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

Author

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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
    Université Claude Bernard Lyon 1, Pathophysiology and Genetics of Neuron and Muscle, CNRS UMR 5261, INSERM U1315)

  • 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)
    Hospital del Mar Medical Research Institute (IMIM)
    Universitat Autònoma de Barcelona)

  • Roberto Capellan

    (Universitat Pompeu Fabra (UPF)
    Hospital del Mar Medical Research Institute (IMIM))

  • Rafael Maldonado

    (Universitat Pompeu Fabra (UPF)
    Hospital del Mar Medical Research Institute (IMIM))

  • 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
    WELBIO)

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.

Suggested Citation

  • Julian Cheron & Leonardo Beccari & Perrine Hagué & Romain Icick & Chloé Despontin & Teresa Carusone & Matthieu Defrance & Sagar Bhogaraju & Elena Martin-Garcia & Roberto Capellan & Rafael Maldonado & , 2023. "USP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44120-2
    DOI: 10.1038/s41467-023-44120-2
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