These findings have important implications for our understanding of the mechanisms linking early maternal behavior and stable changes in behavior later in adulthood as well as on our understanding of the mechanisms responsible for maintaining the DNA methylation pattern
in adult postmitotic tissues. First, our data support the idea that demethylation is driven by activation of chromatin and that HDAC inhibitors produce demethylation even in nondividing cells (ie, in a replication-independent manner). Second, our data are consistent with the hypothesis that the demethylation of GR exon 17 in offspring of highLG rats early after birth is driven by increased histone acetylation, Inhibitors,research,lifescience,medical as discussed above. Third, these data provide evidence that molecular mechanisms that underlie the effects of early life-experience neural function are potentially reversible in adulthood. This consideration is of obvious social and therapeutic implications. Fourth, these data provide in vivo evidence for our hypothesis that the DNA methylation pattern Inhibitors,research,lifescience,medical is dynamic even in postmitotic tissues and that its steady state Inhibitors,research,lifescience,medical is maintained by the state of chromatin acetylation.99 Finally, the data provide a framework for understanding of how environmental signals could change the DNA methylation pattern and thus
the chemistry of the genome itself, even I-BET151 during adulthood. Dissection of the molecular mechanisms linking maternal behavior and active demethylation of GR exon 17 promoter in the hippocampus The data discussed above support the hypothesis Inhibitors,research,lifescience,medical that histone acetylation could produce active demethylation of the GR exon 17 promoter, yet several questions remain unanswered. How, for example, is histone acetylation targeted to the exon 17 promoter as a consequence of
maternal behavior? We propose that maternal behavior stimulates 5-HT, which stimulates NGFIA, and that NGFIA then targets HATs and eventually demethylases to the GR exon 17 promoter. To dissect the different Inhibitors,research,lifescience,medical molecular components of this hypothesis, we took advantage of both hippocampal primary neuronal cell cultures as well as nonneuronal cell lines. The two systems have different strengths and could be used enough to test different components of the model. First, we tested the hypothesis that 5-HT acts through cAMP to produce hypomethylation. Hippocampal cell cultures treated with either 5-HT or 8-bromo-cAMP, a stable cAMP analog, show increased GR expression following 4 days of treatment. Treatment of hippocampal cells in culture with 5-HT also results in the hypomethylation of the 5′ CpG dinucleotide of the NGFIA consensus sequence within the exon 17 promoter of the GR gene, with no effect at the 3′ site (Weaver IGC et al, unpublished results). Treatment with 8-bromocAMP produces an even more pronounced effect on cytosine methylation at the 5′ CpG site.