Epigenetics at the base of alternative splicing changes that promote colorectal cancer

Abstract

Human genes, as well as those of most multicellular eukaryotes, are organized as mosaics of exons and introns. RNA polymerase II (RNAPII) transcribes the DNA sequence of each gene to generate a precursor mRNA molecule (pre-mRNA) that contains both exons and introns and serves as the substrate for splicing, the process by which introns are removed and exons are joined, yielding the mature mRNA that will eventually be translated to protein.One of the evolutionary advantages of premRNA splicing is the ability to alter mature mRNA via alternative splicing, which allows generation of multiple mRNA and protein variants from each gene, thereby greatly expanding the coding capacity of the genome. Indeed, the number of proteincoding genes in humans is not radically different from that in the worm Caenorhabditis elegans (~20,000). However, alternative splicing is prevalent in vertebrates (1), strongly suggesting a key role in the higher complexity of these organisms. As a compelling example, alternative splicing occurs in more than 95% of mammalian genes (2). In alternative splicing, a single type of pre-mRNA can be spliced in different ways, leading to similar but not identical mature mRNA species. A simple metaphor is that of a textile industry (transcription) that generates many copies of a fabric piece of the same length and quality (pre-mRNAs) and the tailor (the spliceosome) who makes different suits (mRNAs) with each piece of fabric, depending on where he/she cuts and sews (splicing) and on the remnants (introns) that are discarded.Splicing is carried out by the spliceosome, a multimolecular complex composed of dozens of proteins and ribonucleoproteins. A single spliceosome assembles at every intron to be excised on each premRNA as soon as it emerges from RNAPII during transcription (3). Indeed, accumulating evidence indicates that splicing, or at least the binding of spliceosome and splicing factors to the pre-mRNA that enables it, occurs cotranscriptionally (4). In turn, this cotranscriptionality allows for a complex molecular interplay between the transcription and splicing machineries so that both processes are mutually coordinated and the kinetics and molecular mechanisms intrinsic to each of them influence each other. As a consequence of this coupling, splicing, like transcription, is highly regulated by chromatin structure and the quality and distribution of posttranslational histone modifications (histone marks). Two modelsTwo nonmutually exclusive models have been proposed for the role of chromatin in alternative splicing. In the transcription kinetics model, the preferential positioning of nucleosomes in exons (5, 6) or deployment of specific histone marks within the gene body hinder or facilitate RNAPII progression. Changes in overall elongation rates of RNAPII have been shown to promote or inhibit the inclusion of alternative exons in the mature mRNA, depending on the identity of the particular alternative splicing event (7-9). Intragenic histone modifications, including H2B monoubiquitylation (10), H3K...

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