The splicing program of SRSF1 transcripts is finely tuned by cell metabolism

One of the best-studied splicing regulator is SRSF1 (formerly known as SF2/ASF, Manley et al., 2010), a prototypical SR protein involved in both constitutive and alternative splicing. SRSF1 promotes exon definition and the use of proximal alternative 5’ splice sites or 3’ splice sites in a concentration-dependent manner, in part through recognition of ESE sequence elements in the pre-mRNA targets. SRSF1 regulates other aspects of RNA metabolism, including mRNA stability (Lemaire et al., 2002), nuclear export (Huang et al., 2003), nonsense-mediated mRNA decay (Zhang et al., 2004), translation, and miRNA processing (Wu et al., 2010). It has been shown that the SRSF1 gene, located on Chromosome 17q23, is amplified in some tumors (Sinclair et al., 2003) and that increased SRSF1 expression is associated with the redistribution of β-catenin, reorganization of actin cytoskeleton, and downregulation of the epithelial marker E-cadherin, a tumor and invasion suppressor in human carcinomas. These morphological and molecular changes represent the hallmarks of the epithelial to mesenchymal transition (EMT), a process occurring during embryonic development but also required for cell invasiveness and metastatic properties of carcinomas in vivo (Thiery J.P. 2002). To avoid these deleterious effects on cells and organisms, the SRSF1 gene expression is tightly regulated through mechanisms operating at different levels, from transcription to translation. SRSF1 is able to recognize splicing regulatory sequence elements on its own transcripts, leading to alternative splicing. Alternative splicing plays a role in this regulation leading to the production of six different transcripts. Isoform I, encodes the full-length protein, and is characterized by a long 3′UTR (Ge H et al., 1991, Krainer et al., 1991). Isoforms II and III retain the third intron (the last in the coding part of the gene). Moreover, Isoforms III and IV undergo splicing of intron 5 in the 3’-UTR. Isoform II, III, and IV are retained in the nucleus. Hence, these molecules can not be translated (Sun et al., 2010) and can be considered as long non-coding RNAs. Isoform IV can undergo further splicing of intron 4 in the 3’-UTR leading to the production of Isoform V, which is exported in the cytoplasm and degraded by the NMD pathway. Similarly, through skipping of exon 4, Isoform III can be matured into Isoform VI, which is exported in the cytoplasm and subjected to NMD (Sun et al., 2010). During the three years of my Ph.D. program, my research activity concerned on the analysis of signals and factors that control the complex SRSF1 splicing program and the function of lncRNAs products, the signals and the mechanisms underlying the choice between the production of the protein coding Isoform I and the expression of the lncRNAs the mechanism and signal controlling alternative splicing of SRSF1 transcripts.