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.

项目摘要 /摘要 Leighton Core博士 - 康涅狄格大学= 正确调节RNA转录对于动态控制细胞对环境的反应至关重要 和发展线索。转录调节和RNA生物学领域的教条转移导致了我们 要欣赏非编码RNA（NCRNA）可以通过多种方式调节蛋白质编码基因的转录 诸如募集激活剂或复制剂为基因启动子和增强子或通过影响的机制 RNA处理。除了RNA的作用外，转录本身的行为还可以正面或负面 当转录模式重叠时会影响启动子活性。这些观察表明，调节 NCRNA生物发生为整体基因表达水平增加了复杂的控制层。该提议的目的是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处理，以及3）研究NCRNA的能力 新基因演变的电容器。理解NCRNA对全部影响的主要障碍 基因转录是对非编码转录本的综合鉴定，以便在功能上进行分类 他们。这里提出的工作将开发新的实验和计算方法，以综合 识别成绩单和将预测功能的分类方案。我们将通过实验测试我们的 功能预测并利用结果为我们的分类系统进行进一步修订。我们将集中精力 在与蛋白质编码启动子中重叠或散发的NCRNA上，以确定它们是否受到调节 独立的信号通路及其生产水平是否影响蛋白质的表达 编码基因。最后，使用进化模型来识别与变化相关的核苷酸变化 NCRNA转录本的生产和处理，我们将识别和测试与NCRNA有关的机制 调节及其如何作为进化过程中基因出生的平台。这些研究将创造 功能转录本注释将是研究任何基因表达的人的主要资源 语境。此外，我们对NCRNA监管和进化的投资将作为基础工作 确定这些转录本如何影响新表型的发育，疾病和获取。