Zebrafish is increasingly being used to study liver injury and regeneration. However, very little is known about molecular players that respond to injury and those important for liver regeneration. We use a metronidazole nitroreductase (MTZ-nfsb)-based system to selectively ablate hepatocytes in adult zebrafish to create a model for liver injury and regeneration. In this study, we generate a comprehensive temporal map of gene expression changes during regeneration through RNA sequencing of liver samples at various stages of injury and regeneration. Analyzing these data, we find that soon after injury the immediate early transcription factor MYC induces a battery of genes that respond to the MTZ-induced ROS by activating oxido-reductase pathways and apoptosis machinery. Immediately after injury, liver cells downregulate many functional genes, including complement protein synthesis, bile acid, and lipid biosynthesis, in a concerted manner. At 6 days postinjury, we find a dramatic induction of cholesterol biosynthesis and protein folding machinery, with expression levels returning to predamage levels by 8 days, suggesting an important role for these pathways in liver regeneration. This chronological transcriptomic map of liver regeneration in zebrafish would serve as a framework for further studies in understanding, and for screening for compounds that augment liver regeneration.

中文翻译：

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斑马鱼肝再生过程中基因表达模式的时间图。

斑马鱼越来越多地用于研究肝损伤和再生。然而，对分子损伤和肝脏再生重要的分子知之甚少。我们使用基于甲硝唑硝基还原酶（MTZ-nfsb）的系统选择性地消融成年斑马鱼的肝细胞，以创建肝脏损伤和再生的模型。在这项研究中，我们通过损伤和再生各个阶段的肝样品的RNA测序，生成了再生期间基因表达变化的综合时间图。分析这些数据，我们发现在损伤后不久，立即早期转录因子MYC通过激活氧化还原酶途径和细胞凋亡机制诱导了一系列基因，这些基因对MTZ诱导的ROS作出反应。受伤后，肝细胞立即下调许多功能基因，包括补体蛋白合成，胆汁酸和脂质生物合成。受伤后第6天，我们发现胆固醇生物合成和蛋白质折叠机制具有显着诱导作用，到8天时表达水平又恢复到损伤前水平，表明这些途径在肝再生中具有重要作用。斑马鱼肝脏再生的这个时间序列转录图谱将为进一步的研究提供框架，以了解和筛选增强肝脏再生的化合物。提示这些途径在肝再生中起重要作用。斑马鱼肝脏再生的这个时间序列转录图谱将为进一步的研究提供框架，以了解和筛选增强肝脏再生的化合物。提示这些途径在肝再生中起重要作用。斑马鱼肝脏再生的这个时间序列转录图谱将为进一步的研究提供框架，以了解和筛选增强肝脏再生的化合物。