title: Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition.
abstract: The epithelial-to-mesenchymal transition (EMT) is an essential biological process during embryonic development that is also implicated in cancer metastasis. While the transcriptional regulation of EMT has been well studied, the role of alternative splicing (AS) regulation in EMT remains relatively uncharacterized. We previously showed that the epithelial cell-type-specific proteins epithelial splicing regulatory proteins 1 (ESRP1) and ESRP2 are important for the regulation of many AS events that are altered during EMT. However, the contributions of the ESRPs and other splicing regulators to the AS regulatory network in EMT require further investigation. Here, we used a robust in vitro EMT model to comprehensively characterize splicing switches during EMT in a temporal manner. These investigations revealed that the ESRPs are the major regulators of some but not all AS events during EMT. We determined that the splicing factor RBM47 is downregulated during EMT and also regulates numerous transcripts that switch splicing during EMT. We also determined that Quaking (QKI) broadly promotes mesenchymal splicing patterns. Our study highlights the broad role of posttranscriptional regulation during the EMT and the important role of combinatorial regulation by different splicing factors to fine tune gene expression programs during these physiological and developmental transitions.
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA Department of Computer Engineering and Computer Science, University of Louisville, Louisville, Kentucky, USA KBRIN Bioinformatics Core, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Juw Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Bebee
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Claude C
authors.initials: CC
authors.lastname: Warzecha
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA School of Computer Science, Northwestern Polytechnical University, Xi'an, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Guo
authors.affiliation: School of Computer Science, Northwestern Polytechnical University, Xi'an, China.
authors.forename: Xuequn
authors.initials: X
authors.lastname: Shang
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA yxing@ucla.edu russcars@upenn.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA yxing@ucla.edu russcars@upenn.edu.
authors.forename: Russ P
authors.initials: RP
authors.lastname: Carstens
mesh_terms: D017398:Alternative Splicing; D045744:Cell Line, Tumor; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D053263:Gene Regulatory Networks; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics; D017423:Sequence Analysis, RNA
chemical_list: C539364:ESRP1 protein, human; C539365:ESRP2 protein, human; C490832:QKI protein, human; C000589380:RBM47 protein, human; D016601:RNA-Binding Proteins