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

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CBP or EP300 genes.
• The precise molecular mechanisms underlying RSTS neurodevelopmental defects are not fully understood.
• Stress-responsive pathways are implicated in brain development but their role in RSTS is unclear.

Purpose of the Study:

• To investigate the role of stress-responsive pathways in RSTS.
• To characterize the interaction between CBP/EP300 and heat-shock factor 2 (HSF2).
• To elucidate the molecular basis of neurodevelopmental defects in RSTS.

Main Methods:

• Analysis of CBP/EP300 acetylation of HSF2.
• Assessment of HSF2 protein stability and levels in RSTS patient-derived cells.
• Generation and analysis of RSTS patient-derived induced pluripotent stem cells (iPSCs) and cerebral organoids.
• Investigation of the CBP/EP300-HSF2-N-cadherin signaling cascade.

Main Results:

• CBP/EP300 directly acetylates HSF2, promoting its stabilization.
• RSTS patient cells exhibit reduced HSF2 levels and altered stress response.
• A CBP/EP300-HSF2-N-cadherin pathway is identified, and its disruption impairs neuroepithelial integrity in RSTS organoid models.

Conclusions:

• HSF2 stabilization by CBP/EP300 is critical for normal brain development and stress response.
• Dysregulation of the CBP/EP300-HSF2 pathway contributes to RSTS pathophysiology.
• This study provides a molecular framework for understanding RSTS and potential therapeutic targets.