Alterations in gene expression contribute to the adaptations of brain reward circuits that underlie persistent behaviors associated with drug abuse. Epigenetic regulation of transcription mediated by posttranslational modification of histone proteins is emerging as an important mechanism used by environmental factors, including drugs of abuse, to control gene expression. Identifying the histone modifying factors that respond to drugs of abuse and understanding how chromatin regulation affects behavior are crucial for making progress toward understanding the neural basis of drug addiction. One intriguing candidate for this process is the methyl-DNA binding transcriptional represser MeCP2 as this protein plays important roles in brain development and function. MeCP2 is known to repress its target genes by recruiting both histone deacetylase and methyltransferase enzymes. Interestingly, given the conservation between activity-dependent and drug-induced mechanisms of transcriptional regulation, we have recently found that MeCP2 is phosphorylated in an activity-dependent manner in neurons at a site that dynamically modulates the ability of MeCP2 to repress its target gene Bdnf. We hypothesize that MeCP2 is a key mediator of cocaine-regulated transcription, and that the regulation of repressive histone methylation contributes to the development of drug sensitization behaviors. We propose to test this hypothesis by combining biochemical analyses of cocaine-dependent regulation of MeCP2 and histone methylation with experimental manipulation of these processes in mouse models of drug abuse.
Our specific aims are: 1) to examine the functional regulation of MeCP2 by drugs of abuse;2) to investigate the contribution of epigenetic transcriptional repression mechanisms to cocaine-regulated gene expression;and 3) to evaluate the contribution of epigenetic mechanisms of gene transcription to drug-induced behavioral sensitization. These studies will fill a critical gap in knowledge by defining new mechanisms that contribute to the effects of cocaine on both neuronal gene expression and behavior. The identification of epigenetic mechanisms involved in regulation of gene expression by drugs of abuse may reveal new targets for therapies in treatment of drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA022202-04S1
Application #
8081334
Study Section
Special Emphasis Panel (ZDA1-RXL-E (07))
Program Officer
Satterlee, John S
Project Start
2006-09-29
Project End
2011-06-30
Budget Start
2010-06-04
Budget End
2010-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$10,099
Indirect Cost
Name
Duke University
Department
Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Schmidt, Heath D; McGinty, Jacqueline F; West, Anne E et al. (2013) Epigenetics and psychostimulant addiction. Cold Spring Harb Perspect Med 3:a012047
West, Anne E (2012) Regulated shuttling of the histone deacetylase HDAC5 to the nucleus may put a brake on cocaine addiction. Neuron 73:1-3
Su, Dan; Cha, Young May; West, Anne E (2012) Mutation of MeCP2 alters transcriptional regulation of select immediate-early genes. Epigenetics 7:146-54
Hutchinson, Ashley N; Deng, Jie V; Aryal, Dipendra K et al. (2012) Differential regulation of MeCP2 phosphorylation in the CNS by dopamine and serotonin. Neuropsychopharmacology 37:321-37
Hutchinson, Ashley N; Deng, Jay V; Cohen, Sonia et al. (2012) Phosphorylation of MeCP2 at Ser421 contributes to chronic antidepressant action. J Neurosci 32:14355-63
Lyons, Michelle R; Schwarz, Charlotte M; West, Anne E (2012) Members of the myocyte enhancer factor 2 transcription factor family differentially regulate Bdnf transcription in response to neuronal depolarization. J Neurosci 32:12780-5
Cohen, Sonia; Gabel, Harrison W; Hemberg, Martin et al. (2011) Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 72:72-85
Lyons, Michelle R; West, Anne E (2011) Mechanisms of specificity in neuronal activity-regulated gene transcription. Prog Neurobiol 94:259-95
West, Anne E (2011) Biological functions and transcriptional targets of CaRF in neurons. Cell Calcium 49:290-5

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