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CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Author

Listed:
  • Aurélie Thonel

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

  • Johanna K. Ahlskog

    (Åbo Akademi University
    University of Turku and Åbo Akademi University)

  • Kevin Daupin

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

  • Véronique Dubreuil

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

  • Jérémy Berthelet

    (Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative)

  • Carole Chaput

    (Université de Paris, CNRS, Epigenetics and Cell Fate
    Ksilink)

  • Geoffrey Pires

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

  • Camille Leonetti

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

  • Ryma Abane

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

  • Lluís Cordón Barris

    (University of Liège, CHU Sart Tilman)

  • Isabelle Leray

    (Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé)

  • Anna L. Aalto

    (Åbo Akademi University
    University of Turku and Åbo Akademi University)

  • Sarah Naceri

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

  • Marine Cordonnier

    (Laboratoire d’Excellence LipSTIC
    University of Bourgogne Franche-Comté
    Centre Georges-François Leclerc)

  • Carène Benasolo

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

  • Matthieu Sanial

    (CNRS, UMR 7592 Institut Jacques Monod)

  • Agathe Duchateau

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

  • Anniina Vihervaara

    (Åbo Akademi University
    University of Turku and Åbo Akademi University
    KTH Royal Institute of Technology)

  • Mikael C. Puustinen

    (Åbo Akademi University
    University of Turku and Åbo Akademi University)

  • Federico Miozzo

    (Université de Paris, CNRS, Epigenetics and Cell Fate
    Neuroscience Institute-CNR (IN-CNR))

  • Patricia Fergelot

    (University Hospital of Bordeaux, Bordeaux, France and INSERM U1211, University of Bordeaux)

  • Élise Lebigot

    (Hopitaux Universitaires Paris-Sud)

  • Alain Verloes

    (Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital
    AP-HP, Robert-Debré University Hospital)

  • Pierre Gressens

    (Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital)

  • Didier Lacombe

    (University Hospital of Bordeaux, Bordeaux, France and INSERM U1211, University of Bordeaux)

  • Jessica Gobbo

    (Laboratoire d’Excellence LipSTIC
    University of Bourgogne Franche-Comté
    Centre Georges-François Leclerc)

  • Carmen Garrido

    (Laboratoire d’Excellence LipSTIC
    University of Bourgogne Franche-Comté
    Centre Georges-François Leclerc)

  • Sandy D. Westerheide

    (University of South Florida)

  • Laurent David

    (Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé)

  • Michel Petitjean

    (Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative)

  • Olivier Taboureau

    (Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative)

  • Fernando Rodrigues-Lima

    (Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative)

  • Sandrine Passemard

    (Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital)

  • Délara Sabéran-Djoneidi

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

  • Laurent Nguyen

    (University of Liège, CHU Sart Tilman)

  • Madeline Lancaster

    (Cambridge Biomedical, Campus)

  • Lea Sistonen

    (Åbo Akademi University
    University of Turku and Åbo Akademi University)

  • Valérie Mezger

    (Université de Paris, CNRS, Epigenetics and Cell Fate)

Abstract

Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.

Suggested Citation

  • Aurélie Thonel & Johanna K. Ahlskog & Kevin Daupin & Véronique Dubreuil & Jérémy Berthelet & Carole Chaput & Geoffrey Pires & Camille Leonetti & Ryma Abane & Lluís Cordón Barris & Isabelle Leray & Ann, 2022. "CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34476-2
    DOI: 10.1038/s41467-022-34476-2
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    References listed on IDEAS

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    1. Rocio Gomez-Pastor & Eileen T. Burchfiel & Daniel W. Neef & Alex M. Jaeger & Elisa Cabiscol & Spencer U. McKinstry & Argenia Doss & Alejandro Aballay & Donald C. Lo & Sergey S. Akimov & Christopher A., 2017. "Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease," Nature Communications, Nature, vol. 8(1), pages 1-17, April.
    2. Henry D. Herce & Wen Deng & Jonas Helma & Heinrich Leonhardt & M. Cristina Cardoso, 2013. "Visualization and targeted disruption of protein interactions in living cells," Nature Communications, Nature, vol. 4(1), pages 1-8, December.
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