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.

Automated summary

The study demonstrated the crucial role of H3K36me3 histone modification in alternative splicing, particularly in the context of mouse cocaine self-administration. Targeted epigenetic editing of H3K36me3 at Srsf11 directly influenced its alternative splicing and enhanced the effects of cocaine self-administration. These findings establish a direct causal relationship between H3K36me3, alternative splicing of Srsf11, and reward behavior.