학술논문
CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder
Document Type
Original Paper
Author
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
Source
Nature Communications. 13(1)
Subject
Language
English
ISSN
2041-1723
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.
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.
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.