both H3 and H4 (see Fig. 1A). Even less overlap was observed with genes hypoacetylated at H3 and H4 (1%). While these overlaps are statistically significant, the very small amount of overlap suggests that acetylation of one histone is sufficient to induce transcription in the NAc in vivo, consistent with cell culture data (Kurdistani et al., 2004; McCool et al., 2007). Moreover, it suggests that cocaine-induced signaling in the NAc converges on at least two mechanistically distinct pathways for histone acetylation of H3 vs. H4, which overlap sparsely. Cocaine-induced changes in H3 acetylation occurred at a larger number of genes than H4 acetylation, consistent with our earlier demonstration that chronic cocaine induces selective H3 acetylation at several candidate gene targets (FosB, Cdk5 [cyclin-dependent kinase 5], Bdnf [brain-derived neurotrophic factor]), with no induction of H4 acetylation observed (Kumar et al., 2005). However, we did observe increased H4 acetylation at several hundred gene promoters after chronic cocaine in the present study, which underscores the importance of this genome-wide investigation.
