Genome-wide Analysis of Chromatin Regulation by Cocaine Reveals a Role for Sirtuins

• Published in: Neuron (Cambridge, Mass.) Mass.), 2009-05, Vol.62 (3), p.335-348
• Main Authors: Renthal, William, Kumar, Arvind, Xiao, Guanghua, Wilkinson, Matthew, Covington, Herbert E., Maze, Ian, Sikder, Devanjan, Robison, Alfred J., LaPlant, Quincey, Dietz, David M., Russo, Scott J., Vialou, Vincent, Chakravarty, Sumana, Kodadek, Thomas J., Stack, Ashley, Kabbaj, Mohamed, Nestler, Eric J.
• Format: Article
• Language: English
• Subjects: Addictions; Addictive behaviors; Animals; Behavior; CELLBIO; Chromatin; Chromatin - drug effects; Cocaine; Cocaine - pharmacology; Cyclic AMP Response Element-Binding Protein - drug effects; Cyclic AMP Response Element-Binding Protein - metabolism; Deoxyribonucleic acid; DNA; DNA methylation; Dopamine Uptake Inhibitors - pharmacology; Feedback, Physiological - drug effects; Gene expression; Gene Expression Regulation - drug effects; Genome-Wide Association Study; Genomes; Male; Methods; Mice; Mice, Inbred C57BL; MOLNEURO; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - physiology; Proteins; Proto-Oncogene Proteins c-fos - drug effects; Proto-Oncogene Proteins c-fos - metabolism; Reinforcement (Psychology); Rodents; Signal Transduction - drug effects; SIGNALING; Sirtuins - drug effects; Sirtuins - metabolism; Studies; Transcription factors
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2009.03.026

Changes in gene expression contribute to the long-lasting regulation of the brain's reward circuitry seen in drug addiction; however, the specific genes regulated and the transcriptional mechanisms underlying such regulation remain poorly understood. Here, we used chromatin immunoprecipitation coupled with promoter microarray analysis to characterize genome-wide chromatin changes in the mouse nucleus accumbens, a crucial brain reward region, after repeated cocaine administration. Our findings reveal several interesting principles of gene regulation by cocaine and of the role of ΔFosB and CREB, two prominent cocaine-induced transcription factors, in this brain region. The findings also provide comprehensive insight into the molecular pathways regulated by cocaine—including a new role for sirtuins (Sirt1 and Sirt2)—which are induced in the nucleus accumbens by cocaine and, in turn, dramatically enhance the behavioral effects of the drug.