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.

Comprehensive analysis of human tissues reveals unique expression and localization patterns of HSF1 and HSF2

“…Unlike HSF1, HSF2 is considered an unstable protein under normal growth conditions, and the expression of HSF2 is tightly regulated both at the mRNA and protein levels, via microRNAs and the ubiquitin-proteasome system. 30 , 43 , 52 , 53 Consequently, we were surprised to detect prominent cytoplasmic HSF2 expression in all studied smooth muscle cells, endothelial cells, and myoepithelial cells ( Table 1 ). The significant difference in signal intensity compared to cell lines, which typically display nuclear HSF2 expression, shows that HSF2 is differently regulated in intact tissues.…”

“…This finding is particularly intriguing considering the recent findings linking HSF2 to the maintenance of cell–cell adhesion contacts. 14 , 30

Fig. 5 Cross-section of cardiac muscle tissue.

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“… 14 In line with these results, deregulation of the HSF2-dependent expression of N-cadherin was recently shown to underlie the characteristic neuroepithelial defects observed in Rubinstein-Taybi syndrome. 30 We envision that analogously to the accumulation of misfolded proteins that titrate the chaperones away from HSF1, enabling HSF1 target gene binding, disrupted cell adhesion protein complexes release HSF2 from its membrane compartment to enable nuclear accumulation and target gene activation. Considering that HSF2 occupancy has been detected at genes coding for cell adhesion proteins in K562 cells 51 and in mouse testis, 39 the disruption of the membrane complex could form a feedback loop promoting the re-establishment of cell adhesion.…”

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

“…She showed that PAE provokes immediate changes in DNA methylation in the mouse developing cortex, which are associated with immediate modifications of gene expression, seem also to persist later in life, and are thus potential biomarkers for the diagnosis and follow-up of at-risk children. Interestingly, stress-responsive transcription factors of the immune/inflammatory pathway (Schang et al 2021 ) and HSFs (de Thonel et al 2022 ) represent the holes in the defense of the developing brain. They are unexpectedly active and necessary for physiological brain development and are deeply disturbed by prenatal stress.…”

Dynamic HSF2 regulation drives breast cancer progression by steering the balance between proliferation and invasion

“…Other cancer models have revealed that HSF2 can either promote or suppress cancer cell growth (Mustafa et al, 2010; Zhong et al, 2016; Meng et al, 2017; Yang et al, 2019; Smith et al, 2022). At the cellular level, maintenance of HSF2 expression is required for cell-cell adhesion contacts (Joutsen et al, 2020; de Thonel et al, 2022). To date, no HSF2-specific gene program supporting tumorigenesis has been identified, and the signaling pathways regulating HSF2 expression and its activity during malignant transformation remain to be uncovered.…”