Epigenetic Mechanisms: Critical Contributors to Long-Term Memory Formation

Department of Neurobiology, Evelyn F McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
The Neuroscientist (Impact Factor: 6.84). 12/2011; 17(6):616-32. DOI: 10.1177/1073858411386967
Source: PubMed

ABSTRACT Recent advances in chromatin biology have identified a role for epigenetic mechanisms in the regulation of neuronal gene expression changes, a necessary process for proper synaptic plasticity and memory formation. Experimental evidence for dynamic chromatin remodeling influencing gene transcription in postmitotic neurons grew from initial reports describing posttranslational modifications of histones, including phosphorylation and acetylation occurring in various brain regions during memory consolidation. An accumulation of recent studies, however, has also highlighted the importance of other epigenetic modifications, such as DNA methylation and histone methylation, as playing a role in memory formation. This present review examines learning-induced gene transcription by chromatin remodeling underlying long-lasting changes in neurons, with direct implications for the study of epigenetic mechanisms in long-term memory formation and behavior. Furthermore, the study of epigenetic gene regulation, in conjunction with transcription factor activation, can provide complementary lines of evidence to further understanding transcriptional mechanisms subserving memory storage.

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    • "However, results presented in figure 4B do not show any enrichment of Tip60 on the Egr1 gene promoter in APP−/− mice, allowing us to rule out the implication of Tip60 in this regulation. On the other hand, acetylation of H4K5 and H4K12 is mediated by CBP/P300, which associates with phosphorylated CREB DNA binding protein [27]. In addition, the Egr1 promoter contains two CREB responsive elements (CRE) (Figure 4A). "
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    ABSTRACT: We previously demonstrated that APP epigenetically regulates Egr1 expression both in cultured neurons and in vivo. Since Egr1 is an immediate early gene involved in memory formation, we wondered whether other early genes involved in memory were regulated by APP and we studied molecular mechanisms involved. By comparing prefrontal (PF) cortex from wild type (APP+/+) and APP knockout mice (APP-/-), we observed that APP down regulates expression of four immediate early genes, Egr1, c-Fos, Bdnf and Arc. Down regulation of Egr1, c-Fos and Bdnf transcription resulted from a decreased enrichment of acetylated histone H4 on the corresponding gene promoter. Further characterization of H4 acetylation at Egr1 and c-Fos promoters revealed increased acetylation of H4K5 and H4K12 residues in APP-/- mice. Whereas APP affected Egr1 promoter activity by reducing access of the CREB transcription factor, its effect on c-Fos appeared to depend on increased recruitment of HDAC2 histone deacetylase to the gene promoter. The physiological relevance of the epigenetic regulation of Egr1 and c-Fos gene transcription by APP was further analyzed following exposure of mice to novelty. Although transcription of Egr1 and c-Fos was increased following exposure of APP+/+ mice to novelty, such an induction was not possible in APP-/- mice with a high basal level of expression of these immediate early genes. Altogether, these results demonstrate that APP-mediated regulation of c-Fos and Egr1 by different epigenetic mechanisms is needed for their induction during exposure to novelty.
    PLoS ONE 06/2014; 9(6):e99467. DOI:10.1371/journal.pone.0099467 · 3.23 Impact Factor
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    • "The consolidation of memory requires gene transcription and protein synthesis (Lubin et al. 2011). "
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    • "Of these changes, one of the most important is histone acetylation (Peixoto and Abel, 2012), a post-translational modification of lysine residues that lie on the histone amino terminal tails (Levenson and Sweatt, 2005; Sananbenesi and Fischer, 2009; Morris et al., 2010). This modification is mostly associated with increases in levels of gene transcription (Chuang et al., 2009; Sananbenesi and Fischer, 2009; Morris et al., 2010; Lubin et al., 2011; Trollope et al., 2012). "
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    ABSTRACT: Chronic exposure to stress is associated with a number of psychiatric disorders, but little is known about the epigenetic mechanisms that underlie the stress response or resilience to chronic stress. We investigated histone acetylation in 7 different brain regions of rats exposed to chronic social defeat stress: the dorsal hippocampus, ventral hippocampus, medial prefrontal cortex, basolateral amygdala, locus coeruleus, paraventricular thalamus, and dorsal raphe nucleus. This stress paradigm was unique in that it allowed rats to display resilience in the form of an active coping mechanism. We found that there was an increase in acetylation of H3K9 and bulk acetylation of H4K5,8,12,16 in the dorsal raphe nucleus of rats that were less resilient. Less resilient rats also displayed increased levels of H3K18 acetylation in the medial prefrontal cortex when compared to non-stressed controls. In the ventral hippocampus, there was an increase in acetylation of H3K18 and H4K12 in rats that were less resilient when compared to non-stressed control rats. In addition, there was a decrease in levels of H4K8 acetylation in both resilient and non-resilient rats as compared to controls. We assessed expression of histone modifying enzymes in the ventral hippocampus and the medial prefrontal cortex using quantitative real time PCR and found changes in expression of a number of targets. These included changes in Sirt1 and Sirt2 in the ventral hippocampus and changes in Kat5 in the medial prefrontal cortex. Overall, these results suggest that changes in histone acetylation and expression of histone modifying enzymes in these regions correlate with the behavioral response to stress in socially defeated rats.
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