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Authors: Claude C. Warzecha, Shihao Shen, Yi Xing and Russ P. Carstens

Claude C. Warzecha

Renal Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA

Shihao Shen

Department of Biostatistics, University of Iowa; Iowa City, IA USA

Yi Xing

Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA

Russ P. Carstens

Renal Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA

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Abstract:

Cell-type and tissue-specific alternative splicing events are regulated by combinatorial control involving both abundant RNA binding proteins as well as those with more discrete expression and specialized functions.  Epithelial Splicing Regulatory Proteins 1 and 2 (ESRP1 and ESRP2) are recently discovered epithelial-specific RNA binding proteins that promote splicing of the epithelial variant of the FGFR2, ENAH, CD44, and CTNND1 transcripts.  To cataloge a larger set of splicing events under the regulation of the ESRPs we profiled splicing changes induced by RNA interference-mediated knockdown of ESRP1 and ESRP2 expression in a human epithelial cell line using the splicing sensitive Affymetrix Exon ST1.0 Arrays.  Analysis of the microarray data resulted in the identification of over a hundred candidate ESRP regulated splicing events.  We were able to independently validate 37 of these targets by RT-PCR.  The ESRP regulated events encompass all known types of alternative splicing events, most prominent being alternative cassette exons and splicing events leading to alternative 3’ terminal exons.  Importantly, a number of these regulated splicing events occur in gene transcripts that encode proteins with well-described roles in the regulation of actin cytoskeleton organization, cell-cell adhesion, cell polarity, and cell migration.  In sum, this work reveals a novel list of transcripts differentially spliced in epithelial and mesenchymal cells, implying that coordinated alternative splicing plays a critical role in determination of cell type identity.  These results further establish ESRP1 and ESRP2 as global regulators of an epithelial splicing regulatory network.