1. Modest reactivation of the mutant FMR1 gene by valproic acid is accompanied by histone modifications but not DNA demethylation
- Author
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Pietro Chiurazzi, Maria Accadia, Umberto Moscato, Ivana De Pascalis, Alessandra Terracciano, Elisabetta Tabolacci, and Giovanni Neri
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Chromatin Immunoprecipitation ,Settore MED/03 - GENETICA MEDICA ,Cell Line ,Histones ,Fragile X Mental Retardation Protein ,epigenetic modification ,Histone methylation ,Genetics ,Humans ,Cancer epigenetics ,Epigenetics ,RNA, Messenger ,General Pharmacology, Toxicology and Pharmaceutics ,fragile X syndrome ,Molecular Biology ,Genetics (clinical) ,biology ,Valproic Acid ,Acetylation ,DNA Methylation ,nervous system diseases ,Histone ,DNA demethylation ,Gene Expression Regulation ,Histone methyltransferase ,DNA methylation ,biology.protein ,Cancer research ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Female ,Histone deacetylase - Abstract
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.
- Published
- 2008