Modest reactivation of the mutant FMR1 gene by valproic acid is accompanied by histone modifications but not DNA demethylation
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.
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Valproic acid is known as a reactivator of silenced genes and appeared to be a weak reactivator of full mutation.
“The third tested compound is valproic acid (101), which is already known as a reactivator of silenced genes (102) that appeared to be a weak reactivator of FM (103).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [103]
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- Authors
- Tabolacci, E., De Pascalis, I., Accadia, M., Terracciano, A., Moscato, U., Chiurazzi, P., & Neri, G.
- Affiliations
- Università Cattolica del Sacro Cuore (IT)
- Corresponding author
- Neri, Giovanni
- Venue
- Pharmacogenetics and Genomics
- Published
- 2008-08
- Volume
- 18
- Issue
- 8
- Pages
- 738-741
- ISSN
- 1744-6872 (ISSN-L)
- OpenAlex
- W2087016730
- Cited by
- 44
- References
- 12
- Citations by year
- 2024: 2 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 8 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 4
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacogenetics and Genomics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- FMR1 gene, fragile X syndrome, valproic acid, histone deacetylase inhibition, histone acetylation, histone methylation, DNA methylation, CGG repeat expansion, gene silencing, FMRP, butyrate, gene reactivation, lymphoblastoid cell lines
- MeSH terms
- Acetylation, Cell Line, Female, Gene Expression Regulation, Histones, Humans, Male, RNA, Messenger, Valproic Acid, DNA Methylation, Chromatin Immunoprecipitation, Fragile X Messenger Ribonucleoprotein 1
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