Synergistic Effect of Histone Hyperacetylation and DNA Demethylation in the Reactivation of the FMR1 Gene
Abstract
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.
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Treatment with histone deacetylase inhibitors TSA, butyrate, and 4-phenylbutyrate potentiated the effect of 5-azadC.
“Furthermore, treatment with histone deacetylase inhibitors (TSA, butyrate, and 4-phenylbutyrate) potentiated the effect of 5-azadC (96).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [96]
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- Authors
- Chiurazzi, P., Grazia Pomponi, M., Pietrobono, R., Bakker, C. E., Neri, G., & Oostra, B. A.
- Affiliations
- Università Cattolica del Sacro Cuore (IT)
- Erasmus University Rotterdam (NL)
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-11-01
- Volume
- 8
- Issue
- 12
- Pages
- 2317-2323
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2151282569
- Cited by
- 217
- References
- 46
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 4 · 2021: 4 · 2020: 9 · 2019: 5 · 2018: 2 · 2017: 9 · 2016: 11 · 2015: 7 · 2014: 12 · 2013: 12 · 2012: 8
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- FRAXA Research Foundation
- 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, CGG repeat expansion, histone hyperacetylation, DNA demethylation, azacitidine, 4-phenylbutyric acid, sodium butyrate, trichostatin A, transcriptional reactivation, drug synergy, gene silencing
- MeSH terms
- Decitabine, Acetylation, Azacitidine, Base Sequence, Cell Line, Enzyme Inhibitors, Fragile X Syndrome, Histones, Humans, Male, Nerve Tissue Proteins, RNA-Binding Proteins, DNA Primers, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, Fragile X Messenger Ribonucleoprotein 1, Histone Deacetylase Inhibitors
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