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