Variation and regulation of alternative splicing in human transcriptomes

人类转录组选择性剪接的变异和调控

• 批准号: 9333758
• 负责人: Yi Xing
• 金额: $ 32.34万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-05 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333758
• 关键词: Alleles; Alternative Splicing; Biological Assay; Cells; Chromatin; Complement; Complex; Computer Analysis; Computing Methodologies; Data; Data Set; Deposition; Development; Discipline; Disease; Disease susceptibility; Epigenetic Process; Eukaryotic Cell; Evolution; Exons; Funding; Gene Expression Regulation; Genes; Genetic Transcription; Genetic Variation; Genome; Genotype-Tissue Expression Project; Human; Individual; Introns; Joints; Knowledge; Maps; Messenger RNA; Methods; Molecular; Pathogenesis; Pattern; Phenotype; Population; Primates; Protein Isoforms; Public Domains; Quantitative Trait Loci; RNA Splicing; RNA-Protein Interaction; Regulation; Regulatory Element; Research; Research Activity; Signal Transduction; Statistical Methods; Technology; Testing; Transcription Elongation; Variant; Work; cell type; computer studies; computerized tools; crosslinking and immunoprecipitation sequencing; epigenetic regulation; epigenome; epigenomics; experimental study; gene function; genomic tools; human tissue; improved; innovation; insight; interest; mRNA Precursor; novel; response; trait; transcriptome; transcriptome sequencing

PROJECT SUMMARY The central objective of this renewal R01 project is to elucidate the variation and regulation of alternative splicing (AS) in human transcriptomes. Eukaryotic cells generate astonishing regulatory diversity and complex phenotypes from a finite set of genes. AS of precursor mRNA is a mechanism essential for generating this regulatory diversity. Almost all multi-exon human genes are alternatively spliced. Widespread changes in AS occur between species, within human populations, in response to developmental signals and environmental perturbations, and in disease pathogenesis. Despite the importance of AS in gene regulation and disease, as well as extensive interest and research activities in this field, there remain many open questions and significant knowledge gaps regarding the landscape, regulation, and functional consequence of AS variation in human transcriptomes. Powerful sequencing technologies for characterizing transcriptome complexity (RNA-seq) and protein-RNA interaction (CLIP-seq), as well as the vast amounts of data continuously deposited into the public domain, create exciting and unprecedented opportunities for studies of AS. This proposal integrates data- driven research leveraging big transcriptome data with hypothesis-driven research using molecular and genomic tools. In three aims, we will investigate the evolution of AS in primates (Aim 1), the genetic variation and phenotypic association of AS in human populations (Aim 2), and epigenetic regulation of AS across human tissues and cell states (Aim 3). We will also develop and disseminate innovative computational and statistical methods for analyzing AS using large, heterogeneous sequencing datasets. As in our previous funding cycle, we will tap into our extensive network of expert collaborators to amplify the impact of our work and pursue new research opportunities within and beyond the scope of the proposed project. Collectively, our research will generate significant novel insights into the variation, regulation, and function of AS, and create broadly applicable computational tools for studying AS variation and mRNA isoform complexity in diverse biomedical disciplines.

项目摘要 该更新R 01项目的中心目标是阐明替代方案的变化和调节， 剪接（AS）在人类转录组。真核细胞产生惊人的调节多样性和复杂性 一组有限的基因的表型。前体mRNA的AS是产生这种 监管多样性。几乎所有的多外显子人类基因都是选择性剪接的。AS的广泛变化 发生在物种之间，在人类种群内，响应于发育信号和环境 干扰，以及疾病的发病机制。尽管AS在基因调控和疾病中的重要性， 尽管人们对这一领域有着广泛的兴趣和研究活动，但仍有许多悬而未决的问题和重要意义。 关于人类AS变异的景观、调控和功能后果的知识缺口 转录组用于表征转录组复杂性的强大测序技术（RNA-seq）， 蛋白质-RNA相互作用（CLIP-seq），以及大量的数据不断存入公众 领域，创造了令人兴奋的和前所未有的机会，研究AS。该提案整合了数据- 利用大转录组数据的假设驱动的研究， 基因组工具在三个目标中，我们将研究灵长类动物AS的进化 (Aim 1、遗传变异 AS在人群中的表型相关性（目的2），以及AS在人类中的表观遗传调控 组织和细胞状态（目标3）。 我们还将开发和传播创新的计算和统计 使用大的异质测序数据集分析AS的方法。与上一个融资周期一样， 我们将利用我们广泛的专家合作者网络，扩大我们工作的影响， 研究项目范围内和范围外的研究机会。总的来说，我们的研究将 对AS的变异、调节和功能产生重要的新见解， 适用于研究AS变异和mRNA异构体复杂性的计算工具， 学科