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Regulation of gene expression via stably altered chromatin is a compelling area of study for highly heritable neuropsychiatric diseases, such as addiction (Walker, Cates, Heller, & Nestler, 2015). However, due to the promiscuous nature of chromatin-remodeling factors (Kennedy et al., 2013; Maze et al., 2011), 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 (Licatalosi & Darnell, 2006) and cocaine exposure in mice (Feng et al., 2014). Recently, a small but compelling literature has described chromatin-regulated alternative splicing (Luco, Allo, Schor, Kornblihtt, & Misteli, 2011), 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 (Feng et al., 2014), in light of novel bioinformatic (Hu, Kim, Feng, Grant, & Heller, 2017) and molecular data that H3K36me3 enrichment is mechanistically linked to alternative exon selection (Luco et al., 2010). We apply highly innovative methods of locus-specific epigenome editing (Heller et al., 2014, 2016) 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.