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异染色质介导的表观基因沉默可导致真菌耐药
2020-09-11 14:18

英国爱丁堡大学Robin C. Allshire小组发现,异染色质介导的表观基因沉默可导致真菌耐药。相关论文于2020年9月9日在线发表在《自然》杂志上。

研究人员发现,在咖啡因阈值水平下生长的裂殖酵母产生了对咖啡因具有抗性的异染色质依赖性表观突变体。具有不稳定抗性的分离菌具有明显的异染色质岛,其嵌入基因的表达降低,包括一些突变赋予咖啡因抗性。在相关位点强制形成异染色质证实了耐药性是由异染色质介导的沉默引起的。
 
这些分析表明,表观遗传过程促进表型可塑性,使野生型细胞适应不利的环境而无需遗传改变。在某些分离菌中,随后或同时发生的基因扩增事件会增加抗药性。咖啡因影响两个抗沉默因子,Epe1被下调,减少其染色质结合,并且表达了Mst2组蛋白乙酰转移酶缩短的同工型。
 
因此,异染色质依赖性表观突变提供了一种对冲策略,使细胞能够暂时适应损伤,同时保持遗传野生型。咖啡因耐药性不稳定的分离株对抗真菌剂表现出交叉耐药性,进而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试剂的耐药性。
 
研究人员介绍,依赖组蛋白H3第9位赖氨酸甲基化(H3K9me)的异染色质能够使基因转录沉默。在裂殖酵母中,H3K9me异染色质可以通过细胞分裂进行传播,前提是不存在抵消性去甲基酶Epe1。异染色质的遗传力可能使得野生型细胞在一定条件下获得表观突变,即通过不稳定的基因沉默而不是DNA改变来影响表型。
 
附:英文原文

Title: Epigenetic gene silencing by heterochromatin primes fungal resistance

Author: Sito Torres-Garcia, Imtiyaz Yaseen, Manu Shukla, Pauline N. C. B. Audergon, Sharon A. White, Alison L. Pidoux, Robin C. Allshire

Issue&Volume: 2020-09-09

Abstract: Heterochromatin that depends on histone H3 lysine 9 methylation (H3K9me) renders embedded genes transcriptionally silent1,2,3. 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.

DOI: 10.1038/s41586-020-2706-x

Source: https://www.nature.com/articles/s41586-020-2706-x

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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