Set2-mediated alternative splicing of Srsf11 regulates cocaine reward behavior

Alternative splicing is a key mechanism for neuronal gene regulation, and is grossly altered in mouse brain reward regions following investigator-administered cocaine. It is well established that cocaine epigenetically regulates transcription, yet mechanism(s) by which cocaine-induced epigenetic modifications regulate alternative splicing is largely unexplored. Our group and others have previously identified the histone modification, H3K36me3, as a putative splicing regulator. However, it has not yet been possible to establish the direct causal relevance of this modification to alternative splicing in brain or any other context. We found that mouse cocaine self-administration caused widespread alternative splicing, concomitant with enrichment of H3K36me3 at splice junctions. Differentially spliced genes were enriched in the motif for splice factor, Srsf11, which was both differentially spliced and enriched in H3K36me3. Epigenetic editing led us to conclude that H3K36me3 functions directly in alternative splicing of Srsf11, and that this mechanism enhances cocaine reward behavior.