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.
Alternative splicing was discovered simultaneously with splicing over three decades ago. Since then, an enormous body of evidence has demonstrated the prevalence of alternative splicing in multicellular eukaryotes, its key roles in determining tissue- and species-specific differentiation patterns, the multiple post- and co-transcriptional regulatory mechanisms that control it, and its causal role in hereditary disease and cancer. The emerging evidence places alternative splicing in a central position in the flow of eukaryotic genetic information, between transcription and translation, in that it can respond not only to various signalling pathways that target the splicing machinery but also to transcription factors and chromatin structure.
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The authors apologize to those researchers whose work could not be cited owing to space constraints. The work in the authors laboratories was supported by grants to A.R.K. and M.J.M. from the Agencia Nacional de Promoción de Ciencia y Tecnología of Argentina (ANPCYT) and the University of Buenos Aires. A.R.K. is a Senior International Research Scholar of the Howard Hughes Medical Institute. I.E.S and G.D. are recipient of Marie Curie postdoctoral fellowships. M.A. and E.P. are recipients of postdoctoral fellowships and A.R.K. and M.J.M are career investigators from the Consejo Nacional de Investigaciones Científicas y Técnicas of Argentina (CONICET).
The authors declare no competing financial interests.
Gene segment that is present in the primary transcript but absent from the mature RNA as a consequence of splicing.
Endonucleolytic cleavage at the poly(A) site and subsequent addition of a poly(A) tail at the 3′ end of the eukaryotic pre-mRNA. The poly(A) site is defined by the poly(A) signal, which contains the consensus sequence AAUAAA.
Any modification of or addition to the mRNA taking place while it is still being transcribed, that is, before its 3′ end is generated by cleavage/polyadenylation.
Gene segments that are or can be present in the mature RNA as a consequence of splicing. Because mRNA exons also harbour 5′ and 3′ untranslated regions (UTRs) and genes encoding RNAs other than mRNAs may have introns, exons cannot be simply defined as protein-coding segments.
- Nonsense-mediated mRNA decay
(NMD). Mechanism that degrades mRNAs harbouring a premature translational termination codon as a result of gene mutation.
Addition of 7-methylguanosine nucleotide to the 5′ end of eukaryotic mRNAs.
- Pol II CTD
(RNA polymerase II carboxy-terminal domain). This domain consists of a repeating consensus heptad amino acid sequence, Tyr-Ser-Pro-Thr-Ser-Pro-Ser (52 repeats in humans and 26 in yeast). The CTD has important roles in pre-mRNA processing.
Sequences that 'isolate' sets of genes co-regulated by the same DNA cis-acting sequences.
Highly basic nuclear protein that is a structural component of a nucleosome (core histone families H2A, H2B, H3 and H4) or associates with DNA that links nucleosomes (linker histone families H1 and H5).
Repeating unit of eukaryotic chromatin that consists of a segment of approximately 147 bp of DNA wound around a histone octamer comprising two copies of each core histone (which are H2A, H2B, H3 and H4).
- Warburg effect
Metabolic property of cancer cells characterized by energy production through a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by mitochondrial aerobic respiration as in most healthy cells.
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Kornblihtt, A., Schor, I., Alló, M. et al. Alternative splicing: a pivotal step between eukaryotic transcription and translation. Nat Rev Mol Cell Biol 14, 153–165 (2013). https://doi.org/10.1038/nrm3525
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