Genomic targets, and histone acetylation and gene expression profiling of neural HDAC inhibition

Histone deacetylase inhibitors (HDACis) have been shown to potentiate hippocampal-dependent memory and synaptic plasticity and to ameliorate cognitive deficits and degeneration in animal models for different neuropsychiatric conditions. However, the impact of these drugs on hippocampal histone acety...

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Bibliographic Details
Published in:Nucleic acids research 2013-09, Vol.41 (17), p.8072-8084
Main Authors: Lopez-Atalaya, Jose P, Ito, Satomi, Valor, Luis M, Benito, Eva, Barco, Angel
Format: Article
Language:English
Subjects:
Acetylation - drug effects
Animals
Binding Sites
Chromatin - drug effects
Chromatin - metabolism
Chromosome Mapping
Female
Gene Expression Profiling
Gene Regulation, Chromatin and Epigenetics
Genomics
Hippocampus - drug effects
Hippocampus - metabolism
Histone Deacetylase Inhibitors - pharmacology
Histones - metabolism
Hydroxamic Acids - pharmacology
Methylation
Mice
NF-kappa B - metabolism
Transcription, Genetic - drug effects
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Summary:Histone deacetylase inhibitors (HDACis) have been shown to potentiate hippocampal-dependent memory and synaptic plasticity and to ameliorate cognitive deficits and degeneration in animal models for different neuropsychiatric conditions. However, the impact of these drugs on hippocampal histone acetylation and gene expression profiles at the genomic level, and the molecular mechanisms that underlie their specificity and beneficial effects in neural tissue, remains obscure. Here, we mapped four relevant histone marks (H3K4me3, AcH3K9,14, AcH4K12 and pan-AcH2B) in hippocampal chromatin and investigated at the whole-genome level the impact of HDAC inhibition on acetylation profiles and basal and activity-driven gene expression. HDAC inhibition caused a dramatic histone hyperacetylation that was largely restricted to active loci pre-marked with H3K4me3 and AcH3K9,14. In addition, the comparison of Chromatin immunoprecipitation sequencing and gene expression profiles indicated that Trichostatin A-induced histone hyperacetylation, like histone hypoacetylation induced by histone acetyltransferase deficiency, had a modest impact on hippocampal gene expression and did not affect the transient transcriptional response to novelty exposure. However, HDAC inhibition caused the rapid induction of a homeostatic gene program related to chromatin deacetylation. These results illuminate both the relationship between hippocampal gene expression and histone acetylation and the mechanism of action of these important neuropsychiatric drugs.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkt590