Bet hedging in yeast by heterogeneous, age-correlated expression of a stress protectant.
Bet hedging in yeast by heterogeneous, age-correlated expression of a stress protectant.
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DOI：
10.1371/journal.pbio.1001325
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Siegal ML
中科院分区：
文献类型：
--
作者：
Levy SF;Ziv N;Siegal ML
一种新的实验方法揭示了无压力克隆酵母细胞中的赌注对冲策略，即它们采用一系列与海藻糖合成调节剂表达相关的生长状态，并预测对未来压力的抵抗力。在同一培养物中生长的遗传相同的细胞在基因表达和其他性状上显示出惊人的细胞间异质性。一个关键的挑战是了解这种异质性在多大程度上反映了一个强大系统的噪声耐受性，以及有多少是生物功能。在细菌中，随机基因表达导致细胞间的异质性，这可能是一种赌注对冲机制，允许少数细胞通过抗菌治疗存活，而其他细胞则死亡。尽管其临床重要性，下注对冲的分子机制仍不清楚。在这里，我们调查的投注对冲在酿酒酵母的机制，使用一种新的高通量显微镜检测，同时监测可变蛋白质的表达，形态，生长速度和数以万计的酵母小菌落的生存结果。我们发现，克隆种群显示广泛的分布的增长率和缓慢的增长预测电阻热杀的概率方式。我们确定了几个基因产物，可能发挥作用，赌注对冲，并确认TSL1，海藻糖合成调节剂，是一个重要的组成部分，这种阻力。tsl 1丰度与生长速率和复制年龄相关，并预测存活率。我们的研究结果表明，酵母赌注对冲的结果从多个表观遗传的增长状态确定的随机和确定性因素的组合。在相同环境中生长的遗传上相同的细胞可以在其形态、行为和其细胞组分的组成上显示异质性。在某些微生物中，这种细胞异质性可能是一种称为赌注对冲的现象的基础，因为它使某些细胞能够在恶劣的环境中生存，从而在环境变化不可预测时增加总体种群适应度。赌注对冲可能是微生物感染人类并逃避抗菌治疗的重要策略，但对细胞异质性如何有助于微生物存活知之甚少。在这里，我们研究了酵母中赌注对冲的机制。我们发现，基因相同的酵母菌群体包含广泛的分布的增长率和缓慢的增长预测耐高温杀死在一个分级的方式。我们确定了几个基因产物，可能发挥作用，在这个赌注对冲策略，并确认TSL1，生产的二糖海藻糖的调节器，是一个重要的组成部分，急性应激抗性。最后，我们发现细胞的衰老与Tsl1丰富的抗应激细胞状态相关。我们的研究结果表明，海藻糖的合成是一个复杂的和多因素的机制，在酵母的赌注对冲的基础。
A new experimental approach reveals a bet-hedging strategy in unstressed, clonal yeast cells, whereby they adopt a range of growth states that correlate with expression of a trehalose-synthesis regulator and predict resistance to future stress. Genetically identical cells grown in the same culture display striking cell-to-cell heterogeneity in gene expression and other traits. A crucial challenge is to understand how much of this heterogeneity reflects the noise tolerance of a robust system and how much serves a biological function. In bacteria, stochastic gene expression results in cell-to-cell heterogeneity that might serve as a bet-hedging mechanism, allowing a few cells to survive through an antimicrobial treatment while others perish. Despite its clinical importance, the molecular mechanisms underlying bet hedging remain unclear. Here, we investigate the mechanisms of bet hedging in Saccharomyces cerevisiae using a new high-throughput microscopy assay that monitors variable protein expression, morphology, growth rate, and survival outcomes of tens of thousands of yeast microcolonies simultaneously. We find that clonal populations display broad distributions of growth rates and that slow growth predicts resistance to heat killing in a probabalistic manner. We identify several gene products that are likely to play a role in bet hedging and confirm that Tsl1, a trehalose-synthesis regulator, is an important component of this resistance. Tsl1 abundance correlates with growth rate and replicative age and predicts survival. Our results suggest that yeast bet hedging results from multiple epigenetic growth states determined by a combination of stochastic and deterministic factors. Genetically identical cells grown in the same environment can display heterogeneity in their morphology, behavior, and composition of their cellular components. In some microorganisms, such cellular heterogeneity can underlie a phenomenon known as bet hedging because it enables some cells to survive in harsh environments, hence increasing the overall population fitness when environmental shifts are unpredictable. Bet hedging is likely to be an important strategy by which microbes infect humans and evade antimicrobial treatments, yet little is known of how cellular heterogeneity contributes to microbial survival. Here, we study the mechanisms underlying bet hedging in yeast. We find that populations of genetically identical yeast contain a broad distribution of growth rates and that slow growth predicts resistance to heat killing in a graded fashion. We identify several gene products that are likely to play a role in this bet-hedging strategy and confirm that Tsl1, a regulator of the production of the disaccharide trehalose, is an important component of acute stress resistance. Finally, we find that old age in cells correlates with a Tsl1-abundant, stress-resistant cell state. Our results suggest that trehalose synthesis is part of a complex and multifactorial mechanism that underlies bet hedging in yeast.
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