of which was very similar to the genome-wide average shown in Supplemental Fig. S1. Two other genes that are upregulated by cocaine (Fosnaugh et al., 1995; Sivam, 1989) and display acetylation patterns similar to the genome-wide average are Arc (activity regulated cytoskeletal-associated protein) and Pdyn (prodynorphin). Distinct from CART, however, the upregulation of ARC and PDYN by cocaine are associated with significant acetylation of a single histone only, H3 or H4, respectively. Per1 (period 1, a circadian gene) is also upregulated by cocaine (McClung and Nestler, 2003) and is only hyperacetylated significantly on H4, but it displays a pattern of acetylation distinct from the genome-wide average. While the acetylation peak closest to the transcription start site overlaps with the region of ΔFosB binding (Table 1 and data not shown), the significance of the more upstream peak is unknown and may represent a region of novel regulatory elements. However, most of the genes regulated by cocaine show only one peak of 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
