Protein level variability determines phenotypic heterogeneity in proteotoxic stress response

Area of Science:

• Molecular Biology
• Systems Biology
• Biophysics

Background:

• Cell-to-cell variability in stress response impedes accurate predictive models for diseases like cancer.
• Phenotypic heterogeneity can result in treatment resistance and cell population persistence.
• The heat shock response network is crucial for proteome protection against cellular injury.

Purpose of the Study:

• To investigate the molecular origins of phenotypic variability within the heat shock response network.
• To understand how single-cell dynamics contribute to heterogeneity in cellular stress responses.

Main Methods:

• Utilized high-throughput measurements to capture single-cell dynamics.
• Employed mathematical modeling to predict the sources of variability.
• Experimentally validated theoretical predictions through gene expression analysis.

Main Results:

• Observed broad diversity in single-cell heat shock response dynamics, including response amplitudes and temporal shapes.
• Confirmed that network ultrasensitivity and variations in heat shock factor 1 (HSF1)-controlled chaperone expression cause phenotypic heterogeneity.
• Mapped response amplitude directly to chaperone and HSF1 expression levels.

Conclusions:

• Cellular heterogeneity in heat shock response is significantly influenced by molecular mechanisms like network ultrasensitivity and gene expression variability.
• Understanding these molecular origins is key to developing more accurate predictive models for disease treatment and clinical diagnosis.