TY - JOUR
T1 - USP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus :
T2 - an epigenetic mechanism involved in cocaine use disorder
AU - Cheron, Julian
AU - Beccari, Leonardo
AU - Hagué, Perrine
AU - Icick, Romain
AU - Despontin, Chloé
AU - Defrance, Matthieu
AU - Bhogaraju, Sagar
AU - Martín-García, Elena,
AU - Capellán Martín, Roberto
AU - Maldonado, Rafael,
AU - Vorspan, Florence
AU - Bonnefont, Jerome
AU - de Kerchove d'Exaerde, Alban
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Addiction
KW - Epigenetics in the nervous system
U2 - 10.1038/s41467-023-44120-2
DO - 10.1038/s41467-023-44120-2
M3 - Article
C2 - 38123574
SN - 2041-1723
VL - 18
JO - Nature Communications
JF - Nature Communications
ER -