In contrast, gene expression profiling in the superior frontal cortex, and central and basolateral nuclei of the amygdala of human alcoholics provided several lines of evidence (transcriptional activation of endogenous retrovirus transposons, downregulation of DNMT1 and upregulation of ribosomal modules) indicating that chronic ethanol abuse induces global DNA hypomethylation, which was hypothesized to reflect a release of transcriptional repression [41]. Moreover, gene coexpression network analysis pinpointed significantly overlapping modules, including those with extreme GC content (GC-rich/GC-poor), and there was a highly significant positive correlation between the direction and magnitude of gene regulation by chronic ethanol abuse and average GC content across modules identified in the three brain regions, which could be partially attributed to increased H3K4 trimethylation. Finally, chronic ethanol abuse induced a global increase in H3K4 trimethylation and an upregulation of several genes encoding elements of the transcription corepressor complex. Altogether this study points to chromatin modifications as a potential mechanism driving the coordination of gene expression patterns in the alcoholic brain.
