CBP-HSF2 Structural and Functional Interplay in Rubinstein-Taybi Neurodevelopmental Disorder

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.

Citing Articles

Second Virtual International Symposium on Cellular and Organismal Stress Responses, September 8-9, 2022.

van Oosten-Hawle P, Backe S, Ben-Zvi A, Bourboulia D, Brancaccio M, Brodsky J Cell Stress Chaperones. 2023; 28(1):1-9.

PMID: 36602710 PMC: 9877255. DOI: 10.1007/s12192-022-01318-5.

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