We next addressed whether ELK1 could play a role in transcriptional regulation relevant to heroin abuse. We chose an unbiased strategy in which downstream gene targets could be identified to guide future studies. As such, we utilized a NAc microarray dataset from a cohort of our heroin postmortem population and examined transcription factor binding motifs common to the observed transcriptome alterations. Interestingly, evaluation of common transcription factors for the significantly regulated genes using the Lists2Networks program (55) revealed that ELK1 (p<0.05) and ETS1 (p<0.01) had the most putative target genes overlapping with down-regulated genes (36/195) (Fig. 6A and Supplementary Table 5), confirming the relevance of ELK1 as a transcriptional regulator of gene expression in heroin abuse. Hierarchical clustering on a subset (N=32) of subjects in the two groups that were most different from one another revealed differential expression of 1518 genes, of which 115 were identified as downregulated ELK1 target genes (p<.000001) (Supplementary Fig 1 and Supplementary Table 6). These findings were validated by measuring mRNA expression levels of the ELK1 target genes BAG1 (80.46 ± 3.61%; p<0.01) and USE1
