CONICET | Buscador de Institutos y Recursos Humanos

Changes in RNA polymerase II (pol II) elongation rates modulate alternative splicing choices, affecting the timing at which nascent pre-mRNA splice sites and regulatory sequences are presented to the spliceosome (an effect known as kinetic coupling). One of the ways in which this situation could be relevant in regulation of endogenous alternative splicing choices is by dynamic changes in intragenic chromatin structure that could in turn affect RNA processivity or elongation rate. Using the exon 18 (E18) of the NCAM gene as a model we have determined that intragenic histone acetylation, triggered by membrane depolarization of N2a cells, decreases exon inclusion. This treatment also causes a more relaxed chromatin conformation in the E18 region. Accordingly, inhibition of DNA methylation by 5-aza-citidine can reduce the differentiation- induced enhancement of E18 inclusion, further suggesting that chromatin relaxation is associated to alternative exon skipping. Analysis of the participation of different histone acetyl transferases (HATs) in alternative splicing regulation show that CBP/p300 is implicated in the regulation of E18 splicing in response to depolarization. These results raise the possibility that balance between different histone modifications could serve as a point of control of transcriptionally-coupled alternative splicing, and that this balance can be modulated in different physiological situations.