Dynamic chromatin remodeling events in hippocampal neurons are associated with NMDA receptor-mediated activation of Bdnf gene promoter 1.
To determine the epigenetic events associated with NMDA receptor-mediated activation of brain-derived neurotrophic factor gene (Bdnf) promoter 1 by hippocampal neurons in culture, we screened 12 loci across 4.5 kb of genomic DNA 5' of the transcription start site (TSS) of rat Bdnf for specific changes in histone modification and transcription factor binding following NMDA receptor stimulation. Chromatin immunoprecipitation (ChIP) assays showed that NMDA receptor stimulation produced a durable, time-dependent decrease in histone H3 at lysine 9 dimethylation (H3K9me2), within 3 h after NMDA treatment across multiple loci. Concomitant increases in H3K4me2 and H3K9/14 acetylation (H3AcK9/14) were associated with transcriptional activation, but occurred at fewer sites within the promoter. The decrease in H3K9me2 was associated with release of HDAC1, MBD1, MeCP2, and REST from specific locations within promoter 1, although with different kinetics. In addition, occupancy of sites proximal to and distal to the TSS by the transcription factors NF-kappaB, CREB-binding protein (CBP), and cAMP-response element-binding protein were correlated with increased occupancy of RNA polymerase II at two loci proximal to the TSS following NMDA receptor stimulation. These temporal changes in promoter occupancy could occur thousands of base pairs 5' of the TSS, suggesting a mechanism that produces waves of Bdnf transcription.
Tian
Feng
F
Section on Molecular Genetics, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
Hu
Xian-Zhang
XZ
Wu
Xuan
X
Jiang
Hong
H
Pan
Hongna
H
Marini
Ann M
AM
Lipsky
Robert H
RH
D000107:Acetylation / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000502:physiology*; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons / Q000502:physiology; D006624:Hippocampus / Q000166:cytology*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D008239:Lysine / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
D001374:Azacitidine; D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D006657:Histones; D006877:Hydroxamic Acids; D008239:Lysine; D051783:Methyl-CpG-Binding Protein 2; D016202:N-Methylaspartate; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C489324:Mbd1 protein, rat; C497394:Mecp2 protein, rat; C012589:trichostatin A; C041519:5-aza-2'-deoxycytidine-5'-monophosphate; C515890:Hdac1 protein, rat