Recently, tremendous success has been achieved in constructing a catalog of genetic variants in disease genomes or across population. The next great challenge is to elucidate the potential function of various genetic variants in biological an disease processes. An important type of functional variants consists of those that affect gene expression in cis. Indeed, cis-regulatory variants are involved in a broad range of diseases and they showed a consistently stronger influence on gene expression than trans-acting determinants. Alternative splicing is an essential mechanism via which cis-regulatory changes may occur. Previous studies estimated that 15- 60% of point mutations that result in human genetic diseases disrupt splicing, highlighting the importance of this regulatory step. In addition to the well-known splice site signals, splicing is closely regulated by many exonic or intronic cis elements, associated with trans-acting proteins. Disruption of these cis-regulatory elements can cause aberrant splicing. Yet this crucial regulatory aspect remains largely unexplored. We propose to combine computational, genomic and molecular approaches to study splicing changes due to genetic variations.
The specific aims are: (1) To globally identify exons and genes that are under differential splicing regulation by the alternative alleles of genetic variant, via bioinformatic analysis of high-throughput sequencing of transcriptome profiles (RNA-Seq). (2) To identify causal genetic variants in splicing alteration using minigene-based experiments. (3) To develop an integrative model to predict causal genetic variants in splicing alteration, using machine learning approaches, RNA- Seq data and molecular validations. This project will elucidate functional cis-regulatory genetic variants in splicing and provide significant insight ino the involvement of genetic variations in human diseases. In addition, this work will generate valuable bioinformatic tools to make full use of the increasingly available RNA-Seq data in a wide variety of cell types for identification and prediction of disease-related genetic variants.

Public Health Relevance

Aberrant splicing can significantly alter gene expression and contribute to human diseases. The proposed research aims to gain a systematic understanding of the functional roles of genetic variations (e.g., mutations or polymorphisms) in the regulation of splicing. This work will provide mechanistic basis for how genetic variations may contribute to diseases, such that future interventions can target specific splicing events therapeutically.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project (R01)
Project #
Application #
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Struewing, Jeffery P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
Zip Code
Yang, Yun; Fan, Xiaojuan; Mao, Miaowei et al. (2017) Extensive translation of circular RNAs driven by N6-methyladenosine. Cell Res 27:626-641
Touma, Marlin; Kang, Xuedong; Gao, Fuying et al. (2017) Wnt11 regulates cardiac chamber development and disease during perinatal maturation. JCI Insight 2:
Cass, Ashley A; Bahn, Jae Hoon; Lee, Jae-Hyung et al. (2016) Global analyses of endonucleolytic cleavage in mammals reveal expanded repertoires of cleavage-inducing small RNAs and their targets. Nucleic Acids Res 44:3253-63
Touma, Marlin; Kang, Xuedong; Zhao, Yan et al. (2016) Decoding the Long Noncoding RNA During Cardiac Maturation: A Roadmap for Functional Discovery. Circ Cardiovasc Genet 9:395-407
Fuxjager, Matthew J; Lee, Jae-Hyung; Chan, Tak-Ming et al. (2016) Research Resource: Hormones, Genes, and Athleticism: Effect of Androgens on the Avian Muscular Transcriptome. Mol Endocrinol 30:254-71
Hasin-Brumshtein, Yehudit; Khan, Arshad H; Hormozdiari, Farhad et al. (2016) Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes. Elife 5:
Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49
Gao, Chen; Ren, Shuxun; Lee, Jae-Hyung et al. (2016) RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure. J Clin Invest 126:195-206
Hsiao, Yun-Hua Esther; Bahn, Jae Hoon; Lin, Xianzhi et al. (2016) Alternative splicing modulated by genetic variants demonstrates accelerated evolution regulated by highly conserved proteins. Genome Res 26:440-50
Bahn, Jae Hoon; Zhang, Qing; Li, Feng et al. (2015) The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin Chem 61:221-30

Showing the most recent 10 out of 23 publications