A Drosophila screen identifies a role for histone methylation in ER stress preconditioning.
A Drosophila screen identifies a role for histone methylation in ER stress preconditioning.
复制标题
果蝇筛选确定了组蛋白甲基化在内质网应激预处理中的作用。
DOI：
10.1101/2023.03.10.532109
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Chow,ClementY
中科院分区：
文献类型：
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作者：
Owings,KatieG;Chow,ClementY
应激预适应发生在短暂的亚致死应激事件影响生物体对抗未来应激的能力时。虽然预处理的影响经常在文献中指出，很少有人知道的基本机制。为了模拟预处理，我们将一组基因多样的果蝇暴露于亚致死热休克，并测量果蝇在随后暴露于内质网（ER）应激中的存活情况。预处理的影响因遗传背景而异，与未预处理相比，预处理的死亡速度从一半到4.5倍不等。随后的关联和转录分析表明，组蛋白甲基化和转录调控都是候选的预处理修饰剂途径。引人注目的是，Set 1/COMPASS复合物中几乎所有亚基（7/8）都被鉴定为预处理的候选修饰剂。对Set 1基因敲除果蝇的功能分析表明，Set 1基因的缺失导致预处理过程中典型ER应激基因的转录失调。基于这些分析，我们提出了一个预处理模型，其中Set 1有助于建立一个临时的转录“记忆”以前的压力事件，导致预处理后的压力反应。
Stress preconditioning occurs when transient, sublethal stress events impact an organism's ability to counter future stresses. Although preconditioning effects are often noted in the literature, very little is known about the underlying mechanisms. To model preconditioning, we exposed a panel of genetically diverseDrosophila melanogasterto a sublethal heat shock and measured how well the flies survived subsequent exposure to endoplasmic reticulum (ER) stress. The impact of preconditioning varied with genetic background, ranging from dying half as fast to 4 and a half times faster with preconditioning compared to no preconditioning. Subsequent association and transcriptional analyses revealed that histone methylation, and transcriptional regulation are both candidate preconditioning modifier pathways. Strikingly, almost all subunits (7/8) in the Set1/COMPASS complex were identified as candidate modifiers of preconditioning. Functional analysis ofSet1knockdown flies demonstrated that loss ofSet1led to the transcriptional dysregulation of canonical ER stress genes during preconditioning. Based on these analyses, we propose a preconditioning model in which Set1 helps to establish an interim transcriptional “memory” of previous stress events, resulting in a preconditioned response to subsequent stress.