N SRSF1binding site necessary for the inclusion of exon 18178180. At

N SRSF1binding site necessary for the inclusion of exon 18178180. At the same time, this mutation creates a binding site for splicing inhibitors hnRNPA1/A2 and DAZAP1, resulting in exon skipping181. Exon 18 exclusion eliminates the first BRCT domain, Wiley Interdiscip Rev RNA. Author manuscript; available in PMC 2015 May 10. Liu and Cheng Page 11 through which BRCA1 interacts with various DNA damage proteins182, 183, thus generating a non-functional BRCA1 mutant protein. These observations illustrate that cis-element mutations can cause aberrant alternative splicing that affects the function of coding genes. Regulation of alternative splicing through trans-acting factors In addition to cis-acting element mutations, trans-acting regulators, i.e. splicing factors, can also be aberrantly regulated at multiple levels, including genomic mutation, Oleandrin transcriptional regulation, post-transcriptional regulation, and post-translational regulation. Mutations in splicing factors–Exome sequencing has demonstrated great power in uncovering somatic mutations that are associated with diseases. Recent identifications of mutations in the SF3B1 and U2AF35 genes in hematopoietic malignancies and other solid tumors suggested a novel means of RNA splicing deregulation that could be a driver for the development of various types of tumors184189. Especially in myelodysplastic syndromes and myelodysplasia, as many as 4585% of patients have mutations in the RNA splicing machinery184. These mutations occur in a mutually exclusive manner, and the mutated genes are involved in the 3′-splice site recognition during splicing. Importantly, introducing the U2AF35 mutant PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19853393 found in patients into cancer cells resulted in enrichment in unspliced introns and increased expression of members of the NMD pathway184. It was suggested that these spliceosomal pathway mutations compete with normal splicing machinery, leading to pathogenesis. It will be interesting to investigate the functional connections GSK1278863 between these mutations and disease phenotypes. Transcriptional regulation–Splicing factors can also be transcriptionally regulated. As noted earlier, ESRP1 promotes an epithelial cellular state40, 45, 135. In response to EMT stimuli, ESRP1 level is markedly decreased, allowing cells to transit to a mesenchymal state. Interestingly, the transcription repressors and EMT inducers, Snail and Zeb1/2, can directly bind at the promoters of ESRP1 or ESRP1’s paralogous ESRP2 to suppress their expression136, 190. Given that ESRP1 inhibits EMT via preventing CD44 variable exon skipping136, these results illustrate a mechanism by which a transcription factor promotes EMT through transcriptional repression of a splicing factor that controls alternative splicing of key genes whose splice isoform is critical for EMT. Post-transcriptional regulation–Splicing regulators are subject to many types of posttranscriptional regulations. One of such regulation is NMD. The splicing regulators SRSF2 and PTB autoregulate their expression by NMD191, 192. It was later found that highly conserved stop codon-containing exons frequently exist in genes that encode splicing regulators193, 194. Interestingly, genes encoding splicing activators such as SR proteins undergo splicing activation-triggered NMD. By contrast, splicing inhibitors including hnRNPs are regulated by NMD through a splicing repression event. Such observations suggest that cells utilize NMD regulation to control the homeostasis of splicing regula.N SRSF1binding site necessary for the inclusion of exon 18178180. At the same time, this mutation creates a binding site for splicing inhibitors hnRNPA1/A2 and DAZAP1, resulting in exon skipping181. Exon 18 exclusion eliminates the first BRCT domain, Wiley Interdiscip Rev RNA. Author manuscript; available in PMC 2015 May 10. Liu and Cheng Page 11 through which BRCA1 interacts with various DNA damage proteins182, 183, thus generating a non-functional BRCA1 mutant protein. These observations illustrate that cis-element mutations can cause aberrant alternative splicing that affects the function of coding genes. Regulation of alternative splicing through trans-acting factors In addition to cis-acting element mutations, trans-acting regulators, i.e. splicing factors, can also be aberrantly regulated at multiple levels, including genomic mutation, transcriptional regulation, post-transcriptional regulation, and post-translational regulation. Mutations in splicing factors–Exome sequencing has demonstrated great power in uncovering somatic mutations that are associated with diseases. Recent identifications of mutations in the SF3B1 and U2AF35 genes in hematopoietic malignancies and other solid tumors suggested a novel means of RNA splicing deregulation that could be a driver for the development of various types of tumors184189. Especially in myelodysplastic syndromes and myelodysplasia, as many as 4585% of patients have mutations in the RNA splicing machinery184. These mutations occur in a mutually exclusive manner, and the mutated genes are involved in the 3′-splice site recognition during splicing. Importantly, introducing the U2AF35 mutant PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19853393 found in patients into cancer cells resulted in enrichment in unspliced introns and increased expression of members of the NMD pathway184. It was suggested that these spliceosomal pathway mutations compete with normal splicing machinery, leading to pathogenesis. It will be interesting to investigate the functional connections between these mutations and disease phenotypes. Transcriptional regulation–Splicing factors can also be transcriptionally regulated. As noted earlier, ESRP1 promotes an epithelial cellular state40, 45, 135. In response to EMT stimuli, ESRP1 level is markedly decreased, allowing cells to transit to a mesenchymal state. Interestingly, the transcription repressors and EMT inducers, Snail and Zeb1/2, can directly bind at the promoters of ESRP1 or ESRP1’s paralogous ESRP2 to suppress their expression136, 190. Given that ESRP1 inhibits EMT via preventing CD44 variable exon skipping136, these results illustrate a mechanism by which a transcription factor promotes EMT through transcriptional repression of a splicing factor that controls alternative splicing of key genes whose splice isoform is critical for EMT. Post-transcriptional regulation–Splicing regulators are subject to many types of posttranscriptional regulations. One of such regulation is NMD. The splicing regulators SRSF2 and PTB autoregulate their expression by NMD191, 192. It was later found that highly conserved stop codon-containing exons frequently exist in genes that encode splicing regulators193, 194. Interestingly, genes encoding splicing activators such as SR proteins undergo splicing activation-triggered NMD. By contrast, splicing inhibitors including hnRNPs are regulated by NMD through a splicing repression event. Such observations suggest that cells utilize NMD regulation to control the homeostasis of splicing regula.