Nature Communications (Nov 2022)
CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder
- Aurélie de Thonel,
- Johanna K. Ahlskog,
- Kevin Daupin,
- Véronique Dubreuil,
- Jérémy Berthelet,
- Carole Chaput,
- Geoffrey Pires,
- Camille Leonetti,
- Ryma Abane,
- Lluís Cordón Barris,
- Isabelle Leray,
- Anna L. Aalto,
- Sarah Naceri,
- Marine Cordonnier,
- Carène Benasolo,
- Matthieu Sanial,
- Agathe Duchateau,
- Anniina Vihervaara,
- Mikael C. Puustinen,
- Federico Miozzo,
- Patricia Fergelot,
- Élise Lebigot,
- Alain Verloes,
- Pierre Gressens,
- Didier Lacombe,
- Jessica Gobbo,
- Carmen Garrido,
- Sandy D. Westerheide,
- Laurent David,
- Michel Petitjean,
- Olivier Taboureau,
- Fernando Rodrigues-Lima,
- Sandrine Passemard,
- Délara Sabéran-Djoneidi,
- Laurent Nguyen,
- Madeline Lancaster,
- Lea Sistonen,
- Valérie Mezger
Affiliations
- Aurélie de Thonel
- Université de Paris, CNRS, Epigenetics and Cell Fate
- Johanna K. Ahlskog
- Faculty of Science and Engineering, Cell Biology, 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
- 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
- Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cells and GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, CHU Sart Tilman
- Isabelle Leray
- Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé
- Anna L. Aalto
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University
- Sarah Naceri
- Université de Paris, CNRS, Epigenetics and Cell Fate
- Marine Cordonnier
- INSERM, UMR1231, Laboratoire d’Excellence LipSTIC
- 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
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University
- Mikael C. Puustinen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University
- Federico Miozzo
- Université de Paris, CNRS, Epigenetics and Cell Fate
- Patricia Fergelot
- Department of Medical Genetics, University Hospital of Bordeaux, Bordeaux, France and INSERM U1211, University of Bordeaux
- Élise Lebigot
- Service de Biochimie-pharmaco-toxicologie, Hôpital Bicêtre, Hopitaux Universitaires Paris-Sud
- Alain Verloes
- Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital
- Pierre Gressens
- Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital
- Didier Lacombe
- Department of Medical Genetics, University Hospital of Bordeaux, Bordeaux, France and INSERM U1211, University of Bordeaux
- Jessica Gobbo
- INSERM, UMR1231, Laboratoire d’Excellence LipSTIC
- Carmen Garrido
- INSERM, UMR1231, Laboratoire d’Excellence LipSTIC
- Sandy D. Westerheide
- Department of Cell Biology, Microbiology, and Molecular Biology, College of Arts and Sciences, 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
- Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cells and GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, CHU Sart Tilman
- Madeline Lancaster
- MRC Laboratory of Molecular Biology, Cambridge Biomedical, Campus
- Lea Sistonen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University
- Valérie Mezger
- Université de Paris, CNRS, Epigenetics and Cell Fate
- DOI
- https://doi.org/10.1038/s41467-022-34476-2
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 1 – 21
Abstract
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.
