Modest reactivation of the mutant FMR1 gene by valproic acid is accompanied by histone modifications but not DNA demethylation.
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.
Tabolacci
Elisabetta
E
Medical Genetics, Catholic University, Rome, Italy.
De Pascalis
Ivana
I
Accadia
Maria
M
Terracciano
Alessandra
A
Moscato
Umberto
U
Chiurazzi
Pietro
P
Neri
Giovanni
G
D000107:Acetylation / Q000187:drug effects; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000187:drug effects*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
D051860:Fragile X Messenger Ribonucleoprotein 1; D006657:Histones; D012333:RNA, Messenger; D014635:Valproic Acid; C497683:FMR1 protein, human