This study provides a genome-wide assessment of chromatin and transcriptional alterations in the NAc in response to repeated cocaine administration. Among the many genes that show regulation by cocaine are a large number reported in previous studies to show altered mRNA or protein expression in the NAc after chronic cocaine (see examples in Table 1). For instance, the cocaine-induced genes that encode ARC, CART, CDK5, NFκB, PDYN, σ-opioid receptor, and Period 1 and 2 (Freeman et al., 2001; McClung and Nestler, 2003; Yao et al., 2004) (see also Supplemental References in Supplemental Information) were shown in the present study to exhibit increased binding of acetylated H3 or H4, with either attenuated or unchanged methylation of H3 at K9/K27. Genes that are known to be downregulated by cocaine, such as the voltage-gated potassium channel Kv8.2 and the microtubule associated protein MTAP2 (Renthal et al., 2007), were often associated with increased methylation of H3 at K9/K27 (Table 1). For each type of histone modification, cocaine induced increases in acetylation or methylation at many more genes than it induced decreases (Fig. 1A). Although
