title: Chromatin and alternative splicing.
abstract: Alternative splicing affects more than 90% of human genes. Coupling between transcription and splicing has become crucial in the complex network underlying alternative splicing regulation. Because chromatin is the real template for nuclear transcription, changes in its structure, but also in the "reading" and "writing" of the histone code, could modulate splicing choices. Here, we discuss the evidence supporting these ideas, from the first proposal of chromatin affecting alternative splicing, performed 20 years ago, to the latest findings including genome-wide evidence that nucleosomes are preferentially positioned in exons. We focus on two recent reports from our laboratories that add new evidence to this field. The first report shows that a physiological stimulus such as neuron depolarization promotes intragenic histone acetylation (H3K9ac) and chromatin relaxation, causing the skipping of exon 18 of the neural cell adhesion molecule gene. In the second report, we show how specific histone modifications can be created at targeted gene regions as a way to affect alternative splicing: Using small interfering RNAs (siRNAs), we increased the levels of H3K9me2 and H3K27me3 in the proximity of alternative exon 33 of the human fibronectin gene, favoring its inclusion into mature messenger RNA (mRNA) through a mechanism that recalls RNA-mediated transcriptional gene silencing.
authors.affiliation: Departamento de Fisiología, Biología Molecular y Celular, Laboratorio de Fisiología y Biología Molecular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Alló
authors.forename: I E
authors.initials: IE
authors.lastname: Schor
authors.forename: M J
authors.initials: MJ
authors.lastname: Muñoz
authors.forename: M
authors.initials: M
authors.lastname: de la Mata
authors.forename: E
authors.initials: E
authors.lastname: Agirre
authors.forename: J
authors.initials: J
authors.lastname: Valcárcel
authors.forename: E
authors.initials: E
authors.lastname: Eyras
authors.forename: A R
authors.initials: AR
authors.lastname: Kornblihtt
mesh_terms: D000200:Action Potentials / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics*; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D005091:Exons / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000502:physiology; D009707:Nucleosomes / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D009707:Nucleosomes