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.

Public Health Relevance

Pre-mRNA alternative splicing generates enormous regulatory and functional diversity from a finite set of genes in eukaryotic genomes. This project will systematically investigate the evolution, genetic variation, and epigenetic regulation of alternative splicing in human transcriptomes. The proposed studies will provide significant insights into the regulation and function of alternative splicing, and how changes in alternative splicing impact complex traits and diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088342-10
Application #
9667440
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ravichandran, Veerasamy
Project Start
2010-04-05
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19146
Zhang, Zijun; Park, Eddie; Lin, Lan et al. (2018) A panoramic view of RNA modifications: exploring new frontiers. Genome Biol 19:11
Park, Eddie; Pan, Zhicheng; Zhang, Zijun et al. (2018) The Expanding Landscape of Alternative Splicing Variation in Human Populations. Am J Hum Genet 102:11-26
Zhou, Chan; Molinie, Benoit; Daneshvar, Kaveh et al. (2017) Genome-Wide Maps of m6A circRNAs Identify Widespread and Cell-Type-Specific Methylation Patterns that Are Distinct from mRNAs. Cell Rep 20:2262-2276
Zhang, Zijun; Xing, Yi (2017) CLIP-seq analysis of multi-mapped reads discovers novel functional RNA regulatory sites in the human transcriptome. Nucleic Acids Res 45:9260-9271
Park, Eddie; Guo, Jiguang; Shen, Shihao et al. (2017) Population and allelic variation of A-to-I RNA editing in human transcriptomes. Genome Biol 18:143
Shen, Shihao; Wang, Yuanyuan; Wang, Chengyang et al. (2016) SURVIV for survival analysis of mRNA isoform variation. Nat Commun 7:11548
Ji, Xinjun; Park, Juw Won; Bahrami-Samani, Emad et al. (2016) ?CP binding to a cytosine-rich subset of polypyrimidine tracts drives a novel pathway of cassette exon splicing in the mammalian transcriptome. Nucleic Acids Res 44:2283-97
Lin, Lan; Jiang, Peng; Park, Juw Won et al. (2016) The contribution of Alu exons to the human proteome. Genome Biol 17:15
Park, Juw Won; Jung, Sungbo; Rouchka, Eric C et al. (2016) rMAPS: RNA map analysis and plotting server for alternative exon regulation. Nucleic Acids Res 44:W333-8
Molinie, Benoit; Wang, Jinkai; Lim, Kok Seong et al. (2016) m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome. Nat Methods 13:692-8

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