Nature has devised sophisticated cellular machinery to process mRNA transcripts produced

Nature has devised sophisticated cellular machinery to process mRNA transcripts produced by RNA Polymerase II removing intronic regions and connecting exons together to produce mature RNAs. in splicing often resulting in aberrant cellular states NS-398 and disease. The epithelial to mesenchymal transition (EMT) which leads to cancer metastasis is influenced by alternative splicing events of chromatin remodelers and epigenetic factors such as DNA methylation and non-coding RNAs. In this review we will discuss the role of epigenetic factors including chromatin chromatin remodelers DNA methyltransferases and microRNAs in the context of alternative splicing and discuss their potential involvement in alternative splicing during the EMT process. embryos revealed that in fact splicing could occur in concert with transcription (Beyer and Osheim 1988). More recently several studies have provided compelling evidence that introns can be removed while the nascent transcript is still tethered to the DNA through the RNA NS-398 polymerase II (Pol II) complex (Dye et al. 2006; Listerman et al. 2006; Pandya-Jones and Black 2009; Ameur et al. 2011; Khodor et al. 2011; Vargas et al. 2011; Khodor et al. 2012; Tilgner et al. 2012). The kinetic model of co-transcriptional splicing was proposed to explain the keen “eyesight” of the spliceosome complex that allowed it to recognize the short often ~100 nt or less sized exons the proverbial needles in the haystack of long several 1000 Kb introns. This model proposed that the rate of Pol II elongation directly affected splice site recognition and spliceosome assembly. In other words if Pol II transcribed at a rapid rate (either due to it being hyperphosphorylated or if there was fairly “open” chromatin along the gene) then the spliceosome would not be able to keep up with the fast moving Pol II (Figure 1). This would result in several alternative splice sites being presented to the spliceosome to choose from and by default it would choose the stronger 3′ splice site more often relative to the weaker site(s) leading to some exons being spliced out (Figure 1). In contrast if the rate of Pol II elongation was hindered in some way either due to NS-398 chromatin factors such as nucleosomes or due to DNA methylation in the intragenic regions the spliceosome machinery is then able to keep up with Pol II elongation and splices all possible exons. In support of this model experiments that used Pol II mutants that slowed down the rate of Pol II elongation (de la Mata et al. 2003) or that inserted DNA elements that ‘paused’ Pol II in reporter constructs (Robson-Dixon and Garcia-Blanco 2004) were able to favor “weak” exon inclusion in the fibronectin (gene switches from several constitutive splicing NS-398 variants (CD44v) found in the epithelial state into a single short isoform CD44s (Figure 2) which is essential for EMT (Brown et al. 2011). This CD44 isoform switch is regulated by the splicing factor Epithelial Splicing Regulatory Protein 1 (ESRP1) (Warzecha et al. 2009; Brown et al. 2011). Both ESRP1 and its related protein ESRP2 are essential for maintaining the epithelial state as loss of these proteins caused cells to transition from the epithelial to the mesenchymal state. Together ESRP1 and ESRP2 regulate the splicing of several genes including Fibroblast Growth Factor Receptor 2(promoter causing repression of the gene transcription (Reinke et al. 2012). ESRP1 when bound to the intronic region flanking a variable exon caused increased variable exon inclusion and expression of caused downregulation of Snail-driven EMT (Reinke et al. 2012). More recently a microarray-based analysis demonstrated that TGF-β induced alternative splicing events by downregulating NS-398 Rabbit Polyclonal to RBM34. ESRP1 and 2 via upregulation of two other EMT transcription factors δEF1 and SIP1 which associated with the promoter of ESRP2 and repressed its expression (Horiguchi et al. 2012). Interestingly ESRP1 and ESRP2 appear to effect alternative splicing by different mechanisms (Ishii et al. 2014). Knockdown of ESRP1 in head and neck cancer cell lines induced the expression of Rac1b which is also known to increase Snail-induced EMT (Radisky et al. 2005) thus affecting actin cytoskeleton dynamics. On the other hand knockdown of ESRP2 caused a decrease in cell-cell adhesion by increasing the expression.