INVESTIGADORES
KORNBLIHTT Alberto Rodolfo
artículos
Título:
Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing.
Autor/es:
SCHOR IGNACIO; RASCOVAN N; PELISCH, F.; ALLO MARIANO; KORNBLIHTT AR
Revista:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Editorial:
NATL ACAD SCIENCES
Referencias:
Año: 2009 p. 4325 - 4330
ISSN:
0027-8424
Resumen:
In search for physiological pathways
affecting alternative splicing through its kinetic coupling with
transcription, we found that membrane depolarization of neuronal cells
triggers the skipping of exon 18 from the neural cell adhesion molecule
(NCAM) mRNA, independently of the calcium/calmodulin protein kinase IV
pathway. We show that this exon responds to RNA polymerase II
elongation, because its inclusion is increased by a slow polymerase II
mutant. Depolarization affects the chromatin template in a specific way,
by causing H3K9 hyper-acetylation restricted to an internal region of
the NCAM gene surrounding the alternative exon. This intragenic histone
hyper-acetylation is not paralleled by acetylation at the promoter, is
associated with chromatin relaxation, and is linked to H3K36
tri-methylation. The effects on acetylation and splicing fully revert
when the depolarizing conditions are withdrawn and can be both
duplicated and potentiated by the histone deacetylase inhibitor
trichostatin A. Our results are consistent with a mechanism involving
the kinetic coupling of splicing and transcription in response to
depolarization through intragenic epigenetic changes on a gene that is
relevant for the differentiation and function of neuronal cells.