Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters.
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.
Dong
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E
Psychiatric Institute, Department of Psychiatry, University of Illinois, Chicago, IL 60612, USA.
Guidotti
A
A
Grayson
D R
DR
Costa
E
E
D000107:Acetylation; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D003596:Cytosine / Q000737:chemistry; D019175:DNA Methylation; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000737:chemistry* / Q000235:genetics*; D006657:Histones / Q000737:chemistry*; D007527:Isoenzymes / Q000737:chemistry* / Q000235:genetics*; D008297:Male; D008745:Methylation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D006657:Histones; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D014635:Valproic Acid; D003596:Cytosine; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1