Cheron, JulianBeccari, LeonardoHagué, PerrineIcick, RomainDespontin, ChloéCarusone, TeresaDefrance, MatthieuBhogaraju, SagarMartín García, Elena, 1975-Capellan, RobertoMaldonado, Rafael, 1961-Vorspan, FlorenceBonnefont, Jérômed'Exaerde, Alban de Kerchove2024-02-062024-02-062023Cheron J, Beccari L, Hagué P, Icick R, Despontin C, Carusone T, Defrance M, Bhogaraju S, Martin-Garcia E, Capellan R, Maldonado R, Vorspan F, Bonnefont J, de Kerchove d'Exaerde A. USP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder. Nat Commun. 2023 Dec 20;14(1):8481. DOI: 10.1038/s41467-023-44120-22041-1723http://hdl.handle.net/10230/58961The risk of developing drug addiction is strongly influenced by the epigenetic landscape and chromatin remodeling. While histone modifications such as methylation and acetylation have been studied in the ventral tegmental area and nucleus accumbens (NAc), the role of H2A monoubiquitination remains unknown. Our investigations, initially focused on the scaffold protein melanoma-associated antigen D1 (Maged1), reveal that H2A monoubiquitination in the paraventricular thalamus (PVT) significantly contributes to cocaine-adaptive behaviors and transcriptional repression induced by cocaine. Chronic cocaine use increases H2A monoubiquitination, regulated by Maged1 and its partner USP7. Accordingly, Maged1 specific inactivation in thalamic Vglut2 neurons, or USP7 inhibition, blocks cocaine-evoked H2A monoubiquitination and cocaine locomotor sensitization. Additionally, genetic variations in MAGED1 and USP7 are linked to altered susceptibility to cocaine addiction and cocaine-associated symptoms in humans. These findings unveil an epigenetic modification in a non-canonical reward pathway of the brain and a potent marker of epigenetic risk factors for drug addiction in humans.application/pdfeng© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-023-44120-2AddictionEpigenetics in the nervous systeminfo:eu-repo/semantics/openAccess