Regulation, evolution, and function of promoter-associated non-coding RNAs

启动子相关非编码 RNA 的调控、进化和功能

• 批准号: 10248356
• 负责人: Leighton James Core
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248356
• 关键词: Affect; Biogenesis; Biology; Birth; Classification; Classification Scheme; Code; Computing Methodologies; Connecticut; Cues; Development; Disease; Doctor of Philosophy; Enhancers; Evolution; Foundations; Gene Expression; Genes; Genetic Transcription; Investigation; Methods; Modeling; Nucleotides; Pattern; Phase; Phenotype; Production; Proteins; RNA; RNA Processing; Regulation; Resources; Role; Signal Pathway; System; Testing; Transcript; Transcriptional Regulation; Translations; Untranslated RNA; Work; promoter; protein expression; recruit; response; transcription factor; transcriptome sequencing

PROJECT SUMMARY / ABSTRACT LEIGHTON CORE, Ph.D. – UNIVERSITY OF CONNECTICUT= Proper regulation of RNA transcription is essential for dynamic control of cellular responses to environmental and developmental cues. Dogmatic shifts in the fields of transcription regulation and RNA biology have led us to appreciate that noncoding RNAs (ncRNAs) can regulate transcription of protein-coding genes by diverse mechanisms such as recruitment of activators or repressors to gene promoters and enhancers or by affecting RNA processing. In addition to the role of the RNA, the act of transcription itself can positively or negatively influence promoter activity when transcription patterns overlap. These observations suggest that regulation of ncRNA biogenesis adds an intricate layer of control to overall gene expression levels. This proposal aims to 1) identify the mechanisms that regulate ncRNA production and destruction, 2) determine ncRNA effect on local protein-coding gene transcription and RNA processing, and 3) investigate the ability of ncRNAs to as capacitors for evolution of new genes. The major obstacles in understanding the full impact of ncRNAs on gene transcription is comprehensive identification of non-coding transcripts and methods to functionally classify them. The work proposed here will develop new experimental and computational methods for comprehensive identification of transcripts and a classification scheme that will predict function. We will experimentally test our functional predictions and use the results to inform further revision of our classification system. We will focus on ncRNAs that overlap with or emanate from protein-coding promoters to determine if they are regulated by independent signaling pathways and whether their level of production influences expression from the protein- coding gene. Finally, using an evolutionary model to identify nucleotide changes associated with altered ncRNA transcript production and processing, we will identify and test mechanisms that are involved in ncRNA regulation and how they may serve as a platform for gene birth during evolution. These studies will create functional transcript annotations that will be a primary resource for those studying gene expression in any context. In addition, our investigation of ncRNA regulation and evolution will serve as foundational work towards determining how these transcripts affect development, disease, and acquisition of new phenotypes.

项目概要/摘要 LEIGHTON CORE 博士 – 康涅狄格大学= RNA转录的正确调节对于动态控制细胞对环境的反应至关重要 转录调控和 RNA 生物学领域的教条转变引导了我们。 了解非编码 RNA (ncRNA) 可以通过多种方式调节蛋白质编码基因的转录 机制，例如招募激活子或阻遏子到基因启动子和增强子或通过影响 RNA加工除了RNA的作用外，转录行为本身也可以是积极的或消极的。 当转录模式重叠时影响启动子活性这些观察表明 ncRNA 生物发生为整体基因表达水平添加了复杂的控制层，该提案旨在 1)。 确定调节 ncRNA 产生和破坏的机制，2) 确定 ncRNA 对局部的影响 蛋白质编码基因转录和 RNA 加工，以及 3) 研究 ncRNA 的能力 理解 ncRNA 对新基因进化的全面影响的主要障碍。 基因转录是对非编码转录本的综合鉴定和功能分类的方法 这里提出的工作将为综合开发新的实验和计算方法。 我们将通过实验测试我们的转录本和预测功能的分类方案。 我们将重点关注功能预测并利用结果为我们的分类系统的进一步修订提供信息。 对与蛋白质编码启动子重叠或源自蛋白质编码启动子的 ncRNA 进行分析，以确定它们是否受 独立的信号通路以及它们的产生水平是否影响蛋白质的表达 最后，使用进化模型来识别与编码基因相关的核苷酸变化。 ncRNA 转录本的产生和处理，我们将识别和测试 ncRNA 涉及的机制 这些研究将创造调控以及它们如何作为进化过程中基因诞生的平台。 功能转录本注释将成为研究任何基因表达的人的主要资源 此外，我们对 ncRNA 调控和进化的研究将作为基础工作。 确定这些转录本如何影响发育、疾病和新表型的获得。