異染色質介導的表觀基因沉默可導致真菌耐藥
作者：
小柯機器人發布時間：2020/9/11 14:18:29
英國愛丁堡大學Robin C. Allshire小組發現，異染色質介導的表觀基因沉默可導致真菌耐藥。相關論文於2020年9月9日在線發表在《自然》雜誌上。
研究人員發現，在咖啡因閾值水平下生長的裂殖酵母產生了對咖啡因具有抗性的異染色質依賴性表觀突變體。具有不穩定抗性的分離菌具有明顯的異染色質島，其嵌入基因的表達降低，包括一些突變賦予咖啡因抗性。在相關位點強制形成異染色質證實了耐藥性是由異染色質介導的沉默引起的。
這些分析表明，表觀遺傳過程促進表型可塑性，使野生型細胞適應不利的環境而無需遺傳改變。在某些分離菌中，隨後或同時發生的基因擴增事件會增加抗藥性。咖啡因影響兩個抗沉默因子，Epe1被下調，減少其染色質結合，並且表達了Mst2組蛋白乙醯轉移酶縮短的同工型。
因此，異染色質依賴性表觀突變提供了一種對衝策略，使細胞能夠暫時適應損傷，同時保持遺傳野生型。咖啡因耐藥性不穩定的分離株對抗真菌劑表現出交叉耐藥性，進而表明相關的異染色質依賴性過程可能有助於植物和人類真菌病原體對此類試劑的耐藥性。
研究人員介紹，依賴組蛋白H3第9位賴氨酸甲基化（H3K9me）的異染色質能夠使基因轉錄沉默。在裂殖酵母中，H3K9me異染色質可以通過細胞分裂進行傳播，前提是不存在抵消性去甲基酶Epe1。異染色質的遺傳力可能使得野生型細胞在一定條件下獲得表觀突變，即通過不穩定的基因沉默而不是DNA改變來影響表型。
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