Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU).
Department of Clinical Engineering, Faculty of Health Sciences, Komatsu University.
Biol Pharm Bull. 2021;44(8):1160-1165. doi: 10.1248/bpb.b21-00432.
The circadian clock is a highly conserved 24 h biological oscillation mechanism and is affected by environmental stimuli such as light, food and temperature. Disruption of the circadian clock results in disorders of diverse biological processes, including the sleep-wake cycle and metabolism. Although we previously identified several components of the circadian clock in zebrafish, our understanding of the relationship between light-inducible clock genes and metabolism remains incomplete. To investigate how light-inducible clock genes regulate metabolism, we performed transcriptomic and metabolomic analyses of the light-inducible clock genes zPer2, zCry1a, and zCry2a in zebrafish. Transcriptomic analysis of zPer2/zCry1a double knockout (DKO) and zPer2/zCry1a/zCry2a triple knockout (TKO) mutants showed that their gene expression profiles differed from that of wild type (WT) zebrafish. In particular, mRNA levels of zKeap1a, which encodes an oxidative stress sensor, were increased in DKO and TKO mutants. Metabolomic analysis showed genotype-dependent alteration of metabolomic profiles. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) showed the alteration of cysteine/methionine metabolism and glutathione metabolism. Specifically, cysteine and glutathione were decreased but methionine sulfoxide was increased in TKO zebrafish. These results indicate that the light-inducible genes zPer2, zCry1a, and zCry2a are involved in regulating the oxidative status of zebrafish.
生物钟是一种高度保守的 24 小时生物振荡机制，受环境刺激（如光、食物和温度）的影响。生物钟的紊乱会导致多种生物过程的紊乱，包括睡眠-觉醒周期和代谢。虽然我们之前已经在斑马鱼中鉴定出了几个生物钟的组成部分，但我们对光诱导的时钟基因与代谢之间的关系的理解仍然不完整。为了研究光诱导的时钟基因如何调节代谢，我们对斑马鱼中的光诱导时钟基因 zPer2、zCry1a 和 zCry2a 进行了转录组和代谢组分析。zPer2/zCry1a 双敲除（DKO）和 zPer2/zCry1a/zCry2a 三敲除（TKO）突变体的转录组分析表明，它们的基因表达谱与野生型（WT）斑马鱼不同。特别是，编码氧化应激传感器的 zKeap1a 的 mRNA 水平在 DKO 和 TKO 突变体中增加。代谢组分析显示基因型依赖的代谢组谱改变。主成分分析（PCA）和偏最小二乘判别分析（PLS-DA）显示半胱氨酸/蛋氨酸代谢和谷胱甘肽代谢的改变。具体来说，TKO 斑马鱼中的半胱氨酸和谷胱甘肽减少，但蛋氨酸亚砜增加。这些结果表明，光诱导基因 zPer2、zCry1a 和 zCry2a 参与调节斑马鱼的氧化状态。
