altered acetylation, suggesting a single regulatory region important for its cocaine-induced activity. Another illustrative gene is Cdk5, which shows selective hyperacetylation of H3 that correlates with cocaine-induced upregulation of its transcription (Bibb et al., 2001). Moreover, the selective increase in acetylated H3 at the Cdk5 promoter after chronic cocaine is consistent with our previous findings using quantitative ChIP (Kumar et al., 2005) and further supports the quality of our genome-wide study. In addition to the genes highlighted here, we identified numerous other cocaine-regulated genes that display significant alterations in histone acetylation on their promoters (see Table 1). Examples include Adcy3 (adenylyl cyclase 3), Adora1 (adenosine receptor A1), Drd3 (dopamine receptor D3), and Rgs9 (regulator of G protein signaling 9). Each of these genes has been implicated in cocaine action in the NAc (see Supplemental References for Table 1 in Supplemental Information). Taken together, a clear pattern emerges from these findings (Fig. 1, Table 1, and Supplemental Tables S1–3): cocaine-induced increases in acetylation of either H3 or H4 correlates strongly with elevated gene expression in the NAc in vivo and reveals numerous novel genes implicated in cocaine action.
