A1 Refereed original research article in a scientific journal
CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder
Authors: de Thonel Aurélie, Ahlskog Johanna K., Daupin Kevin, Dubreuil Véronique, Berthelet Jérémy, Chaput Carole, Pires Geoffrey, Leonetti Camille, Abane Ryma, Barris Lluís Cordón, Leray Isabelle, Aalto Anna L., Naceri Sarah, Cordonnier Marine, Benasolo Carène, Sanial Matthieu, Duchateau Agathe, Vihervaara Anniina, Puustinen Mikael C., Miozzo Federico, Fergelot Patricia, Lebigot Élise, Verloes Alain, Gressens Pierre, Lacombe Didier, Gobbo Jessica, Garrido Carmen, Westerheide Sandy D., David Laurent, Petitjean Michel, Taboureau Olivier, Rodrigues-Lima Fernando, Passemard Sandrine, Sabéran-Djoneidi Délara, Nguyen Laurent, Lancaster Madeline, Sistonen Lea, Mezger Valérie
Publisher: NATURE PORTFOLIO
Publication year: 2022
Journal: Nature Communications
Journal name in source: NATURE COMMUNICATIONS
Journal acronym: NAT COMMUN
Article number: 7002
Volume: 13
Issue: 1
Number of pages: 21
eISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-022-34476-2
Web address : https://www.nature.com/articles/s41467-022-34476-2
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/177597977
Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder with unclear underlying mechanisms. Here, the authors unravel the contribution of a stress-responsive pathway to RSTS where impaired HSF2 acetylation, due to RSTS-associated CBP/EP300 mutations, alters the expression of neurodevelopmental players, in keeping with hallmarks of cell-cell adhesion defects.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.
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