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.

项目摘要该更新R01项目的核心目的是阐明替代方案的变化和调节人类转录组中的剪接（AS）。真核细胞产生惊人的调节多样性和复杂性来自有限基因的表型。从前体mRNA开始是产生此机制的一种机制监管多样性。几乎所有的多外结果人类基因都是剪接的。广泛的变化AS 响应于发展信号和环境的物种之间的物种之间发生扰动和疾病发病机理。尽管在基因调节和疾病中很重要，但以及该领域的广泛兴趣和研究活动，还有许多开放问题和重大的问题关于人类变异的景观，调节和功能后果的知识差距转录组。强大的测序技术来表征转录组复杂性（RNA-SEQ）和蛋白-RNA相互作用（夹子seq），以及不断沉积在公众中的大量数据域，创造令人兴奋且前所未有的AS研究机会。该提案整合了数据 - 通过使用分子和基因组工具。在三个目标中，我们将研究灵长类动物的AS的演变（AIM 1），遗传变异与人类种群中的AS（AIM 2）和AS的表观遗传调节组织和细胞状态（AIM 3）。我们还将开发和传播创新的计算和统计分析使用大型异质测序数据集的方法。就像我们以前的资金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的工作影响并追求新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的变化，调节和功能产生重大的新颖见解，并广泛创建用于研究的适用计算工具，以变异和mRNA同工型复杂性学科。

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