title: Multiphasic and Dynamic Changes in Alternative Splicing during Induction of Pluripotency Are Coordinated by Numerous RNA-Binding Proteins.
abstract: Alternative splicing (AS) plays a critical role in cell fate transitions, development, and disease. Recent studies have shown that AS also influences pluripotency and somatic cell reprogramming. We profiled transcriptome-wide AS changes that occur during reprogramming of fibroblasts to pluripotency. This analysis revealed distinct phases of AS, including a splicing program that is unique to transgene-independent induced pluripotent stem cells (iPSCs). Changes in the expression of AS factors Zcchc24, Esrp1, Mbnl1/2, and Rbm47 were demonstrated to contribute to phase-specific AS. RNA-binding motif enrichment analysis near alternatively spliced exons provided further insight into the combinatorial regulation of AS during reprogramming by different RNA-binding proteins. Ectopic expression of Esrp1 enhanced reprogramming, in part by modulating the AS of the epithelial specific transcription factor Grhl1. These data represent a comprehensive temporal analysis of the dynamic regulation of AS during the acquisition of pluripotency.
authors.affiliation: Department of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cieply
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY 40292, USA; KBRIN Bioinformatics Core, University of Louisville, Louisville, KY 40292, USA.
authors.forename: Juw Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences and Institute for Regenerative Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Nakauka-Ddamba
authors.affiliation: Department of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Bebee
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA; School of Computer Science, Northwestern Polytechnical University, Xian 710072, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Guo
authors.affiliation: School of Computer Science, Northwestern Polytechnical University, Xian 710072, China.
authors.forename: Xuequn
authors.initials: X
authors.lastname: Shang
authors.affiliation: Department of Biomedical Sciences and Institute for Regenerative Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: yxing@ucla.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: russcars@upenn.edu.
authors.forename: Russ P
authors.initials: RP
authors.lastname: Carstens
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D065150:Cellular Reprogramming; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: C000588453:ESRP1 protein, mouse; C528337:Grhl1 protein, mouse; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D012097:Repressor Proteins