TY - JOUR
T1 - Modest reactivation of the mutant FMR1 gene by valproic acid is accompanied by histone modifications but not DNA demethylation
AU - Tabolacci, Elisabetta
AU - De Pascalis, Ivana
AU - Accadia, Maria
AU - Terracciano, Alessandra
AU - Moscato, Umberto
AU - Chiurazzi, Pietro
AU - Neri, Giovanni
PY - 2008/8
Y1 - 2008/8
N2 - Fragile X syndrome (FXS), the leading cause of inherited mental retardation, is due to expansion and methylation of a CGG sequence in the FMR1 gene, which result in its silencing. We previously demonstrated a reactivation of FMR1 in FXS cells treated with the DNA demethylating drug 5-azadeoxycytidine, and, to a lesser extent, with the histone deacetylating drug butyrate. To identify other reactivating drugs, we now treated three FXS lymphoblastoid cell lines with valproic acid (VPA), a well-known antiepileptic drug, causing histone deacetylase inhibition and, possibly, DNA demethylation. After VPA treatment, FMR1-mRNA levels were low and FMRP protein was undetectable. The gene remained methylated, whereas histones were acetylated and a modest variation of histone methylation was observed. These results confirm the histone hyperacetylating effect of VPA but do not support its putative DNA demethylation activity. The primary role of DNA demethylation in the reactivation of the FMR1 gene was confirmed.
AB - Fragile X syndrome (FXS), the leading cause of inherited mental retardation, is due to expansion and methylation of a CGG sequence in the FMR1 gene, which result in its silencing. We previously demonstrated a reactivation of FMR1 in FXS cells treated with the DNA demethylating drug 5-azadeoxycytidine, and, to a lesser extent, with the histone deacetylating drug butyrate. To identify other reactivating drugs, we now treated three FXS lymphoblastoid cell lines with valproic acid (VPA), a well-known antiepileptic drug, causing histone deacetylase inhibition and, possibly, DNA demethylation. After VPA treatment, FMR1-mRNA levels were low and FMRP protein was undetectable. The gene remained methylated, whereas histones were acetylated and a modest variation of histone methylation was observed. These results confirm the histone hyperacetylating effect of VPA but do not support its putative DNA demethylation activity. The primary role of DNA demethylation in the reactivation of the FMR1 gene was confirmed.
KW - DNA methylation
KW - Epigenetic modifications
KW - Fragile X syndrome
KW - Histone acetylation
KW - Valproic acid
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U2 - 10.1097/FPC.0b013e32830500a1
DO - 10.1097/FPC.0b013e32830500a1
M3 - Article
C2 - 18622267
AN - SCOPUS:55749110434
VL - 18
SP - 738
EP - 741
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
SN - 1744-6872
IS - 8
ER -