CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum.
Remodeling chromatin is essential for cAMP-regulated gene expression, necessary not only for development but also for memory storage and other enduring mental states. Histone acetylation and deacetylation mediate long-lasting forms of synaptic plasticity in Aplysia as well as cognition in mice. Here, we show that histone acetylation by the cAMP-response element binding protein (CREB)-binding protein (CBP) mediates sensitivity to cocaine by regulating expression of the fosB gene and its splice variant, DeltafosB, a transcription factor previously implicated in addiction. Using the chromatin immunoprecipitation assay with antibodies against histone H4 or CBP, we find that CBP is recruited to the fosB promoter to acetylate histone H4 in response to acute exposure to cocaine. We show that mutant mice that lack one allele of the CBP gene and have normal levels of fosB expression are less sensitive to chronic (10-day) administration of cocaine than are wild-type mice. This decreased sensitivity is correlated with decreased histone acetylation and results in decreased fosB expression and diminished accumulation of DeltafosB. Thus, CBP, which forms part of the promoter complex with CREB, mediates sensitivity to cocaine by acetylating histones.
Levine
Amir A
AA
Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, and Howard Hughes Medical Institute, 1051 Riverside Drive, New York, NY 10032, USA.
Guan
Zhonghui
Z
Barco
Angel
A
Xu
Shiqin
S
Kandel
Eric R
ER
Schwartz
James H
JH
D000107:Acetylation; D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism / Q000502:physiology*; D002843:Chromatin / Q000737:chemistry; D047369:Chromatin Immunoprecipitation; D003042:Cocaine / Q000737:chemistry / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D016678:Genome; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000737:chemistry; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D013997:Time Factors
D002843:Chromatin; C483819:Fosb protein, mouse; D006657:Histones; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D000242:Cyclic AMP; D050882:CREB-Binding Protein; D003042:Cocaine