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

Abstract

Altres ajuts: JC is a research fellow of FRS-FNRS and Fonds Erasme. LB is a Ramon y Cajal fellow (CBMSO). AKE is a research director of the FRS-FNRS and a WELBIO investigator. Funding was provided by FRS-FNRS grants 23587797, 33659288, 33659296 (A.K.E.), WELBIO grant 30256053 (A.K.E.), Fondation Simone et Pierre Clerdent 2018 Prize (A.K.E.), Fondation ULB (A.K.E.), Fondation Cigrang (A.K.E.), Dotation Jeune Chercheur INSERM (L.B.), AFM stratégique 2 MyoNeurAlp (L.B.), Agence Nationale pour la Recherche grant ANR- 21-CE11-0013 (S.B.), EMBL Interdisciplinary Postdocs (EIPOD4) initiative co-funded by Marie Skłodowska-Curie (grant 847543) (T.C.), Mission Inter-Ministérielle de Lutte Contre la Drogue et la Toxicomanie grant ASE07082KSA (F.V.), Direction de la Recherche Clinique et du Développement de l'Assistance Publique - Hôpitaux de Paris grant OST07013 (F.V.), French Ministry of Health, Programme Hospitalier de Recherche Clinique National AOM10165 (F.V.).

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. This study uncovers the role of epigenetic H2A monoubiquitination in the mouse brain's response to chronic cocaine use. It also identifies genetic variations in humans linked to H2A monoubiquitination, modifying susceptibility to cocaine addiction and aggression, and paving the way for tailored treatments.