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Article Dans Une Revue Nature Communications Année : 2022

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

Anna L Aalto
Matthieu Sanial
Anniina Vihervaara
Laurent David
Lea Sistonen

Résumé

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.
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hal-04044701 , version 1 (24-03-2023)

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Aurélie de Thonel, Johanna K Ahlskog, Kevin Daupin, Véronique Dubreuil, Jérémy Berthelet, et al.. CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder. Nature Communications, 2022, 13 (1), pp.7002. ⟨10.1038/s41467-022-34476-2⟩. ⟨hal-04044701⟩
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