform of Mst2 histone acetyltransferase is expressed. Thus, heterochromatin-dependent epimutation provides a bet-hedging strategy allowing cells to adapt transiently to insults while remaining genetically wild type. Isolates with unstable caffeine resistance show cross-resistance to antifungal agents, suggesting that related heterochromatin-dependent processes may contribute to resistance of plant and human fungal pathogens to such agents.
| S-EPMC7116710 | biostudies-literature
Project description:Constitutive domains of repressive heterochromatin are maintained within the fission yeast genome through self-reinforcing mechanisms involving histone methylation and small RNAs. Non-coding RNAs generated from heterochromatic regions are processed into small RNAs by the RNA interference pathway, and are subject to silencing through both transcriptional and post-transcriptional mechanisms. While the pathways involved in maintenance of the repressive heterochromatin state are reasonably well understood, less is known about the requirements for its establishment. Here we describe a novel role for the post-transcriptional regulatory factor Mkt1 in establishment of heterochromatin at pericentromeres in fission yeast. Loss of Mkt1 does not affect maintenance of existing heterochromatin, but does affect its recovery following depletion, as well as de novo establishment of heterochromatin on a mini-chromosome. Pathway dissection revealed that Mkt1 is required for RNAi-mediated post-transcriptional silencing, downstream of small RNA production. Mkt1 physically associates with pericentromeric transcripts, and is additionally required for maintenance of silencing and heterochromatin at centromeres when transcriptional silencing is impaired. Our findings provide new insight into the mechanism of RNAi-mediated post-transcriptional silencing in fission yeast, and unveil an important role for post-transcriptional silencing in establishment of heterochromatin that is dispensable when full transcriptional silencing is imposed.
2019-11-28 | PXD015484 | 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 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:It is important to accurately regulate the expression of genes involved in development and environmental response. In the fission yeast Schizosaccharomyces pombe, meiotic genes are tightly repressed during vegetative growth. Despite being embedded in heterochromatin these genes are transcribed and believed to be repressed primarily at the level of RNA. However, the mechanism of facultative heterochromatin formation and the interplay with transcription regulation is not understood. We show genome-wide that HDAC-dependent histone deacetylation is a major determinant in transcriptional silencing of facultative heterochromatin domains. Indeed, mutation of class I/II HDACs leads to increased transcription of meiotic genes and accumulation of their mRNAs. Mechanistic dissection of the pho1 gene where, in response to phosphate, transient facultative heterochromatin is established by overlapping lncRNA transcription shows that the Clr3 HDAC contributes to silencing independently of SHREC, but in an lncRNA-dependent manner. We propose that HDACs promote facultative heterochromatin by establishing alternative transcriptional silencing.
2018-03-19 | GSE108668 | GEO
Project description:Histone deacetylation primes chromatin to preserve epigenetic memory for self-propagation of heterochromatin domains
| PRJNA764716 | ENA
Project description:Abstract: In the yeast S. pombe, multiple chromatin-modifying enzymes are required for heterochromatin formation, yet how their actions alter chromatin structure to block access to DNAby the transcriptional machinery is unknown. We constructed high-resolution nucleosome occupancy maps of heterochromatic regions in wild-type strains and in mutants lacking the H3K9 methyltransferase Clr4 or one of the two activities of the silencing effector complex SHREC. Fourier analysis reveals that these enzymes do not increase the regularity of nucleosome spacing. Rather, their principal effect was to induce the elimination of nucleosome-free regions (NFRs). Both NFRs associated with transcription initiation sites as well as those not associated with promoters are affected. As in S. cerevisiae, repressed genes in euchromatin retain their NFRs. Thus, NFR elimination cannot be explained as a secondary consequence of repression. The maps also show that TFIIIC boundary elements have NFRs resistant to silencing, suggesting a potential role in preventing lateral spread of heterochromatin. NFR elimination offers a mechanism by which heterochromatin restricts access of the transcriptional machinery to DNA. Nucleosome positions in either heterochromatin or euchromatin were mapped in various mutants to determine whether chromatin structure is altered upon heterochromatic silencing. Eight strains were assayed for nucleosome positioning in heterochromatin while two strains were assayed for nucleosome positioning in euchromatin. Two biological replicates were assayed for each strain. No dye swaps were done. RNA transcripts were also mapped using the heterochromatin tiling arrays to determine where RNA transcripts accumulate in heterochromatin. Three strains were assayed for transcripts in heterochromatin by hybridizing cy5-labeled cDNA created from total RNA against cy3-labeled cDNA created from RNA synthesized from sonicated genomic DNA. Two biological replicates were assayed for each strain.
2010-11-24 | E-GEOD-19596 | biostudies-arrayexpress
Project description:Histone deacetylation promotes transcriptional silencing at facultative heterochromatin
| PRJNA428233 | ENA
Project description:We found PEAT complexes mediate histone deacetylation and heterochromatin condensation and thereby facilitate heterochromatin silencing.
2018-06-21 | GSE116066 | GEO
Project description:We found PEAT complexes mediate histone deacetylation and heterochromatin condensation and thereby facilitate heterochromatin silencing.
2018-06-21 | GSE116065 | GEO