The noncoding RNA PRANCR regulates splicing of Fibronectin-1 to control keratinocyte proliferation and migration

Abstract

Most human genes undergo alternative splicing (AS), but the regulation and functional consequences of most splicing events remain unknown. Long noncoding RNAs (lncRNAs) have recently been discovered to have novel roles in the regulation of AS. Here we investigate whether PRANCR, a lncRNA recently identified to be essential for epidermis formation, functions by controlling AS of cell fate genes. Using transcriptome-wide analysis, we identified 238 exonic splicing events regulated by PRANCR. Among these is alternative splicing of an exon containing the extra domain A (EDA) in the gene fibronectin-1 (FN1). Expression of the FN1-EDA+ isoform is enriched in proliferating keratinocytes. We find that PRANCR regulates EDA inclusion by controlling expression of the serine/arginine-rich splicing factors (SRSFs) 1 and 7. Depletion of PRANCR or FN1-EDA resulted in decreased proliferation, increased CDKN1A/p21, and inhibition of keratinocyte migration. We find that these cellular phenotypes can be explained by reduced phosphorylation of focal adhesion kinase (FAK). Collectively, these results identify a lncRNA regulating skin function through alternative splicing of a cell fate gene.