Functional RNA elements in the human genome

人类基因组中的功能性RNA元件

基本信息

批准号：
9381421
负责人：
XIANG-DONG FU
金额：
$ 69.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9381421
关键词：
Address Alternative Splicing Area Binding Binding Proteins Binding Sites Bioinformatics Biology Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Coupling DNA DNA Polymerase II DNA-Directed RNA Polymerase Data Set Development Disease Dissection Elements Epigenetic Process Event Funding Gene Expression Genes Genetic Transcription Genomic approach Genomics Goals Grant Human Genome Individual Lead Mammalian Cell Mass Spectrum Analysis Messenger RNA Metabolism Methodology Methods Molecular National Human Genome Research Institute Nuclear Export Nuclear Pore Pathology Pathway Analysis Pathway interactions Pattern Phase Polyadenylation Positioning Attribute Productivity Protein Analysis Proteins Publications RANGAP1 gene RNA RNA Binding RNA Processing RNA Recognition Motif RNA Splicing RNA analysis RNA-Binding Proteins RNA-Protein Interaction Reaction Recruitment Activity Regulation Regulatory Pathway Reproducibility Research Role Sequence Homology Series Testing Transcriptional Regulation Untranslated RNA Zinc Fingers computerized tools effective therapy genome-wide genomic RNA genomic tools human disease infancy innovation insight mRNA Precursor mammalian genome novel novel strategies nucleocytoplasmic transport protein profiling protein protein interaction screening technological innovation transcription factor transcriptome treatment strategy

项目摘要

Project Summary This proposal seeks competitive renewal of a multi-PI project (Fu and Yeo), which aims to use global approaches to elucidate the regulatory principles of RNA binding proteins (RBPs) in mammalian genomes. Built upon our accomplishments in the past funding cycle, we propose to leverage the powerful experimental and computational tools we have developed to pursue four specific aims. In Aim 1, we will couple gain- and lost-of-function multi-target screens to deduce regulatory pathways at both splicing and polyadenylation levels. We will focus on determining the specific function of different RNA polymerase II (Pol II) subunits, rather than by the Pol II CTD alone, in the recruitment of RNA processing machineries for co-transcriptional RNA processing. In Aim 2, we will develop a general strategy for systematic identification of chromatin-associated RBPs to determine direct contribution of some RBPs to transcription and co-transcriptional RNA processing reactions. We will concentrate our efforts in dissecting a potential new pathway in epigenetic control of alternative splicing as well as broader roles of specific RBPs in direct transcriptional control. In Aim 3, we will use a novel strategy for identification and characterization of non-canonical RBPs. Focusing on a large number of newly identified finger zinc (Znf) proteins, we propose to determine their roles in binding to both DNA and RNA and deduce their transcriptome-wide interactions with RNA. We also propose to pursue a specific paradigm in this aim on a newly identified RBP known to associate with the nuclear pore to determine its role in selective mRNA nuclear export, which is pertinent to an ALS-regulated disease pathology. Combined, we believe that this comprehensive, interconnected, and hypothesis-driven research plan will greatly advance our understanding of regulated RNA processing and associated disease mechanisms.

项目概要该提案寻求对多 PI 项目（Fu 和 Yeo）进行竞争性更新，旨在利用全球阐明哺乳动物基因组中 RNA 结合蛋白 (RBP) 调控原理的方法。基于我们在过去的融资周期中取得的成就，我们建议利用强大的实验我们开发了计算工具来实现四个具体目标。在目标 1 中，我们将耦合增益和功能丧失的多靶点筛选，以推断剪接和聚腺苷酸化水平的调控途径。我们将重点确定不同 RNA 聚合酶 II (Pol II) 亚基的具体功能，而不是仅由 Pol II CTD 招募用于共转录 RNA 的 RNA 加工机器加工。在目标 2 中，我们将制定系统鉴定染色质相关蛋白的总体策略 RBP 用于确定某些 RBP 对转录和共转录 RNA 加工的直接贡献反应。我们将集中精力剖析表观遗传控制的潜在新途径选择性剪接以及特定 RBP 在直接转录控制中的更广泛作用。在目标 3 中，我们将使用一种新的策略来识别和表征非规范 RBP。着眼于大新鉴定的指状锌 (Znf) 蛋白的数量，我们建议确定它们在与两者结合中的作用 DNA 和 RNA 并推断它们与 RNA 的转录组范围内的相互作用。我们还建议推行该特定范式的目标是新鉴定的 RBP 已知与核孔相关，以确定它在选择性 mRNA 核输出中的作用，这与 ALS 调节的疾病病理学相关。结合起来，我们相信这个全面的、相互关联的、假设驱动的研究计划将极大地增进了我们对RNA加工调控和相关疾病机制的理解。