As observed for ΔFosB, many gene promoters (e.g., Ephb1, Wnt7a, Mbd2) showed greater enrichment of phospho-CREB binding in cocaine-treated mice vs. saline-treated mice, which is likely related to the increased levels of phospho-CREB present in the NAc at this time point. Interestingly, however, this pattern was not observed for all phospho-CREB targets (e.g., Pdyn, c-Fos): these genes showed equivalent levels of phospho-CREB binding under cocaine-and saline-treated conditions despite higher levels of expression of these genes after cocaine. These findings suggest that changes in gene activity can be coordinated by recruitment of other cofactors, such as CBP (Levine et al., 2005; Zhang et al., 2005), to a constant level of phospho-CREB on the promoter. Moreover, on average, the genome-wide spatial pattern of phospho-CREB binding relative to gene transcription start sites, which exhibits a relatively sharp peak between −500 and +200 bp and a weaker peak beyond −500 bp up to −1500 bp (Supplemental Fig. S1), is not altered by chronic cocaine exposure.
