A1 Refereed original research article in a scientific journal

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




Authorsde 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

PublisherNATURE PORTFOLIO

Publication year2022

JournalNature Communications

Journal name in sourceNATURE COMMUNICATIONS

Journal acronymNAT COMMUN

Article number 7002

Volume13

Issue1

Number of pages21

eISSN2041-1723

DOIhttps://doi.org/10.1038/s41467-022-34476-2

Web address https://www.nature.com/articles/s41467-022-34476-2

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/177597977


Abstract

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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