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

• DOI: 10.1038/s41467-022-34476-2
• Publication Date: 2022-11-16T16:03:27Z
• Authors: 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 Rodrigue...; Sandrine Passemard; Délara Sabéran-Dj...; Laurent Nguyen; Madeline Lancaster; Lea Sistonen; Valérie Mezger
• Keywords: Rubinstein–Taybi syndrome

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 defects remain elusive. Here, we unravel contribution of stress-responsive pathway to RSTS. We characterize structural and functional interaction between CBP/EP300 heat-shock factor 2 (HSF2), tuner brain cortical development major player prenatal stress responses neocortex: acetylates HSF2, leading stabilization HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels HSF2-dependent alteration their repertoire molecular chaperones response. Moreover, CBP/EP300-HSF2-N-cadherin cascade that is also active contexts, its deregulation disturbs neuroepithelial integrity 2D 3D organoid models cerebral development, generated from iPSC cells, providing reading key for this complex pathology.