IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
artículos
Título:
Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing
Autor/es:
IGNACIO E. SCHOR; NICOLÁS RASCOVÁN; FEDERICO PELISCH; MARIANO ALLÓ; ALBERTO R. KORNBLIHTT
Revista:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Editorial:
National Academy of Sciences of the USA
Referencias:
Año: 2009 vol. 106 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. 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 histone hyperacetylation, restricted to an internal of region the NCAM gene surrounding the alternative exon. This intragenic 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. The effects on acetylation, pol II processivity and splicing are fully reverted when the depolarizing conditions are withdrawn and can be both duplicated and potentiated by the histone deacetylase inhibitor trichostatin A. Our results place the kinetic coupling of pre-mRNA processing and transcription in a physiological context by demonstrating how an external signal modulates this coupling through intragenic epigenetic changes on a gene that is relevant for the differentiation and function of neuronal cells.