Differential regulation of duplicated fatty acid-binding protein genes of zebrafish

在生命进化过程中，促进生物体日益复杂的主要机制之一是基因和整个基因组的复制。我们正在研究属于多基因家族的重复基因编码的细胞内脂质结合蛋白（iLBP）的斑马鱼的调控和进化。该家族包括斑马鱼的脂肪酸、视黄醇（维生素A衍生物）和视黄酸结合蛋白。iLBP涉及从长链脂肪酸、胆汁盐和类维生素A的摄取和细胞内转运到调节人类基因调控、神经发生和疾病状态的无数细胞过程。我们选择斑马鱼作为实验模式生物进行研究，因为它具有哈代、抗病、易于饲养和成本低廉等优点，并且在实验胚胎学和遗传分析中具有重要的应用价值。此外，斑马鱼是研究脊椎动物发育的模型系统，其中胚胎发生的阶段被很好地表征。到目前为止，我们已经确定了22个成员的斑马鱼iLBP多基因家族。许多iLBP基因的复制是由于整个基因组复制事件发生在约2.3亿至4亿年前的鳍鱼谱系中。我们已经表明，几个斑马鱼iLBP基因的转录诱导的膳食脂肪酸，我们建议测试这些iLBP基因的重复拷贝是否已保留在斑马鱼基因组中，由于功能的进化（S）。所提出的研究的目的是确定iLBP基因启动子中的顺式作用元件。此外，我们计划确定哪些核转录因子及其激活配体（例如，脂肪酸和氯贝特，一种已知可诱导某些参与脂质代谢的哺乳动物基因的药物）结合顺式元件以诱导特定的iLBP基因，以及这些顺式和反式作用因子如何进化。此外，由于控制斑马鱼正常胚胎发生、生长和繁殖的许多基因在哺乳动物中是相似或相同的，我们使用斑马鱼作为模型系统的研究可能会深入了解iLBP基因在人类发育和疾病（如糖尿病、动脉粥样硬化和肥胖）中的作用。

One of the major mechanisms thought to facilitate the increasing complexity of organisms in the evolution of life is duplication of genes and entire genomes. We are investigating the regulation and evolution of duplicated genes belonging to the multigene family coding for intracellular lipid-binding proteins (iLBP) of zebrafish. This family includes the fatty acid-, retinol- (a vitamin A derivative) and retinoic acid-binding proteins of zebrafish. iLBPs have been implicated in a myriad of cellular processes from uptake and intracellular transport of long-chain fatty acids, bile salts and retinoids, to modulating gene regulation, neurogenesis, and disease states in humans. We chose zebrafish as the experimental model organism for our studies as it is hardy, disease resistant, easily and inexpensively reared, and useful in the application of both experimental embryology and genetic analysis. Moreover, zebrafish is a model system to study vertebrate development in which stages of embryogenesis are well characterized. To date, we have characterized 22 members of the zebrafish iLBP multigene family. Many iLBP genes are duplicated owing to a whole genome duplication event that occurred in the ray-finned fish lineage ~230-400 million years ago. We have shown that transcription of several zebrafish iLBP genes is induced by dietary fatty acids and we propose to test whether duplicated copies of these iLBP genes have been retained in the zebrafish genome owing to evolution of function(s). The objectives of the proposed studies are to identity the cis-acting elements in the iLBP gene-promoters. Furthermore, we plan to determine which nuclear transcription factors and their activating ligands (e.g., fatty acids and clofibrate, a drug known to induce some mammalian genes involved in lipid metabolism) bind cis-elements to induce specific iLBP genes, and how these cis- and trans-acting factors evolved. In addition, since many of the genes that control normal embryogenesis, growth and reproduction in zebrafish are similar, or the same, in mammals, our studies using zebrafish as a model system may provide insights into the roles of the iLBP genes implicated in human development and disease, such as diabetes, atherosclerosis and obesity.