Regulation of microRNA Strand Selection in Caenorhabditis elegans

项目摘要/摘要 对基因表达程序的精确控制对于维持细胞内环境平衡和确保正常 动物发育。不适当的基因表达与许多人类病理有关，强调 调控基因表达的重要性。MicroRNAs(MiRNAs)是真核基因的关键调控因子 表情。虽然超过一半的人类mRNAs是miRNAs的预测目标，但我们的理解是 关于miRNA冥想的基因抑制是如何实现的，目前还不完全。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。每个人 MiRNA双链由两条注定不同命运的链组成：一条链被装载到ArgAerte效应器中 蛋白质形成miRNA诱导的沉默复合体(MiRISC)，而另一条链被降解。作为任何一种 MiRNA链可以是功能性的，决定哪条miRNA链被有效地装载到ArgAerte中 确定miRISC的目标曲目。不适当的miRNA链选择可能会产生严重的后果，如 在许多人类疾病中已经观察到可选的miRNA链选择，包括心房颤动， 多发性硬化症和几种癌症。这项提案的目标是调查监管机构 利用可遗传的线虫模型系统进行体内miRNA链选择的机制。这就做 建立针对miRNA链调节的miRNA双链内在和外在特征的层次结构 选择。我的中心假设是，外部调控因素可以超越核苷酸序列线索，从而 以“开关”的方式调节miRNA链的选择。总体而言，这项提案的完成将显著 扩大我们对miRNA链选择如何在发育中的复杂背景下进行调控的理解 有机体。这些发现应该为理解miRNA是如何链的提供必要的基本见解 人类疾病中的选择被打乱了。

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.