Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene
| Autor: | Giovanni Neri, Roberta Pietrobono, M. Grazia Pomponi, Pietro Chiurazzi, Cathy E. Bakker, Ben A. Oostra |
|---|---|
| Přispěvatelé: | Clinical Genetics |
| Rok vydání: | 1999 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities Nerve Tissue Proteins Decitabine Phenylbutyrate Cell Line Histones Fragile X Mental Retardation Protein chemistry.chemical_compound Gene expression Genetics medicine Humans Enzyme Inhibitors Molecular Biology Genetics (clinical) DNA Primers Base Sequence biology Reverse Transcriptase Polymerase Chain Reaction RNA-Binding Proteins Acetylation Sodium butyrate General Medicine DNA Methylation Molecular biology nervous system diseases Histone Deacetylase Inhibitors Histone Trichostatin A DNA demethylation chemistry Fragile X Syndrome DNA methylation Azacitidine biology.protein medicine.drug |
| Zdroj: | Human Molecular Genetics, 8(12), 2317-2323. Oxford University Press |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|