ChIP represents a powerful advance in establishing regulation of gene transcription by cocaine, but traditional methods are still limited by the analysis of individual genes of interest one at a time. Moreover, regulation of a gene may be mediated by many types of coincident alterations of histones and related modifications (Kouzarides, 2007). These considerations argue for the importance of analyzing the immunoprecipitated DNA, not for an individual gene, but genome-wide using ChIP-chip assays, to gain a global view of genes that show markers of activation or repression after cocaine. In the present study, we mapped the genomic effects of chronic cocaine in the NAc by performing ChIP-chip for acetylated and methylated histones and for ΔFosB and phospho-CREB (the activated form of this transcription factor). We then demonstrate that one family of novel target genes, the sirtuins, discovered by ChIP-chip to be regulated in the NAc by chronic cocaine, contributes directly to addiction-related behaviors. These findings provide fundamentally new insight into cocaine’s regulation of gene transcription in this brain reward region.
