Abstract
It is widely accepted that memory consolidation requires de-novo transcription of memory-related genes. Epigenetic modifications, particularly histone acetylation, may facilitate gene transcription, but their potential molecular targets are poorly characterized. In the current study, we addressed the question of epigenetic control of atypical protein kinases (aPKC) that are critically involved in memory consolidation and maintenance. We examined the patterns of expression of two aPKC genes (Prkci and Prkcz) in rat cultured cortical neurons treated with histone deacetylase inhibitors. Histone hyperacetylation in the promoter region of Prkci gene elicited direct activation of transcriptional machinery, resulting in increased production of PKCλ mRNA. In parallel, histone hyperacetylation in the upstream promoter of Prkcz gene led to appearance of the corresponding PKCζ transcripts that are almost absent in the brain in resting conditions. In contrast, histone hyperacetylation in the downstream promoter of Prkcz gene was accompanied by a decreased expression of the brain-specific PKMζ products. We showed that epigenetically-triggered differential expression of PKMζ and PKCζ mRNA depended on protein synthesis. Summarizing, our results suggest that genes, encoding memory-related aPKC, may represent the molecular targets for epigenetic regulation through posttranslational histone modifications.
Highlights
The nature of the molecular basis of memory remains a challenging problem in neurobiology
It has been convincingly shown that two aPKC isoforms, protein kinase Cλ (PKCλ) and protein kinase Mζ (PKMζ), are enriched in the brain, while the third isoform, protein kinase Cζ (PKCζ), was found in the nervous tissue in trace amounts[42,49,53]
Using chromatin immunoprecipitation assays (ChIP), we observed that histone acetylation levels in the promoter region of Prkci gene were substantially elevated in resting conditions (Fig. 1a; Supplementary Fig. S1a)
Summary
The nature of the molecular basis of memory remains a challenging problem in neurobiology. Experimental data suggest the existence of critical time windows, during which transient (labile) functional changes may be converted to persistent (stable) long-term memories[7,8,9,10,11,12] These transformations, at least partially, were attributed to gene expression, since blockade of transcription during critical periods of plasticity disrupts memory consolidation in mammals and invertebrates[9,11,12]. The observed changes were associated with substantially decreased DNA methylation levels in the downstream Prkcz promoter, responsible for PKMζ synthesis[52] These data encouraged us to investigate the potential role of epigenetic mechanisms in regulation of aPKC expression
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