USP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus

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 u...

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Detalles Bibliográficos
Autores: Cheron, Julian|||0000-0001-6369-0019, Beccari, Leonardo|||0000-0001-6472-5105, Hagué, Perrine, Icick, Romain|||0000-0002-5078-4048, Despontin, Chloé|||0000-0002-4919-5617, Defrance, Matthieu|||0000-0002-3090-3142, Bhogaraju, Sagar|||0000-0001-9998-5927, Martín-García, Elena|||0000-0002-4487-3028, Capellán Martín, Roberto|||0000-0001-9586-0684, Maldonado, Rafael|||0000-0002-4359-8773, Vorspan, Florence|||0000-0001-5168-3727, Bonnefont, Jerome|||0000-0001-5283-8428, de Kerchove d'Exaerde, Alban|||0000-0002-0682-5877
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:291544
Acceso en línea:https://ddd.uab.cat/record/291544
https://dx.doi.org/urn:doi:10.1038/s41467-023-44120-2
Access Level:acceso abierto
Palabra clave:Addiction
Epigenetics in the nervous system
Descripción
Sumario: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.

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