title: Histone H3K9 modifications are a local chromatin event involved in ethanol-induced neuroadaptation of the NR2B gene.
abstract: Expression of the NMDA receptor 2B (NR2B) gene is upregulated following chronic intermittent ethanol (CIE) treatment and withdrawal, which underlies behavioral alterations in addiction. The goal of this study was to characterize the changes of histone modifications induced by CIE treatment and its subsequent removal associated to the upregulation of NR2B gene transcription. To investigate the involvement of histone acetylation in the effect of ethanol on the NR2B gene, we examined the influence of CIE on histone acetylation in the 5' regulatory region of NR2B using a qChIP assay. CIE treatment and its subsequent removal produced a remarkable and selected increase in histone H3K9 acetylation. Interestingly, the majority of the increased H3K9 acetylation occurred after ethanol removal, which was coincident with a decrease in H3K9 methylation in the same time duration. Further examination of the mechanisms of ethanol-induced alterations on the histone modifications revealed that CIE-induced acetylation of H3K9 was not due to the changes in global enzyme activities or the expression of histone acetyltransferases (HATs) and deacetylase (HDACs). Instead, we found a significant downregulation in some histone methyltransferases (HMTs) at both the global level and the local chromatin of the NR2B gene following CIE treatment. Moreover, our experiments also indicated a decrease of G9a, Suv39 h1 and HDAC1-3 in the chromatin of the NR2B gene promoter, which may be responsible for the altered H3K9 modifications. Taken together, the findings suggest a mechanism where the changes in H3K9 modifications in the local chromatin of the NR2B gene underlie alcohol-induced neuroadaptation.
authors.affiliation: Department of Pharmacology; The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. qiang@uthscsa.edu　
authors.forename: Mei
authors.initials: M
authors.lastname: Qiang
authors.forename: Ashley
authors.initials: A
authors.lastname: Denny
authors.forename: Mai
authors.initials: M
authors.lastname: Lieu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Carreon
authors.forename: Ji
authors.initials: J
authors.lastname: Li
mesh_terms: D000107:Acetylation; D000220:Adaptation, Biological; D000818:Animals; D002843:Chromatin / Q000737:chemistry* / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000235:genetics; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics; D006657:Histones / Q000737:chemistry*; D008780:Methyltransferases / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D011401:Promoter Regions, Genetic; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D012097:Repressor Proteins; D000431:Ethanol; C498700:Suv39h1 protein, mouse; D000076983:Histone Methyltransferases; D008780:Methyltransferases; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases