INVESTIGADORES
SCHOR Ignacio Esteban
congresos y reuniones científicas
Título:
Epigenetic changes during neuronal differentiation contribute to neuro-specific alternative splicing patterns
Autor/es:
SCHOR IE; FISZBEIN A; PETRILLO E; KORNBLIHTT AR
Lugar:
Iguazú
Reunión:
Simposio; Gene Expression and RNA Processing; 2011
Institución organizadora:
ICGEB - ANPCYT - CONICET
Resumen:
Alternative
splicing is coupled to transcription, with changes in transcriptional
elongation properties resulting in different splicing outcomes. Our previous
work shows an example of how intragenic chromatin modulation can affect
alternative splicing: depolarization of the membrane potential of neuronal
cells triggers an increase in intragenic H3 acetylation along the NCAM gene,
which results in skipping of the alternative exon 18 (E18) from the mature
mRNA. Other results from our group have shown that induction of an intragenic
repressive chromatin conformation results in more inclusion of an alternative
exon associated with less processivity of the RNA pol II.
Using the
NCAM E18 exon as a model, we found evidence that neuronal differentiation of
N2a cells causes, contrary to what is seen after depolarization, intragenic
increase in repressive histone modifications (H3K9me2 and H3K27me3) which
correlates with enhanced E18 inclusion. Also, differentiation-induced inclusion
can be reversed by treatment with DNA and histone methyltransferases
inhibitors. The same association between repressive histone marks and increased
inclusion of alternative exons is seen for the fibronectin gene. Also, by
combining available ChIP-seq and splicing microarray data we were able a new
gene (Tcf7l2) with apparent chromatin-dependent regulation of alternative
splicing during neuronal differentiation. As predicted, the increase of the
neuro-specific isoform of Tcf7l2 is also prevented by inhibiting DNA
methylation.
This leads
to a model where intragenic chromatin can be physiologically modulated in both
directions (repressive/permissive) with functional consequences to coupled
alternative splicing.