Regulation of microRNA Strand Selection in Caenorhabditis elegans

秀丽隐杆线虫 microRNA 链选择的调控

• 批准号: 10682406
• 负责人: Jeffrey Christopher Medley
• 金额: $ 7.26万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-08 至 2024-08-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682406
• 关键词: Address; Affect; Animals; Atrial Fibrillation; Base Sequence; Biogenesis; Biological Models; CRISPR/Cas technology; Caenorhabditis elegans; Complex; Cues; Data; Detection; Development; Ensure; Event; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Goals; Homeostasis; Human; Human Pathology; In Vitro; Malignant Neoplasms; Mediating; Medicine; Meditation; Messenger RNA; MicroRNAs; Modification; Molecular; Multiple Sclerosis; Mutate; Nucleotides; Organism; Pathologic; Pathway interactions; Play; Proteins; Regulation; Regulator Genes; Repression; Research; Role; Testing; Therapeutic; adenylate; gene repression; genetic analysis; genome editing; genome-wide; human disease; in vivo; insight; mutant; overexpression; programs; pup; stem; tool; uridylate

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.

项目概要/摘要 基因表达程序的精确控制对于维持细胞稳态并确保正常运转至关重要 动物发育不当与许多人类病理有关。 调控基因表达的重要性。microRNA (miRNA) 是真核基因的关键调控因子。 尽管超过一半的人类 mRNA 是 miRNA 的预测目标，但我们的理解是。 miRNA 介导的基因抑制是如何实现的仍然不完整，这是 miRNA 依赖性的一个关键步骤。 基因调控是将茎环 miRNA 前体加工成双链 miRNA 双链体。 miRNA 双链体包含两条具有不同命运的链：一条链被加载到 Argonaute 效应器中 蛋白质形成 miRNA 诱导的沉默复合物 (miRISC)，而另一条链则被降解。 miRNA 链可以发挥功能，决定哪条 miRNA 链有效加载到 Argonaute 中 决定 miRISC 的目标库 不正确的 miRNA 链选择可能会产生严重后果，例如 在许多人类疾病中观察到替代 miRNA 链选择，包括心房颤动、 该提案的目的是调查监管情况。 我将使用遗传上适合的线虫模型系统进行体内 miRNA 链选择的机制。 建立 miRNA 双链体内在和外在特征的层次结构，以调控 miRNA 链 我的中心假设是外部调节因素可以凌驾于核苷酸序列线索之上。 以“类似开关”的方式调节 miRNA 链的选择，总体而言，该提案的完成将具有重大意义。 扩展我们对 miRNA 链选择如何在发育中的复杂背景下进行调节的理解 这些发现应该为理解 miRNA 如何链提供必要的基本见解。 选择在人类疾病中被破坏。