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Chromatin-Mediated Alternative Splicing Regulates Cocaine Reward Behavior

Mechanisms by which epigenetic modifications regulate alternative splicing are largely unexplored. Differential alternative splicing and histone modification enrichment are key mechanisms for neuronal gene regulation. Both are grossly altered in mouse brain following investigator-administered cocaine. Our group and others have identified the histone modification, H3K36me3, as a putative splicing regulator. In the current study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with enrichment of H3K36me3 at differentially spliced junctions. The splice factor motif for Srsf11 was enriched in splice junctions of cocaine induced alternative exons, yet Srsf11 expression was unchanged by cocaine treatment. Rather, Srsf11 was both differentially spliced and enriched in H3K36me3. Epigenetic editing showed that H3K36me3 functions directly in alternative splicing of Srsf11. Finally, both Srsf11-targeted and global H3K36me3 enrichment enhanced cocaine self-administration. These findings established the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior.