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.

神经元选择性剪接是大脑中的关键基因调控机制。然而，剪接体机制不足以完全指定剪接复杂性。在考虑表观基因组在活性依赖性可变剪接中的作用时，我们和其他人发现组蛋白修饰 H3K36me3 是一种假定的剪接调节因子。在这项研究中，我们发现小鼠可卡因自我给药引起了广泛的差异选择性剪接，伴随着 H3K36me3 在差异剪接处的富集。重要的是，只有靶向表观遗传编辑才能区分 H3K36me3 在剪接中的直接作用和通过调节基因组其他地方的剪接因子表达的间接作用。我们针对 Srsf11，在可卡因自我给药后，其在大脑中交替剪接和 H3K36me3 富集。Srsf11 上 H3K36me3 的表观遗传编辑足以驱动其选择性剪接和增强可卡因自我给药，确定 H3K36me3 与 Srsf11 选择性剪接和奖励行为的直接因果关系。