RESUMO
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.
Assuntos
Proteína de Ligação a CREB , Proteínas de Choque Térmico , Transtornos do Neurodesenvolvimento , Síndrome de Rubinstein-Taybi , Fatores de Transcrição , Humanos , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Histonas/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismoRESUMO
The Heat Shock Factors (HSFs) have been historically identified as a family of transcription factors that are activated and work in a stress-responsive manner, after exposure to a large variety of stimuli. However, they are also critical in normal conditions, in a life long manner, in a number of physiological processes that encompass gametogenesis, embryonic development and the integrity of adult organs and organisms. The importance of such roles is emphasized by the devastating impact of their deregulation on health, ranging from reproductive failure, neurodevelopmental disorders, cancer, and aging pathologies, including neurodegenerative disorders. Here, we provide an overview of the delicate choreography of the regulation of HSFs during neurodevelopment, at prenatal and postnatal stages. The regulation of HSFs acts at multiple layers and steps, and comprises the control of (i) HSF mRNA and protein levels, (ii) HSF activity in terms of DNA-binding and transcription, (iii) HSF homo- and hetero-oligomerization capacities, and (iv) HSF combinatory set of post-translational modifications. We also describe how these regulatory mechanisms operate in the normal developing brain and how their perturbation impact neurodevelopment under prenatal or perinatal stress conditions. In addition, we put into perspective the possible role of HSFs in the evolution of the vertebrate brains and the importance of the HSF pathway in a large variety of neurodevelopmental disorders.