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.

项目摘要该提案寻求竞争性更新的多PI项目（FU和YEO），该项目旨在使用全球阐明哺乳动物基因组中RNA结合蛋白（RBP）的调节原理的方法。基于我们在过去的资金周期中的成就，我们建议利用强大的实验性和计算工具我们已经开发了四个特定目标。在AIM 1中，我们将夫妇获得并获得失去功能多目标屏幕，无法在剪接和聚腺苷酸水平上推断调节途径。我们将专注于确定不同RNA聚合酶II（POL II）亚基的特定功能，而不是仅由Pol II CTD，在招募共同转录RNA的RNA加工机器中加工。在AIM 2中，我们将制定一种系统识别染色质相关的一般策略 RBP确定某些RBP对转录和共转录RNA处理的直接贡献反应。我们将集中精力在剖析潜在的新途径中的表观遗传控制中特定RBP在直接转录控制中的替代剪接以及更广泛的作用。在AIM 3中，我们将使用一种新的策略来识别和表征非规范的RBP。专注于大型新鉴定的手指锌（ZNF）蛋白的数量，我们建议确定它们在与两者结合的作用 DNA和RNA并推导其与RNA的全转录组相互作用。我们还建议追求在此目标中，特定的范式以新近确定的RBP与核孔相关以确定它在选择性mRNA核输出中的作用，这与ALS调节的疾病病理有关。结合在一起，我们认为这个全面，相互联系和假设驱动的研究计划将大大提高了我们对受调节的RNA处理和相关疾病机制的理解。