Unbiased discovery of mechanisms regulating circRNA

circRNA调节机制的公正发现

基本信息

批准号：
9332410
负责人：
Julia Salzman
金额：
$ 31.21万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-21 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332410
关键词：
Address Affect Algorithms Alternative Splicing Attention Biochemical Biochemical Pathway Biogenesis Biological Biology Brain CRISPR/Cas technology Cardiomyopathies Cells Data Data Set Detection Development Disease Engineering Event Evolution Exons Foundations Gene Expression Genes Genetic Screening Genetic Transcription Genome Genomics Health Heart Human Human Development Introns Kinetics Length Life Malignant Neoplasms Messenger RNA Methods Modeling Molecular Mutate Nerve Degeneration Nuclear Export Organism Play Post-Transcriptional Regulation Postdoctoral Fellow Production Protein Isoforms Proteins RNA RNA Processing RNA Splicing Regulation Reporter Role Screening Result Signal Pathway Signal Transduction Site Specificity Statistical Algorithm Statistical Data Interpretation Statistical Methods Statistical Models Systems Analysis Techniques Testing Time Trans-Activators Variant Work base cell type circular RNA computer science experimental study genome editing genome-wide genome-wide analysis human disease improved knock-down novel programs public health relevance tool transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant) RNA is an ancient carrier of biological information, whose many functions became necessary for the evolution of cellular life, and transcriptional and post-transcriptional regulation of RNA is central to health and the progression of human disease. Remarkably, we have discovered that thousands of human genes produce circular RNA (circRNA) isoforms and in hundreds of genes, the circRNA is more abundant than the linear isoform. Our recent work has shown that circRNA expression is particularly regulated during human development. We have also demonstrated that circular RNAs are produced in organisms separated by billions of years of evolution, which suggests that the machinery, and by implication, function, of circRNA is central to eukaryotic gene expression programs: either conserved over billions of years, or a feature that has re-evolved multiple times which implies a functional role for circRNAs in the cell. Together, our work suggests a fundamental hypothesis that alternative splicing has functional consequences apart from protein production, including the production of circRNA isoforms. Yet, the field lacks a predictive mechanistic model of the cis sequences and trans-acting factors that specifically regulate circRNA, meaning a) the biochemical signaling pathways used by the cell to produce circRNA are unknown; b) we lack molecular tools to specifically express circRNA without background transcription of off-target RNAs. Such tools are required for discovery and rigorous experimental tests of circRNA function. This proposal aims to discover the mechanisms controlling circRNA production and regulation and promises to reveal novel biology regarding how biochemical signals are transduced into alternatively spliced RNA molecules and provide crucial tools for discovering the function of circRNA. Specifically, we aim to 1) engineer statistical algorithms for detecting and quantifying circRNA variants, and statistical methods for integrating expression across datasets; 2) discover trans-acting factors regulating circRNA production, export and decay; 3) systematically discover cis sequence control of circRNA abundance. The work will build on our discoveries of regulated expression of circular in human development, to delineate their regulation under normal circumstances, and how dysregulation may contribute to diseases such as neurodegeneration and cardiomyopathy.

描述（由申请人提供） RNA 是一种古老的生物信息载体，其许多功能成为细胞生命进化所必需的，并且 RNA 的转录和转录后调控对于健康和人类疾病的进展至关重要。基因产生环状 RNA (circRNA) 同种型，并且在数百个基因中，circRNA 比线性同种型更丰富。我们最近的工作表明，circRNA 表达在人类发育过程中受到特别调节。数十亿年的进化相隔，这表明 circRNA 的机制以及暗示的功能是真核基因表达程序的核心：要么在数十亿年中保守，要么是已经多次重新进化的特征，这意味着总之，我们的工作提出了一个基本假设，即选择性剪接除了蛋白质生产之外还具有功能性后果，包括 circRNA 同工型的生产，然而，该领域缺乏预测机制模型。特异性调节 circRNA 的顺式序列和反式作用因子，这意味着 a) 细胞用于产生 circRNA 的生化信号通路是未知的；b) 我们缺乏在没有脱靶 RNA 背景转录工具的情况下特异性表达 circRNA 的分子工具。该提案旨在发现控制 circRNA 产生和调节的机制，并有望揭示有关生化信号如何转导为选择性剪接 RNA 分子的新生物学，并为研究提供关键工具。具体来说，我们的目标是 1) 设计用于检测和量化 circRNA 变异的统计方法，以及用于整合跨数据集表达的统计方法；2) 系统地发现调节 circRNA 生成算法、输出和衰减的反式作用因子；发现 circRNA 丰度的顺式序列控制这项工作将建立在我们对人类发育中 circRNA 调节表达的发现的基础上，以描述其在正常情况下的调节，以及调节失调如何导致神经退行性疾病等疾病。心肌病。