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

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 MiozzoPatricia 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

Research output: Contribution to journalArticleScientificpeer-review

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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.

Original languageEnglish
Article number7002
Number of pages21
JournalNature Communications
Issue number1
Publication statusPublished - 16 Nov 2022
MoE publication typeA1 Journal article-refereed


  • Humans
  • CREB-Binding Protein/genetics
  • Heat-Shock Proteins/genetics
  • Histones/genetics
  • Mutation
  • Neurodevelopmental Disorders/genetics
  • Rubinstein-Taybi Syndrome/genetics
  • Transcription Factors/genetics
  • E1A-Associated p300 Protein/genetics


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