IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Chromatin, Pol II elongation and alternative splicing
Autor/es:
MUÑOZ M; SCHOR IE; ALLÓ M; PEREZ SANTANGELO S; RASCOVAN N; DE LA MATA M; KORNBLIHTT AR
Lugar:
Mar del Plata, Buenos Aires, Argentina
Reunión:
Congreso; LIII Reunión Científica Anual SAIC; 2008
Institución organizadora:
Sociedad Argentina de Investigación Clínica (SAIC)
Resumen:
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Regulation of alternative splicing
through its kinetic coupling with transcription can occur via changes in
chromatin structure or modulation of RNA polymerase II (pol II) elongation
rates. As an example of the first mode we found that siRNAs targeted at
intronic sequences located downstream of the fibronectin EDI exon are able to
regulate AS through a mechanism known as transcriptional gene silencing (TGS).
The effect needs both AGO-1 and AGO-2 and is abolished by factors that favor an
open chromatin structure or increase transcriptional elongation. The mechanism
involves the formation of facultative heterochromatin epigenetic marks (H3K9me2
and H3K27me3) at the target site that creates a roadblock to pol II elongation.
Changes in chromatin structure
affecting AS can be triggered by physiological external signals. We found that
depolarization of nerve cells causes lower inclusion of NCAM alternatively
spliced exon 18. Inhibition of histone deacetylation by
trichostatin A causes a similar effect, opposite to the one of inhibition of
pol II elongation by flavopiridol. When inducing membrane depolarization, the
effects of these drugs are abolished, which suggests that depolarization
promotes histone acetylation, facilitating pol II elongation leading to exon 18
exclusion. ChIP analysis confirmed our predictions.
The second mode is illustrated by the effects
of UV light on AS. The UV effect
does not require p53 or damage of the DNA template in cis. It is observed only when splicing is co-transcriptional and
is the consequence of inhibition of pol II elongation caused by
hyperphosphorylation of the carboxy terminal domain of pol II at serines 2 and
5.