Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

Yueqin Yang; Juw Won Park; Thomas W Bebee; Claude C Warzecha; Yang Guo; Xuequn Shang; Yi Xing; Russ P Carstens

doi:10.1128/MCB.00019-16

Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition

Mol Cell Biol. 2016 May 16;36(11):1704-19. doi: 10.1128/MCB.00019-16. Print 2016 Jun 1.

Authors

Yueqin Yang¹, Juw Won Park², Thomas W Bebee¹, Claude C Warzecha¹, Yang Guo³, Xuequn Shang⁴, Yi Xing⁵, Russ P Carstens⁶

Affiliations

¹ 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.
² 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.
³ 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.
⁴ School of Computer Science, Northwestern Polytechnical University, Xi'an, China.
⁵ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA yxing@ucla.edu russcars@upenn.edu.
⁶ 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.

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.

Publication types

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

MeSH terms

Alternative Splicing*
Cell Line, Tumor
Down-Regulation
Epithelial-Mesenchymal Transition*
Gene Regulatory Networks*
Humans
Models, Biological
Neoplasms / genetics*
RNA-Binding Proteins / genetics
Sequence Analysis, RNA

Substances

ESRP1 protein, human
ESRP2 protein, human
QKI protein, human
RBM47 protein, human
RNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding