DE THONEL, Aurelie; AHLSKOG, Johanna K; DAUPIN, Kevin; DUBREUIL, Veronique; BERTHELET, Jeremy; CHAPUT, Carole; PIRES, Goeffrey; LEONETTI, Camille; ABANE, Ryma; BARRIS, Lluis Cordon; LERAY, Isabelle; AALTO, Anna L; NACERI, Sarah; CORDONNIER, Marine; BENASOLO, Carene; SANIAL, Matthieu; DUCHATEAU, Agathe; VIHERVAARA, Anniina; PUUSTINEN, Mikael C; MIOZZO, Federico; FERGELOT, Patricia; LEBIGOT, Elise; VERLOES, Alain; GRESSENS, Pierre; LACOMBE, Didier; GOBBO, Jessica; GARRIDO, Carmen; WESTERHEIDE, Sandy D; DAVID, Laurent; PETITJEAN, Michel; TABOUREAU, Olivier; RODRIGUES-LIMA, Fernando; PASSEMARD, Sandrine; SABERAN-DJONEIDI, Delara; NGUYEN, Laurent; LANCASTER, Madeline; SISTONEN, Lea; MEZGER, Valerie

doi:10.1038/s41467-022-34476-2

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Nature Communications. 2022-11-16, vol. 13, n° 1, p. 7002

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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.< Leer menos

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https://oskar-bordeaux.fr/handle/20.500.12278/182215

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http://dx.doi.org/10.1038/s41467-022-34476-2

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Maladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211

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

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