Chromatin-mediated alternative splicing regulates cocaine-reward behavior.

Autor:	Xu SJ; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA., Lombroso SI; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA., Fischer DK; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA., Carpenter MD; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA., Marchione DM; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA., Hamilton PJ; Department of Brain and Cognitive Sciences, Virginia Commonwealth University, Richmond, VA 23298, USA., Lim CJ; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA., Neve RL; Gene Delivery Technology Core, Massachusetts General Hospital, Cambridge, MA 02139, USA., Garcia BA; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Wimmer ME; Department of Psychology, Temple University, Philadelphia, PA 19121, USA., Pierce RC; Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA., Heller EA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA,19104, USA; Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: eheller@pennmedicine.upenn.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2021 Sep 15; Vol. 109 (18), pp. 2943-2966.e8. Date of Electronic Publication: 2021 Sep 03.
DOI:	10.1016/j.neuron.2021.08.008
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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