Moreover, relatively few cocaine-regulated genes were associated with reductions of histone acetylation or methylation, suggesting that the most common mechanisms of cocaine-induced gene regulation in the NAc involve increases in histone acetylation for gene activation (rather than demethylation) or histone methylation for gene repression (rather than deacetylation). For example, the gene encoding the K+ channel subunit, Kcnv2, which is downregulated by cocaine (Renthal et al., 2007), showed increased H3 dimethyl-K9/K27 at its promoter without a change in histone acetylation, while PDYN and ARC, which are upregulated by cocaine (Fosnaugh et al., 1995; McClung and Nestler, 2003; Sivam, 1989), showed increased acetylation on their promoters without any changes in methylation (see Fig. 1B). Although increases in acetylation or methylation predominate, a subset of genes show reduced H3 acetylation or methylation after chronic cocaine exposure (e.g., the genes encoding semaphorin 5b and adenosine deaminase). Thus, hypoacetylation and hypomethylation may play an important role in gene regulation at a smaller subset of genes in response to chronic cocaine exposure.
