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

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.

SUBMITTER: de Thonel A

PROVIDER: S-EPMC9668993 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

de Thonel Aurélie A Ahlskog Johanna K JK Daupin Kevin K Dubreuil Véronique V Berthelet Jérémy J Chaput Carole C Pires Geoffrey G Leonetti Camille C Abane Ryma R Barris Lluís Cordón LC Leray Isabelle I Aalto Anna L AL Naceri Sarah S Cordonnier Marine M Benasolo Carène C Sanial Matthieu M Duchateau Agathe A Vihervaara Anniina A Puustinen Mikael C MC Miozzo Federico F Fergelot Patricia P Lebigot Élise É Verloes Alain A Gressens Pierre P Lacombe Didier D Gobbo Jessica J Garrido Carmen C Westerheide Sandy D SD David Laurent L Petitjean Michel M Taboureau Olivier O Rodrigues-Lima Fernando F Passemard Sandrine S Sabéran-Djoneidi Délara D Nguyen Laurent L Lancaster Madeline M Sistonen Lea L Mezger Valérie V

Nature communications 20221116 1

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 p ...[more]

PMID: 36385105

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Project description:Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder in humans characterized by growth and psychomotor delay, abnormal gross anatomy, and mild to severe mental retardation (Rubinstein and Taybi, Am J Dis Child 105:588-608, 1963, Hennekam et al., Am J Med Genet Suppl 6:56-64, 1990). RSTS is caused by de novo mutations in epigenetics-associated genes, including the cAMP response element-binding protein (CREBBP), the gene-encoding protein referred to as CBP, and the EP300 gene, which encodes the p300 protein, a CBP homologue. Recent studies of the epigenetic mechanisms underlying cognitive functions in mice provide direct evidence for the involvement of nuclear factors (e.g., CBP) in the control of higher cognitive functions. In fact, a role for CBP in higher cognitive function is suggested by the finding that RSTS is caused by heterozygous mutations at the CBP locus (Petrij et al., Nature 376:348-351, 1995). CBP was demonstrated to possess an intrinsic histone acetyltransferase activity (Ogryzko et al., Cell 87:953-959, 1996) that is required for CREB-mediated gene expression (Korzus et al., Science 279:703-707, 1998). The intrinsic protein acetyltransferase activity in CBP might directly destabilize promoter-bound nucleosomes, facilitating the activation of transcription. Due to the complexity of developmental abnormalities and the possible genetic compensation associated with this congenital disorder, however, it is difficult to establish a direct role for CBP in cognitive function in the adult brain. Although aspects of the clinical presentation in RSTS cases have been extensively studied, a spectrum of symptoms found in RSTS patients can be accessed only after birth, and, thus, prenatal genetic tests for this extremely rare genetic disorder are seldom considered. Even though there has been intensive research on the genetic and epigenetic function of the CREBBP gene in rodents, the etiology of this devastating congenital human disorder is largely unknown.

Dataset Information

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

Publications

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

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