Regulation of microRNA Strand Selection in Caenorhabditis elegans

项目总结/摘要 精确控制基因表达程序对于维持细胞内稳态和确保正常的细胞生长至关重要。 动物发展。不适当的基因表达与许多人类病理学有关， 调控基因表达的重要性。microRNAs（miRNAs）是真核生物基因调控的关键因子 表情尽管超过一半的人类mRNA是miRNA的预测靶点，但我们的了解 miRNA介导的基因抑制是如何实现的，这一点仍然不完整。miRNA依赖的关键步骤 基因调控是将茎环miRNA前体加工成双链miRNA双链体。每个 miRNA双链体包含两条注定不同命运的链：一条链装载到Argonaute效应子中， 蛋白质形成miRNA诱导的沉默复合物（miRISC），而另一条链被降解。作为 miRNA链可以是功能性的，决定哪条miRNA链有效地装载到Argonaute中 决定了miRISC的目标库。错误的miRNA链选择可能会产生严重的后果， 在许多人类疾病包括心房纤维性颤动， 多发性硬化症和几种癌症该提案的目的是调查监管机构 使用遗传上顺从的C. elegans模型系统。我会 建立miRNA双链体内在和外在特征对miRNA链调控的层次结构 选择.我的中心假设是，外部调节因素可以超越核苷酸序列线索， 以“开关样”方式调节miRNA链选择。总的来说，完成这项提案将大大 扩大我们对miRNA链选择如何在发展中国家的复杂背景下进行调节的理解， 有机体这些发现应该提供必要的基本见解，以了解如何miRNA链 在人类疾病中选择被破坏。

Project Summary/Abstract Precise control of gene expression programs is critical to maintain cellular homeostasis and ensure normal animal development. Improper gene expression is associated with numerous human pathologies, highlighting the importance of regulated gene expression. microRNAs (miRNAs) are key regulators of eukaryotic gene expression. Although more than half of all human mRNAs are predicted targets of miRNAs, our understanding of how miRNA-meditated gene repression is achieved remains incomplete. A critical step of miRNA-dependent gene regulation is the processing of stem-loop miRNA precursors into double-stranded miRNA duplexes. Each miRNA duplex comprises two strands destined for different fates: one strand is loaded into an Argonaute effector protein to form the miRNA-induced silencing complex (miRISC), while the other strand is degraded. As either miRNA strand can be functional, the decision of which miRNA strand is loaded into Argonaute effectively determines the target repertoire of miRISC. Improper miRNA strand choice can have severe consequences, as alternative miRNA strand selection has been observed in numerous human diseases including atrial fibrillation, multiple sclerosis, and several cancers. The objective of this proposal is to investigate the regulatory mechanisms of miRNA strand selection in vivo using the genetically amenable C. elegans model system. I will establish the hierarchy of miRNA duplex intrinsic and extrinsic features towards the regulation of miRNA strand selection. My central hypothesis is that external regulatory factors can override nucleotide sequence cues to regulate miRNA strand selection in a ‘switch-like’ fashion. Overall, completion of this proposal will significantly expand our understanding of how miRNA strand selection is regulated in the complex context of a developing organism. These findings should provide fundamental insights necessary to understand how miRNA strand selection becomes disrupted in human disease.