Transcription factor oscillations induce differential gene expressions

Area of Science:

• Molecular Biology
• Systems Biology
• Genetics

Background:

• Intracellular protein levels of transcription factors (TFs) oscillate over time.
• The impact of these TF oscillations on gene expression remains largely uncharacterized.

Purpose of the Study:

• To investigate how TF oscillations influence gene expression compared to non-oscillatory conditions.
• To elucidate the mechanisms by which TF oscillations lead to differential gene transactivation.

Main Methods:

• Comparative analysis of gene expression levels with and without TF oscillations at equivalent mean TF concentrations.
• Modeling of nonlinear TF transcription kinetics, including sigmoid kinetics for specific TFs.

Main Results:

• Oscillatory TFs induce gene expression levels distinct from non-oscillatory TFs across various nonlinear kinetics.
• Conditions for TF oscillations to increase or decrease average gene expression were identified.
• Oscillatory dynamics, particularly amplitude and mean concentration relative to binding affinity, dictate differential target gene regulation.
• Predicted trends for NF-κB and glucocorticoid receptor oscillations align with experimental data.
• p53 oscillations are predicted to promote apoptosis upon DNA damage through differential upregulation of apoptotic genes.
• An oscillatory TF can generate numerous distinct patterns of differential transactivation for multiple target genes.

Conclusions:

• TF oscillations are a key mechanism for differential gene expression and biological regulation.
• The interplay between TF oscillation properties (mean concentration, amplitude) and target gene promoter affinity determines regulatory outcomes.
• TF oscillations play a significant role in cellular responses, such as programmed cell death.