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Gene Regulation by Alternative Splicing
Many eukaryotic protein-coding genes are mosaic with non-coding regions (introns) interspersed among coding regions (exons). Such genes give rise to similarly mosaic precursor messenger RNAs (pre-mRNAs), from which intronic regions have to be excised and exonic regions have to be ligated in a process termed pre-mRNA splicing to generate mature mRNA for protein biosynthesis by the ribosome. As most protein-coding genes in higher eukaryotes, such as humans, contain more than one intron, their pre-mRNAs can be alternatively spliced to generate multiple mature mRNAs that can give rise to multiple proteins or serve other gene regulatory purposes. The analysis of different splicing pathways and how alternative splicing is regulated is an active area of research in Biochemistry.
- Alternative splicing can be controlled through the formation of secondary structures in the pre-mRNA. You have found an alternative exon that is flanked by complementary sequences in the upstream and downstream introns. Design an experiment to test whether formation of Watson-Crick base pairs between the upstream and downstream intronic elements is required for exon exclusion.
- Certain mutations that lead to changes in specific splicing factors are associated with a degenerative eye disease, retinitis pigmentosa. Discuss how such changes in a factor that is involved in pre-mRNA splicing can result in a tissue-specific phenotype. How could you experimentally test your hypotheses?
- How can you test whether and to which extent splicing in vivo occurs co-transcriptionally?
- In vitro splicing in nuclear extract involves the stepwise assembly and catalytic activation of a spliceosome on a substrate pre-mRNA. How can you test whether splicing in vivo follows the same principle?
- In 2016, the first drug based on an antisense oligonucleotide that modulates alternative splicing was approved. Describe the different steps, from basic research to in vivo models that led to the approval of this drug.