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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：
9097762
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9097762
关键词：
Alternative Splicing Binding Binding Proteins Cells Code Collection Complement Complex Computing Methodologies Coupling Custom DNA Sequence Alteration Data Data Set Development Disease Dissection Double-Stranded RNA Ectopic Expression Epigenetic Process Event Funding Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Grant Health Human Human Genome Indium Individual Laboratories Length Libraries Link Malignant Neoplasms Mammalian Cell Mediating Messenger RNA Molecular Mutation National Human Genome Research Institute Nerve Degeneration Neurodegenerative Disorders Open Reading Frames Pathway Analysis Pathway interactions Positioning Attribute Process Productivity Protein Isoforms Proteins Proteomics Publications Publishing RNA RNA Interference RNA Processing RNA Splicing RNA analysis RNA interference screen RNA-Binding Proteins Reagent Regulation Regulator Genes Research Resources Ribonucleases Series Signal Pathway Signaling Molecule Structure System Technology Translations Untranslated RNA base cell type cis acting element computerized tools effective therapy gain of function genome-wide genomic RNA genomic data genomic tools human disease innovation insight leukemia mammalian genome novel overexpression predictive modeling protein TDP-43 protein complex protein protein interaction response screening small hairpin RNA transcriptome sequencing transcriptomics treatment strategy two-dimensional

项目摘要

DESCRIPTION (provided by applicant): This proposal seeks renewal of a multi-PI project (Fu and Yeo) to use global approaches to elucidate regulatory principles in the regulation of alternative splicing in mammalian genomes. Built upon our accomplishments in the past funding cycle, including extensive preliminary results, we propose to conduct several systematic loss- and gain-of-function studies to identify genes, gene networks, and pathways involved in the regulation of alternative splicing in three specific aims. The first aim is to perform large-scale network analysis of regulated alternative splicing. Using the two-dimensional mRNA isoform profiling platform developed in our labs, we propose to conduct both genome-wide RNAi and overexpression screening in HEK293 cells and score a set of commonly regulated splicing events (~400) in each treatment condition. We will also complement these genome-wide perturbation studies with transcriptomic analyses by comprehensive RNA-seq against shRNA-mediated depletion (already completed) and ectopic expression of ~300 carefully selected RNA binding proteins (RBPs). These data will help identify new splicing factors, integrate RBPs into transcription, epigenetic and signaling pathways, and decipher both unique and dominant functions of individual RBPs. In the second aim, we propose to analyze RBP-centric protein-protein interaction networks. In particular, we propose to take full advantage of our validated library of open reading frames encoding RBPs for quantitative proteomic analysis of 300 RBPs with and without RNase treatment to identify both RNA-dependent and independent interactions within the framework of RBP complexes. Using the large datasets of functional RNA targets (Aim 1) and RBP-centric protein-protein interactions (Aim 2), we will in Aim 3 perform integrated analysis of RNA genomics data to build predictive models of the regulation of alternative splicing by RBPs. We will use or develop a set of computational tools to predict novel RBP targets, refine individual RBP-central gene networks, and most importantly, integrate comprehensive RBP cis and trans interactomes with system-wide perturbation to build predictive models for cell-specific regulation of alternative splicing. We believe that such integrated analysis will have major impacts on our understanding of regulated splicing and associated disease mechanisms.

描述（由申请人提供）：