We found that chronic cocaine reduced levels of H3 dimethyl-K9/K27 at the promoter regions of 209 genes while increasing it at 898 genes in the NAc compared to saline-treated controls (Fig. 1A; see Supplemental Table S4). Interestingly, the genome-wide distribution of this methylation mark occurred on a much broader promoter span (from −1600 to +500 bp) compared to that observed for histone acetylation (Supplemental Fig. S1), similar to the pattern of histone methylation observed in cultured cell lines and yeast (Li et al., 2007). Although the genome-wide distribution did not change after chronic cocaine exposure, cocaine increased histone methylation levels at several-fold more genes than it decreased. This finding suggests that cocaine represses the expression or dampens the induction of many genes, despite the predominant effect of cocaine being gene activation (McClung and Nestler, 2003). Moreover, just as few genes showed significant changes in acetylation of both H3 and H4, there was minimal (~2%) overlap between genes that showed reduced histone acetylation and those that showed increased H3 methylation after chronic cocaine (see Fig. 1A and Supplemental Table S5). These
