As stated, the dramatic cell type differences that have been reported for the genomic targets of a given transcription factor between even two types of cultured cells means that an absolutely crucial next step in the field is to define modes of chromatin regulation that occur in the brain in vivo. Indeed, well beyond identifying lists of genes that show interesting patterns of chromatin regulation by cocaine, results of the present study reveal several novel principles by which cocaine regulates gene expression in the NAc of behaving animals. Among the lessons revealed are that most cocaine-regulated genes show altered acetylation either of histone H3 or of H4, with changes at H3 predominating, and alterations either in histone acetylation or in histone methylation, but only rarely both modifications together on the same gene. Another striking lesson is that phospho-CREB exerts complex transcriptional effects and can act as a transcriptional activator or repressor in the brain in vivo. This is also true for ΔFosB, which has been shown previously (Kumar et al., 2005; McClung and Nestler, 2003; Renthal et al., 2008) and
