Heterochromatin that depends on histone H3 lysine 9 methylation (H3K9me) renders embedded genes transcriptionally silent 1 – 3 . In the fission yeast Schizosaccharomyces pombe , H3K9me heterochromatin can be transmitted through cell division provided the counteracting demethylase Epe1 is absent 4 , 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 change 6 , 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. Fission yeast grown in sublethal levels of caffeine develop heterochromatin-dependent epimutations conferring unstable heritable gene silencing that conveys resistance to caffeine, while remaining genetically wild type.

中文翻译：

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异染色质引起的表观遗传基因沉默引发真菌抗性

依赖于组蛋白 H3 赖氨酸 9 甲基化 (H3K9me) 的异染色质使嵌入基因转录沉默 1 – 3 。在裂殖酵母 Schizosaccharomyces pombe 中，H3K9me 异染色质可以通过细胞分裂传递，前提是不存在反作用的去甲基化酶 Epe1 4, 5。异染色质遗传力可能允许野生型细胞在某些条件下获得表观突变，这可能通过不稳定的基因沉默而不是 DNA 改变来影响表型 6、7。在这里，我们展示了对咖啡因具有抗性的异染色质依赖性表突变体出现在以咖啡因阈值水平生长的裂殖酵母中。具有不稳定耐药性的分离株具有明显的异染色质岛，嵌入基因的表达减少，包括一些其突变赋予咖啡因抗性的基因。在相关位点强制异染色质形成证实了异染色质介导的沉默导致耐药性。我们的分析表明，表观遗传过程促进表型可塑性，让野生型细胞在不改变基因的情况下适应不利环境。在一些分离株中，随后或同时发生的基因扩增事件增强了耐药性。咖啡因影响两个抗沉默因子：Epe1 下调，减少其染色质结合，并表达 Mst2 组蛋白乙酰转移酶的缩短亚型。因此，异染色质依赖性表突变提供了一种 bet-hedging 策略，允许细胞暂时适应侮辱，同时保持遗传野生型。具有不稳定咖啡因抗性的分离物显示出对抗真菌剂的交叉抗性，表明相关的异染色质依赖性过程可能有助于植物和人类真菌病原体对此类药物的抗性。在亚致死水平的咖啡因中生长的裂殖酵母产生异染色质依赖性外突变，赋予不稳定的可遗传基因沉默，传达对咖啡因的抗性，同时保持遗传野生型。