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.

Authors and Affiliations

E Dong, A Guidotti, D R Grayson

Keywords

Related Articles

Quantitation of human immunodeficiency virus type 1 during pregnancy: relationship of viral titer to mother-to-child transmission and stability of viral load.

To develop strategies to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1), it is important to define the factors determining it. We examined the relationship between maternal HIV-1 tite...

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...

Activation of apurinic/apyrimidinic endonuclease in human cells by reactive oxygen species and its correlation with their adaptive response to genotoxicity of free radicals.

Apurinic/apyrimidinic (AP) endonuclease (APE; EC 4.2.99.18) plays a central role in repair of DNA damage due to reactive oxygen species (ROS) because its DNA 3'-phosphoesterase activity removes 3' blocking groups in DNA...

Substance P markedly potentiates the antinociceptive effects of morphine sulfate administered at the spinal level.

The undecapeptide substance P and the alkaloid morphine sulfate are two agents previously thought to have opposite roles in the mediation of spinal nociceptive processes. The present report, however, demonstrates that lo...

Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease.

Huntington's disease (HD) is an untreatable neurological disorder caused by selective and progressive degeneration of the caudate nucleus and putamen of the basal ganglia. Although the etiology of HD pathology is not ful...

Download PDF file
  • EP ID EP83948
  • DOI -
  • Views 49
  • Downloads 0

How To Cite

E Dong, A Guidotti, D R Grayson (2007). Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters.. Proceedings of the National Academy of Sciences of the United States of America, 104(11), 4676-4681. https://europub.co.uk/articles/-A-83948