Transcriptional profiling of fasted H3K27ac-deficient Caenorhabditis elegans nematodes.

Exposure to low levels of environmental challenges, known as hormetic stress, such as nutrient deprivation and heat shock, fosters subsequent stress resistance and promotes healthy aging in later life. However, specific mechanisms governing transcriptional reprogramming upon hormetic nutrient stress remain elusive. In this study, we identified histone H3 lysine 27 acetylation (H3K27ac) as a crucial driver of transcriptomic adaptation to hormetic fasting. Beyond its immediate function of enhancing lipid catabolism for alternative energy sources, stress-induced H3K27ac activates lifelong antioxidant defenses, thereby reducing reactive oxygen species (ROS) produced by stress-induced fatty acid oxidation and their accumulation during aging. The increase in H3K27ac, mediated by pioneer factor PHA-4/FOXA and cooperating transcription factor NHR-49/HNF4, is crucial for lifespan extension under hermetic nutrient stress in Caenorhabditis elegans. Our findings establish H3K27ac as a key transcriptional switch that bridges nutrient status with transcriptomic reprogramming, underpinning the pro-longevity effects of hormetic fasting through orchestrating lipid catabolism and antioxidative defenses. Overall design: Wild-type (N2) animals and H3K27ac-deficient animals, bearing jmjd-3.1(gk384) null mutation and cbp-1 RNAi knockdown, were synchronized to adult day 1 (D1), transferred to ad libitum E. coli or fasted NGM RNAi plates for 24 hours, and subsequently collected for total RNA extraction in biologically independent quadruplicates (16 total samples).

暴露于被称为兴奋性应激（hormetic stress）的低水平环境刺激，例如营养剥夺与热休克，可增强机体后续的应激抵抗能力，并促进晚年健康衰老。然而，介导兴奋性营养应激下转录重编程的具体机制仍不明晰。本研究鉴定出组蛋白H3赖氨酸27乙酰化（histone H3 lysine 27 acetylation，H3K27ac）是转录组适应兴奋性禁食应激的关键驱动因子。除了通过增强脂质分解代谢以获取替代能源的即时功能外，应激诱导的H3K27ac还会激活终身性的抗氧化防御系统，从而减少应激诱导脂肪酸氧化产生的活性氧（reactive oxygen species，ROS）及其在衰老过程中的积累。由先锋转录因子PHA-4/FOXA与协同转录因子NHR-49/HNF4介导的H3K27ac水平升高，对于秀丽隐杆线虫（Caenorhabditis elegans）在兴奋性营养应激下的寿命延长至关重要。本研究结果证实，H3K27ac是连接营养状态与转录组重编程的关键转录开关，通过协调脂质分解代谢与抗氧化防御，为兴奋性禁食应激的延寿效应提供了分子基础。实验设计：将野生型（N2）动物与携带jmjd-3.1(gk384)纯合缺失突变且经cbp-1 RNAi敲低的H3K27ac缺陷型动物同步化至成虫第1天（D1），随后转移至充满大肠杆菌的自由进食培养基或禁食NGM RNAi平板中培养24小时，之后收集样本进行总RNA提取，每个生物学重复设置4次独立重复，总计16个样本。