Epigenetic Regulation of Transcriptional Repression by Drugs of Abuse

Duke University, Durham NC

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Abstract

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