biostudies-literatureXu SJNIDA NIH HHSNIGMS NIH HHS2943-2966.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC8454057biostudies-literatureUnknown109(18)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 H3NeuronChromatin-mediated alternative splicing regulates cocaine-reward behavior.PMC8454057T32 GM008076T32 DA028874DP1 DA044250R00 DA045795R36 DA050877R01 DA033641R01 DA015214K01 DA039308Wimmer MEPierce RCXu SJFischer DKHeller EAHamilton PJNeve RLMarchione DMGarcia BALim CJLombroso SICarpenter MDfalseChromatin-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 H32021-01-01T00:00:00Z2021 Sep2026-05-08T11:19:26.955Z2025-04-05T23:24:30.223ZS-EPMC84540573448086610.1016/j.neuron.2021.08.008