Alternative splicing: a pivotal step between eukaryotic transcription and translation

Key Points The alternative splicing regulatory network is modulated by functional coupling between transcription and RNA processing. The transcription machinery can influence alternative splicing decisions by affecting the time in which cis -regulatory elements are transcribed (kinetic model) or by assisting in the recruitment of trans -acting regulatory proteins (recruitment model). Kinetic coupling, which requires changes in the elongation rate of RNA polymerase II (Pol II), can be induced by the presence of transcriptional roadblocks in specific intragenic regions or by modification of the Pol II complex such as phosphorylation of the carboxy-terminal domain (CTD) of its core catalytic subunit. Chromatin structure is a major regulator of splicing, affecting several steps of its coupling with transcription. These include the modulation of transcriptional properties through chromatin conformation and chromatin marks, the recruitment of splicing factors through adaptor proteins that recognize specific histone modifications and specific pausing at exons through preferential nucleosome positioning. Alternative splicing provides multicellular organisms with an extended proteome, the possibility of cell type- and species-specific protein isoforms without increasing the gene number, and the possibility of regulating the production of different proteins through specific signalling pathways. Its importance is supported by the increasing number of diseases associated with alternative splicing misregulation. Emerging evidence indicates that there are common structural and functional features of the polypeptide sequences encoded by alternative cassette exons in comparison to those encoded by constitutive exons. Such features include an increased flexibility and higher number of post-translational modifications. Several gene therapy strategies are being designed to cure hereditary disease by targeting misregulated alternative splicing events. In one of the most advanced studies the use of modified oligonucleotides has proved to be effective in restoring normal levels of a protein defective in spinal muscular atrophy. The prevalence and physiological importance of alternative splicing in multicellular eukaryotes has led to increased interest in its control. Much has been learnt about how transcription and chromatin structure influence splicing events, as well as the effects of signalling pathways, and this understanding may hold promise for the development of gene the