Human Molecular Genetics, Vol 8, 2317-2323, Copyright © 1999 by Oxford University Press
P Chiurazzi, MG Pomponi, R Pietrobono, CE Bakker, G Neri and BA Oostra
Most fragile X syndrome patients have expansion of a (CGG)(n)sequence with
>200 repeats (full mutation) in the FMR1 gene responsible for this
condition. Hypermethylation of the expanded repeat and of the FMR1 promoter
is almost always present and apparently suppresses transcription, resulting
in absence of the FMR1 protein. We recently showed that transcriptional
reactivation of FMR1 full mutations can be achieved by inducing DNA
demethylation with 5-azadeoxycytidine (5- azadC). The level of histone
acetylation is another important factor in regulating gene expression;
therefore, we treated lymphoblastoid cell lines of non-mosaic full mutation
patients with three drugs capable of inducing histone hyperacetylation. We
observed a consistent, although modest, reactivation of the FMR1 gene with
4-phenylbutyrate, sodium butyrate and trichostatin A, as shown by RT-PCR.
However, we report that combining these drugs with 5-azadC results in a 2-
to 5-fold increase in FMR1 mRNA levels obtained with 5-azadC alone, thus
showing a marked synergistic effect of histone hyperacetylation and DNA
demethylation in the reactivation of FMR1 full mutations.
ARTICLES
Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene
Istituto di Genetica Medica, Universit# Cattolica and Centro Ricerche per la Disabilit# Mentale e Motoria, Associazione Anni Verdi, Largo F. Vito 1, 00168 Rome, Italy and
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