Chromatin-mediated alternative splicing regulates cocaine-reward behavior

Neuronal alternative splicing is a key gene regulatory mechanism in the brain. However, the spliceosome machinery is insufficient to fully specify splicing complexity. In considering the role of the epigenome in activity-dependent alternative splicing, we and others find the histone modification H3K36me3 to be a putative splicing regulator. In this study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with the enrichment of H3K36me3 at differentially spliced junctions. Importantly, only targeted epigenetic editing can distinguish between a direct role of H3K36me3 in splicing and an indirect role via regulation of splice factor expression elsewhere on the genome. We targeted Srsf11, which was both alternatively spliced and H3K36me3 enriched in the brain following cocaine self-administration. Epigenetic editing of H3K36me3 at Srsf11 was sufficient to drive its alternative splicing and enhanced cocaine self-administration, establishing the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior. [Display omitted] •Cocaine self-administration regulates alternative splicing and H3K36me3 enrichment•Alternative splicing of splice factor Srsf11 is accompanied by enrichment of H3K36me3•CRISPR epigenetic editing of H3K36me3 drives alternative splicing of Srsf11 in brain•Srsf11 regulates downstream splice events and augments cocaine-reward behavior Drugs of abuse, such as cocaine, regulate neuronal gene expression through changes in histone modifications. Xu et al. apply epigenetic editing to define a novel role for the histone modification H3K36me3 in alternative splicing of the splice factor gene Srsf11 and the regulation of cocaine-reward behavior.