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 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. We performed transcriptional profiling of hippocampal samples from willd-type and cbp+/- mice (C57/DBA F1 hybrid females). Treatments consisted in intraperioneal treatment with HDACi TSA (2.4 mg/kg) o vehicle (DMSO/Saline). Samples were obtained 75 min after TSA administration. Novelty consisted of placing an individual animal in a white plexiglas square box containing plastic tubing and small toys for 1h. For TSA and Novelty condition animals were injected with TSA and 15 min later were allowed to exploration in the Novelty paradigm. We obtained quintuplicate (standar housing) and triplicate (novelty; TSA; and novelty + TSA) samples containing total RNA from the hippocampi of 3-4 three-month old females of either genotype (cbp+/- and wild-type mice) (in total >100 mice were used in the experiment). NOTE: The microarray experiments described here and those presented in the series GSE30880 were performed in paralell. Therefore, control samples (wt and cbp+/-) are part of both datasets.