How is DNA methylation regulated at specific genes?

Neuronal activity, brain development, memory formation, and cognitive disease states are all associated with reorganization of DNA methylation patterns at specific genes with defined temporal dynamics (Day et al., 2013; De Jager et al., 2014; Guo, Ma, et al., 2011; Lim et al., 2014; Lister et al., 2013; Lubin et al., 2008; Miller et al., 2010; Miller & Sweatt, 2007; Nwaobi, Lin, Peramsetty, & Olsen, 2014). This observation suggests active regulation of methylation and demethylation targeting at specific genes and possibly even specific cytosine nucleotides. Although some DNA methylation patterns could be attributed to the local sequence preferences of DNMT1 and DNMT3a (Handa & Jeltsch, 2005) or to the formation of complexes with other DNA binding proteins (Robertson et al., 2000), this does not explain how specific genes undergo experience- dependent changes in DNA methylation. In some cases, behavioral experiences can directly alter the expression of DNA methylation machinery, as observed for Dnmt3a (Miller & Sweatt, 2007), Gadd45b (Sultan et al., 2012), Tetl (Kaas et al., 2013), and Tet3 (Li et al., 2014). However, these expression changes would result in global alterations in levels of these enzymes, making it unclear how epigenetic specificity can be obtained.

Noncoding RNAs represent one possible gene-specific regulator of DNA modification processes. For example, piwi-interacting RNAs (piRNAs) are a short (26-31 nucleotide) noncoding RNA species that are important for methylation-induced silencing of transposable elements in the germline (Aravin, Sachidanandam, Girard, Fejes-Toth, & Hannon, 2007; Brennecke et al., 2008). piRNAs were also found to exist in the Aplysia CNS, where they are increased in response to a serotonin stimulation protocol that induces long-term synaptic facilitation (Rajasethupathy et al., 2012). Although the precise mechanism is not known, piRNA induction was found to regulate CREB2 promoter methylation via DNMT activity, resulting in a sustained promoter hypermethylation after serotonin stimulation (Rajasethupathy et al., 2012). Similarly, long noncoding RNAs have been implicated in direct control over DNA methylation via interactions with DNA methyltransferases (Di Ruscio et al., 2013; Holz-Schietinger & Reich, 2012). In contrast to piRNAs, which are associated with gene methylation, these long noncoding RNAs have an inhibitory relationship with DNA methylation, likely by binding to DNMTs and blocking catalytic activity. Importantly, one class of DNMT-interacting RNAs (termed extra-coding RNA) are synthesized from genomic loci that overlap protein coding genes, in effect establishing a gene-specific mechanism for control of methylation status at that gene (Di Ruscio et al., 2013). However, neither piRNAs nor DNMT-interacting long noncoding RNAs have been investigated in the vertebrate nervous system, making it unclear how these mechanisms may contribute to neuronal plasticity and memory formation. Additional studies are required to understand how behavioral experiences result in gene-specific DNA modifications, and whether specific modifications regulate memory strength and persistence.

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