Transcriptional Activation by Small RNA: Mechanism and Design Rules

小 RNA 的转录激活：机制和设计规则

• 批准号: 7938802
• 负责人: HAO LI
• 金额: $ 45.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938802
• 关键词: Address; Bioinformatics; Biological; Cells; Disease; Double-Stranded RNA; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Silencing; Gene Targeting; Genomics; Goals; Life; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Molecular Biology; Molecular Machines; Physiological; Process; Public Health; RNA Interference; Sensitivity and Specificity; Small RNA; Transcriptional Activation; design; gene function; gene therapy; improved; insight; promoter; public health relevance; tool

DESCRIPTION (provided by applicant): The goal of this application is to establish a new paradigm of gene regulation mediated by small RNA. Until recently, small RNAs have been thought to function mainly as the mediators of an evolutionally conserved gene silencing mechanism known as RNAi. We and others discovered that small double stranded RNA (dsRNA) targeting gene promoter sequence can induce potent and prolonged gene activation at the transcriptional level and in a sequence-specific manner, a phenomenon we termed RNAa. Despite the enormous potential for reprogramming gene expression in living cells, the molecular mechanism of RNAa is largely unknown and the rules for target selection are still quite obscure. We propose to use a combination of genomic, bioinformatic, and molecular biology approaches to address the following questions: How is transcriptional activation by promoter-targeted dsRNA achieved? What are the molecular machines involved? Is RNAa naturally exploited by cells for physiological function? What are the general rules governing the sensitivity and specificity of dsRNA-promoter targeting? Understanding the molecular mechanism of RNAa and establishing it as a new paradigm are likely to transform the way gene function is studied and diseases such as cancer are treated. PUBLIC HEALTH RELEVANCE: RNAa is potentially a biological mechanism of fundamental importance. Understand this mechanism will have enormous potential for improving public health. First, RNAa may provide new insight to many physiological and diseases processes; second, RNAa can be used as a tool to interrogate gene function and study their involvement in diseases; lastly, RNAa may serve as a promising surrogate for traditional gene therapy for many diseases especially cancer.

描述（由申请人提供）：本申请的目标是建立由小RNA介导的基因调控的新范例。直到最近，小RNA一直被认为主要充当进化上保守的基因沉默机制（称为RNAi）的介体。我们和其他人发现，靶向基因启动子序列的小双链 RNA (dsRNA) 可以在转录水平上以序列特异性方式诱导有效且延长的基因激活，我们将这种现象称为 RNAa。尽管在活细胞中重编程基因表达具有巨大的潜力，但 RNAa 的分子机制在很大程度上仍是未知的，并且靶标选择的规则仍然相当模糊。我们建议结合使用基因组学、生物信息学和分子生物学方法来解决以下问题：启动子靶向的 dsRNA 是如何实现转录激活的？涉及哪些分子机器？ RNAa 是否自然地被细胞利用来发挥生理功能？控制 dsRNA 启动子靶向的敏感性和特异性的一般规则是什么？了解 RNAa 的分子机制并将其建立为新的范式可能会改变基因功能的研究方式和癌症等疾病的治疗方式。 公共卫生相关性：RNAa 可能是一种具有根本重要性的生物学机制。了解这一机制将具有改善公共卫生的巨大潜力。首先，RNAa可能为许多生理和疾病过程提供新的见解；其次，RNAa 可用作探查基因功能并研究其与疾病的关系的工具；最后，RNAa 可能作为传统基因疗法的有前景的替代品，治疗许多疾病，尤其是癌症。