IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
- Chromatin structure controls alternative splicing through its kinetic coupling with transcription.
Autor/es:
SCHOR IE; ALLO M; KORNBLIHTT AR
Lugar:
Madison, Wisconsin, USA
Reunión:
Congreso; 14th Annual Meeting of the RNA Society; 2009
Institución organizadora:
RNA Society
Resumen:
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Alternative
splicing affects the expression of 70% of human genes, generates high protein
diversity and is implicated in human disease. The rate of transcription
elongation determines the outcome of competing splicing reactions that occur
co-transcriptionally. For example, in many cases rapid transcription favors
exon skipping, whereas slower transcription favors exon inclusion. The
chromatin context affects RNA polymerase II (pol II) elongation rates and in
turn, alternative splicing. We report here that membrane depolarization of
neuronal cells triggers the skipping of exon 18 from the neural cell adhesion
molecule (NCAM) mRNA. We show that this exon responds to RNA pol II elongation,
because its inclusion is increased by a slow pol II mutant. Depolarization
affects the chromatin template in a specific way, by causing H3K9
hyperacetylation, restricted to an internal region of the NCAM gene surrounding
the alternative exon. This intragenic histone hyperacetylation is not
paralleled by acetylation at the promoter, is associated with chromatin
relaxation and is linked to increases in pol II processivity and H3K36
tri-methylation.
On the other
hand, when searching for new tools to control alternative splicing at the
chromatin level, we found that small interfering RNAs (siRNAs) targeting the
intron located downstream of the fibronectin EDI alternative exon affect
alternative splicing through a mechanism known as transcriptional gene
silencing (TGS). The intronic siRNAs trigger heterochromatinization on DNA
target sequences by causing histone H3 Lys9 dimethylation and reduce pol II
processivity. This suggests that the effect on alternative splicing is probably
due to the creation of roadblocks to pol II elongation. The effects of intronic
siRNAs on alternative splicing are not caused by conventional
post-transcriptional gene silencing (PTGS), are abolished by inhibitors of
histone deacetylation and methylation and depend on the presence of the protein
AGO2, known to be necessary for TGS.