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

被引：4

作者：

Cheron, Julian ^{[1
]}

Beccari, Leonardo ^{[2
,3
]}

Hague, Perrine ^{[1
]}

Icick, Romain ^{[4
]}

Despontin, Chloe ^{[1
]}

Carusone, Teresa ^{[5
]}

Defrance, Matthieu ^{[6
]}

Bhogaraju, Sagar ^{[5
]}

Martin-Garcia, Elena ^{[7
,8
,9
]}

Capellan, Roberto ^{[7
,8
]}

Maldonado, Rafael ^{[7
,8
]}

Vorspan, Florence ^{[4
]}

Bonnefont, Jerome ^{[10
]}

de Kerchove d'Exaerde, Alban ^{[1
,11
]}

机构：

[1] ULB, ULB Neurosci Inst, Neurophysiol Lab, Brussels, Belgium

[2] UAM, Ctr Biol Mol Severo Ochoa, CSIC, Madrid, Spain

[3] Univ Claude Bernard Lyon 1, Pathophysiol & Genet Neuron & Muscle, CNRS, UMR 5261,INSERM,U1315, Lyon, France

[4] Univ Paris Cite, INSERM, UMRS 1144, Paris, France

[5] European Mol Biol Lab, Grenoble, France

[6] ULB, Interuniv Inst Bioinformat Brussels, Brussels, Belgium

[7] UPF, Dept Med & Life Sci, Lab Neuropharmacol Neurophar, Barcelona, Spain

[8] Hosp del Mar Med Res Inst IMIM, Barcelona, Spain

[9] Univ Autonoma Barcelona, Dept Psicobiol & Metodol Ciencies Salut, Barcelona 08193, Spain

[10] ULB, ULB Neurosci Inst, Inst Rech Biol Humaine & Mol IRIBHM, Brussels, Belgium

[11] WELBIO, Wavre, Belgium

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

关键词：

HIDDEN-MARKOV MODEL; GENOTYPE IMPUTATION; ACTIVE-SITE; HISTONE H2A; EXPRESSION; POLYCOMB; SENSITIZATION; CHROMATIN; BEHAVIOR; NUCLEUS;

D O I：

10.1038/s41467-023-44120-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：18

共 97 条

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