Transcriptional and Epigenetic Mechanisms of Addiction
Figure 4. Epigenetic basis of drug regulation of gene expression.
The figure is based on the mechanisms by which chronic cocaine, through ΔFosB, activates the cdk5 gene (top) and represses the c-fos gene (bottom). Top: ΔFosB binds to the cdk5 gene and recruits several co-activators, including CBP (CREB binding protein) — a type of histone acetyltransferase (HAT) leading to increased histone acetylation, transcription factor BRG1 (also known as brahma-related gene 1) — a type of chromatin remodeling factor — and SUG1 (proteasome 26S ATPase subunit 5), another type of chromatin regulatory protein. ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. Bottom: In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). The gene also shows increased G9a binding and repressive histone methylation (despite global decreases in these marks). The net result is c-fos gene repression. As transcriptional regulatory complexes contain dozens or hundreds of proteins, much further work is needed to further define the activational and repressive complexes that cocaine recruits to particular genes to mediate their transcriptional regulation and to explore the range of distinct activational and repressive complexes involved in cocaine action.