학술논문
CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder
Document Type
article
Author
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
Source
Nature Communications, Vol 13, Iss 1, Pp 1-21 (2022)
Subject
Language
English
ISSN
2041-1723
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.