Multiphasic and Dynamic Changes in Alternative Splicing during Induction of Pluripotency Are Coordinated by Numerous RNA-Binding Proteins

Benjamin Cieply; Juw Won Park; Angela Nakauka-Ddamba; Thomas W Bebee; Yang Guo; Xuequn Shang; Christopher J Lengner; Yi Xing; Russ P Carstens

doi:10.1016/j.celrep.2016.03.025

Multiphasic and Dynamic Changes in Alternative Splicing during Induction of Pluripotency Are Coordinated by Numerous RNA-Binding Proteins

Cell Rep. 2016 Apr 12;15(2):247-55. doi: 10.1016/j.celrep.2016.03.025. Epub 2016 Mar 31.

Authors

Benjamin Cieply¹, Juw Won Park², Angela Nakauka-Ddamba³, Thomas W Bebee¹, Yang Guo⁴, Xuequn Shang⁵, Christopher J Lengner³, Yi Xing⁶, Russ P Carstens⁷

Affiliations

¹ Department of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² 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.
³ Department of Biomedical Sciences and Institute for Regenerative Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ 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.
⁵ School of Computer Science, Northwestern Polytechnical University, Xian 710072, China.
⁶ Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
⁷ Department of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing / genetics*
Animals
Cellular Reprogramming
Gene Expression Regulation, Developmental
Genome
Induced Pluripotent Stem Cells / metabolism*
Mice
Protein Isoforms / genetics
Protein Isoforms / metabolism
RNA-Binding Proteins / metabolism*
Repressor Proteins / genetics
Repressor Proteins / metabolism
Time Factors

Substances

ESRP1 protein, mouse
Grhl1 protein, mouse
Protein Isoforms
RNA-Binding Proteins
Repressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding