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

ABSTRACT: Reelin and glutamic acid decarboxylase 67 (GAD(67)) expression down-regulation in GABAergic interneurons of mice exposed to protracted treatment with l-methionine (MET) is attributed to RELN and GAD(67) 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 GAD(67) 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 GAD(67) (base pairs -1133 to -942) promoter methylation and MeCP2 bound to methylated cytosines of RELN (base pairs -520 to -198) and GAD(67) (base pairs -446 to -760) promoters. Levels of RELN and GAD(67) promoter hypermethylation induced by 7 days of MET treatment declines by approximately 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 GAD(67) promoter demethylation in 48-72 h. At these doses, VPA and MS-275 effectively increased the binding of acetylhistone-3 to RELN and GAD(67) 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.

SUBMITTER: Dong E

PROVIDER: S-EPMC1815468 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Stromal cell-derived factor alpha (SDF1alpha) and its cognate receptor CXCR4 play an important role in neuronal development in the hippocampus, but the genes directly regulated by SDF1alpha/CXCR4 signaling are unknown. To study the role of CXCR4 targeted genes in neuronal development, we used neuronal cultures established from embryonic day 18 rats. Hippocampal neurons express CXCR4 receptor proteins and are stimulated by SDF1alpha resulting in activation of extracellular signal-regulated kinase (ERK)1/2 and the transcription factor cAMP-response element-binding protein. SDF1alpha rapidly induces the expression of the early growth response gene Egr1, a transcription factor involved in activity-dependent neuronal responses, in a concentration-dependent manner. Gel-shift analysis showed that SDF1alpha enhances DNA binding activity to the Egr1-containing promoter for GAD67. Chromatin immunoprecipitation analysis using an Egr1 antibody indicated that SDF1alpha stimulation increases binding of Egr1 to a GAD67 promoter DNA sequence. SDF1alpha stimulation increases the expression of GAD67 at both the mRNA and protein levels, and increases the amount and neurite localization of gamma-aminobutyric acid (GABA) in neurons already expressing GABA. SDF1alpha-induced Egr1/GAD67 expression is mediated by the G protein-coupled CXCR4 receptor and activation of the ERK pathway. Reduction of Egr1 gene expression using small interfering RNA technology lowers the level of GAD67 transcripts and inhibits SDF1alpha-induced GABA production. Inhibition of CXCR4 activation in the developing mouse brain in utero greatly reduced Egr1 and GAD67 mRNA levels and GAD67 protein levels, suggesting a pivotal role for CXCR4 signaling in the development of GABAergic neurons in vivo. Our data suggest that SDF1alpha/CXCR4/G protein/ERK signaling induces the expression of the GAD67 system via Egr1 activation, a mechanism that may promote the maturation of GABAergic neurons during development.

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

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