USP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder

Julian Cheron, Leonardo Beccari, Perrine Hagué, Romain Icick, Chloé Despontin, Teresa Carusone, Matthieu Defrance, Sagar Bhogaraju, Elena Martin-Garcia, Roberto Capellan, Rafael Maldonado, Florence Vorspan, Jérôme Bonnefont and Alban de Kerchove d’Exaerde ()
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Julian Cheron: Université Libre de Bruxelles (ULB), ULB Neuroscience Institute, Neurophysiology Laboratory
Leonardo Beccari: Centro de Biología Molecular Severo Ochoa, CSIC-UAM
Perrine Hagué: Université Libre de Bruxelles (ULB), ULB Neuroscience Institute, Neurophysiology Laboratory
Romain Icick: INSERM UMRS_1144, Université Paris Cité
Chloé Despontin: Université Libre de Bruxelles (ULB), ULB Neuroscience Institute, Neurophysiology Laboratory
Teresa Carusone: European Molecular Biology Laboratory
Matthieu Defrance: Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles (ULB)
Sagar Bhogaraju: European Molecular Biology Laboratory
Elena Martin-Garcia: Universitat Pompeu Fabra (UPF)
Roberto Capellan: Universitat Pompeu Fabra (UPF)
Rafael Maldonado: Universitat Pompeu Fabra (UPF)
Florence Vorspan: INSERM UMRS_1144, Université Paris Cité
Jérôme Bonnefont: Université Libre de Bruxelles (ULB), ULB Neuroscience Institute, Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM)
Alban de Kerchove d’Exaerde: Université Libre de Bruxelles (ULB), ULB Neuroscience Institute, Neurophysiology Laboratory

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract The 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.

Date: 2023
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DOI: 10.1038/s41467-023-44120-2

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