(Renthal et al., 2007), were often associated with increased methylation of H3 at K9/K27 (Table 1). For each type of histone modification, cocaine induced increases in acetylation or methylation at many more genes than it induced decreases (Fig. 1A). Although there are a few examples where reductions in acetylation or methylation are associated with respective changes in gene expression, our data suggest that chronic cocaine more commonly regulates transcription by either increasing histone H3 or H4 acetylation (to elevate mRNA levels), or by increasing histone H3 dimethyl-K9/27 (to reduce mRNA expression). However, these are observations of genome-wide data and exceptions likely exist. There is also a subset of genes which is highly regulated at the chromatin level but show no detectible change in steady-state mRNA expression. For example, mRNA’s for HDAC4 and myocyte-enhancer factors 2A and 2D (MEF2A and MEF2D) are not altered by cocaine (data not shown), but their promoters are dramatically altered after cocaine treatment by histone modifications and/or transcription factor binding. These are particularly interesting examples given the potent influence of HDAC4 (Kumar et al., 2005) and of MEF2 (Pulipparacharuvil et al., 2008) in the NAc on cocaine responses, and may illustrate a new layer of regulation
