A Role For The Transcription Factor SNAIL In Alternative Splicing

Abstract

The transcription factor SNAIL is one of the key regulators of an early developmental process called the Epithelial to Mesenchymal Transition. This process is characterized by a cell‐state change from a highly differentiated, epithelial phenotype to a less differentiated, migratory mesenchymal phenotype. SNAIL binds to E‐box motifs in promoter regions and recruits chromatin remodelers to repress or activate gene expression. To identify proteins associated with SNAIL, we used co‐immunoprecipitation of SNAIL‐bound proteins followed by mass spectrometry. A large number of splicing proteins associated with SNAIL, including SRSF1, a regulator of alternative splicing.Co‐immunofluorescence and co‐immunoprecipitation data from our lab indicate that SNAIL associates with splicing protein SRSF1. Further, SNAIL co‐immunoprecipitated with SRSF1 in the presence of DNase, but not in the presence of RNase, indicating that the SNAIL‐SRSF1 association is RNA‐dependent. Knockdown of SNAIL with siRNA resulted in loss of mesenchymal splice isoforms and reversion to epithelial specific isoforms. RNA Immunoprecipitation of SNAIL‐ and SRSF1‐ associated RNAs showed increased enrichment for mesenchymal specific isoforms of mRNAs, suggesting that SNAIL and SRSF1 influence alternative splicing.We hypothesize that SNAIL regulates alternative splicing by binding to RNA and recruiting SRSF1. We are currently investigating genome‐wide changes in alternative splicing regulated by SNAIL, and working to understand the mechanism by which SNAIL interaction with the spliceosome leads to alternative splicing. As transcription and splicing are closely coupled, we predict that transcription factor regulation of splicing through RNA binding is universally utilized by other biological systems to alter phenotype in response to external stimuli.Support or Funding InformationUniversity of North Dakota, NIH Grant #1P30GM103329 and NIH COBRE #P20GM104360‐01This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.