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Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters

Reelin and glutamic acid decarboxylase 67 (GAD67) expression down-regulation in GABAergic interneurons of mice exposed to protracted treatment with l-methionine (MET) is attributed to RELN and GAD67 promoter cytosine-5-hypermethylation. This process recruits various transcription repressor proteins [methyl-CpG binding protein (MeCP2) and histone deacetylases (HDACs)] leading to formation of transcriptionally inactive chromatin. Here, we tested the hypothesis that RELN and GAD67 promoter cytosine-5-hypermethylation induced by a protracted MET treatment is reversible and that repeated administration of HDAC inhibitors influences this process by an activation of DNA-cytosine-5-demethylation. In the frontal cortices of mice receiving MET (5.2 mmol/kg twice a day for 7 days) and killed at 1, 2, 3, 6, and 9 days during MET washout, we measured RELN (base pairs −414 to −242) and GAD67 (base pairs −1133 to −942) promoter methylation and MeCP2 bound to methylated cytosines of RELN (base pairs −520 to −198) and GAD67 (base pairs −446 to −760) promoters. Levels of RELN and GAD67 promoter hypermethylation induced by 7 days of MET treatment declines by ≈50% after 6 days of MET withdrawal. When valproate (VPA) (2 mmol/kg) or MS-275 (0.015–0.12 mmol/kg), two structurally unrelated HDAC inhibitors, was given after MET treatment termination, VPA and MS-275 dramatically accelerated RELN and GAD67 promoter demethylation in 48–72 h. At these doses, VPA and MS-275 effectively increased the binding of acetylhistone-3 to RELN and GAD67 promoters, suggesting that histone-3 covalent modifications modulate DNA demethylation in terminally differentiated neurons, supporting the view that, directly or indirectly, HDAC inhibitors may facilitate DNA demethylation.