Locus-Specific Epigenetic Editing in Reward Pathology

Regulation of gene expression via stably altered chromatin is a compelling area of study for highly heritable neuropsychiatric diseases, such as addiction. However, due to the promiscuous nature of chromatin-remodeling factors, previous studies have largely failed to distinguish between the mere presence and the functional relevance of drug-induced histone post-translational modifications (HPTMs). Furthermore, regulation of alternative splicing is implicated in neurological disease in humans and cocaine exposure in mice. Recently, a small but compelling literature has described chromatin-regulated alternative splicing, suggesting a novel function for drug-induced neuroepigenetic remodeling. Of particular interest are genes that show both cocaine-regulated enrichment of histone H3 lysine 36 methylation (H3K36me3) and alternative exon expression, in light of novel data that H3K36me3 enrichment is mechanistically linked to alternative exon selection via recruitment of splicing factors. The current proposal aims to test the hypothesis that alternative splicing is functionally coupled to cocaine-induced H3K36me3 enrichment at specific genes. We apply highly innovative methods of locus-specific epigenome editing in vivo to elucidate the causal relevance of HPTMs in addiction, which will have widespread applications throughout drug abuse research as well as other fields.