Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins.
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 DeltaFosB 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.
Renthal
William
W
Department of Psychiatry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Kumar
Arvind
A
Xiao
Guanghua
G
Wilkinson
Matthew
M
Covington
Herbert E
HE
Maze
Ian
I
Sikder
Devanjan
D
Robison
Alfred J
AJ
LaPlant
Quincey
Q
Dietz
David M
DM
Russo
Scott J
SJ
Vialou
Vincent
V
Chakravarty
Sumana
S
Kodadek
Thomas J
TJ
Stack
Ashley
A
Kabbaj
Mohamed
M
Nestler
Eric J
EJ
D000818:Animals; D002843:Chromatin / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D055106:Genome-Wide Association Study; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D012054:Reinforcement, Psychology; D015398:Signal Transduction / Q000187:drug effects; D037761:Sirtuins / Q000187:drug effects / Q000378:metabolism*
D002843:Chromatin; D017362:Cyclic AMP Response Element-Binding Protein; D018765:Dopamine Uptake Inhibitors; C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D037761:Sirtuins; D003042:Cocaine