VARIATION AND REGULATION OF ALTERNATIVE SPLICING IN HUMAN TRANSCRIPTOMES

人类转录组中选择性剪接的变异和调控

基本信息

批准号：
9912772
负责人：
Yi Xing
金额：
$ 36.96万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-05 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912772
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 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 individual variation innovation insight interest mRNA Precursor novel response trait transcriptome transcriptome sequencing

项目摘要

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.

项目概要 R01 更新项目的中心目标是阐明替代方案的变化和监管人类转录组中的剪接（AS）。真核细胞产生惊人的调控多样性和复杂性来自一组有限基因的表型。前体 mRNA 的 AS 是产生这种物质所必需的机制监管多样性。几乎所有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、人类内部，响应发育信号和环境干扰和疾病发病机制。尽管 AS 在基因调控和疾病中很重要，但尽管该领域存在广泛的兴趣和研究活动，但仍然存在许多悬而未决的问题和重要的问题关于人类 AS 变异的景观、调节和功能后果的知识差距转录组。用于表征转录组复杂性的强大测序技术 (RNA-seq) 和蛋白质-RNA相互作用（CLIP-seq），以及不断向公众存入的大量数据域，为 AS 研究创造令人兴奋和前所未有的机会。该提案整合了数据—— 利用大转录组数据驱动的研究以及利用分子和技术的假设驱动的研究基因组工具。我们将通过三个目标研究灵长类动物中 AS 的进化（目标1），遗传变异人群中 AS 和表型关联（目标 2），以及人类 AS 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型异构测序数据集分析 AS 的方法。与我们之前的融资周期一样，我们将利用我们广泛的专家合作者网络来扩大我们工作的影响力并追求新的目标拟议项目范围内外的研究机会。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颖见解，并创造广泛的用于研究不同生物医学中 AS 变异和 mRNA 亚型复杂性的适用计算工具学科。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CLIP-seq analysis of multi-mapped reads discovers novel functional RNA regulatory sites in the human transcriptome.

DOI：
10.1093/nar/gkx646
发表时间：
2017-09-19
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Zhang Z;Xing Y
通讯作者：
Xing Y

Genetic variation of pre-mRNA alternative splicing in human populations.

DOI：
10.1002/wrna.120
发表时间：
2012-07
期刊：
WILEY INTERDISCIPLINARY REVIEWS-RNA
影响因子：
7.3
作者：
Lu, Zhi-Xiang;Jiang, Peng;Xing, Yi
通讯作者：
Xing, Yi

SURVIV for survival analysis of mRNA isoform variation.

DOI：
10.1038/ncomms11548
发表时间：
2016-06-09
期刊：
Nature communications
影响因子：
16.6
作者：
Shen S;Wang Y;Wang C;Wu YN;Xing Y
通讯作者：
Xing Y

PrimerSeq: Design and visualization of RT-PCR primers for alternative splicing using RNA-seq data.

DOI：
10.1016/j.gpb.2014.04.001
发表时间：
2014-04
期刊：
GENOMICS PROTEOMICS & BIOINFORMATICS
影响因子：
9.5
作者：
Tokheim, Collin;Park, Juw Won;Xing, Yi
通讯作者：
Xing, Yi

Deep-learning augmented RNA-seq analysis of transcript splicing.

DOI：
10.1038/s41592-019-0351-9
发表时间：
2019-04
期刊：
Nature methods
影响因子：
48
作者：
Zhang Z;Pan Z;Ying Y;Xie Z;Adhikari S;Phillips J;Carstens RP;Black DL;Wu Y;Xing Y
通讯作者：
Xing Y